Immediate transient thrombocytopenia at the time of alemtuzumab infusion in multiple sclerosis.

Science.gov (United States)

Ranganathan, Usha; Kaunzner, Ulrike; Foster, Stacyann; Vartanian, Timothy; Perumal, Jai S

2018-04-01

Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported. We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab. In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients.

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Clark, Rachael A; Watanabe, Rei; Teague, Jessica E; Schlapbach, Christoph; Tawa, Marianne C; Adams, Natalie; Dorosario, Andrew A; Chaney, Keri S; Cutler, Corey S; Leboeuf, Nicole R; Carter, Joi B; Fisher, David C; Kupper, Thomas S

2012-01-18

Cutaneous T cell lymphoma (CTCL) is a cancer of skin-homing T cells with variants that include leukemic CTCL (L-CTCL), a malignancy of central memory T cells (T(CM)), and mycosis fungoides (MF), a malignancy of skin resident effector memory T cells (T(EM)). We report that low-dose alemtuzumab (αCD52) effectively treated patients with refractory L-CTCL but not MF. Alemtuzumab depleted all T cells in blood and depleted both benign and malignant T(CM) from skin, but a diverse population of skin resident T(EM) remained in skin after therapy. T cell depletion with alemtuzumab required the presence of neutrophils, a cell type frequent in blood but rare in normal skin. These data suggest that T(CM) were depleted because they recirculate between the blood and the skin, whereas skin resident T(EM) were spared because they are sessile and non-recirculating. After alemtuzumab treatment, skin T cells produced lower amounts of interleukin-4 and higher amounts of interferon-γ. Moreover, there was a marked lack of infections in alemtuzumab-treated L-CTCL patients despite the complete absence of T cells in the blood, suggesting that skin resident T(EM) can protect the skin from pathogens even in the absence of T cell recruitment from the circulation. Together, these data suggest that alemtuzumab may treat refractory L-CTCL without severely compromising the immune response to infection by depleting circulating T(CM) but sparing the skin resident T(EM) that provide local immune protection of the skin.

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

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Kalincik, Tomas; Brown, J William L; Robertson, Neil; Willis, Mark; Scolding, Neil; Rice, Claire M; Wilkins, Alastair; Pearson, Owen; Ziemssen, Tjalf; Hutchinson, Michael; McGuigan, Christopher; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Alroughani, Raed; Pucci, Eugenio; Sola, Patrizia; Hupperts, Raymond; Lechner-Scott, Jeannette; Terzi, Murat; Van Pesch, Vincent; Rozsa, Csilla; Grand'Maison, François; Boz, Cavit; Granella, Franco; Slee, Mark; Spitaleri, Daniele; Olascoaga, Javier; Bergamaschi, Roberto; Verheul, Freek; Vucic, Steve; McCombe, Pamela; Hodgkinson, Suzanne; Sanchez-Menoyo, Jose Luis; Ampapa, Radek; Simo, Magdolna; Csepany, Tunde; Ramo, Cristina; Cristiano, Edgardo; Barnett, Michael; Butzkueven, Helmut; Coles, Alasdair

2017-04-01

Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], pmultiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly

Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment, discount, and disutility.

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Montgomery, Stephen M; Kusel, Jeanette; Nicholas, Richard; Adlard, Nicholas

2017-09-01

Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis. A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs. Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient. When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming application of only a modest level of

Economic implications of using bendamustine, alemtuzumab, or chlorambucil as a first-line therapy for chronic lymphocytic leukemia in the US: a cost-effectiveness analysis

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Kongnakorn T

2014-04-01

Full Text Available Thitima Kongnakorn,1 James A Sterchele,2 Christopher G Salvador,3 Denis Getsios,4 Mkaya Mwamburi51Evidera, Bangkok, Thailand; 2formerly of Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA, 3Oncology Market Research, Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA, 4Evidera, Lexington, MA, 5Tufts University School of Medicine, Public Health and Community Medicine, Boston, MA, USABackground: The objective of this analysis was to evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C chronic lymphocytic leukemia (CLL in the US.Methods: A discrete event simulation of the disease course of CLL was developed to evaluate the economic implications of single-agent treatment with bendamustine, alemtuzumab, or chlorambucil, which are indicated for a treatment-naïve patient population with Binet stage B or C CLL. Data from clinical trials were used to create a simulated patient population, risk equations for progression-free survival and survival post disease progression, response rates, and rates of adverse events. Costs from a US health care payer perspective in 2012 US dollars, survival (life years, and quality-adjusted life years (QALYs were estimated over a patient's lifetime; all were discounted at 3% per year.Results: Compared with alemtuzumab, bendamustine was considered to be a dominant treatment providing greater benefit (6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs at lower cost ($78,776 versus $121,441. Compared with chlorambucil, bendamustine was associated with higher costs ($78,776 versus $42,337 but with improved health outcomes (6.10 versus 5.21 life years and 4.02 versus 3.30 QALYs, resulting in incremental cost-effectiveness ratios of $40,971 per life year gained and $50,619 per QALY gained.Conclusion: Bendamustine is expected to provide cost savings and greater health benefit than alemtuzumab in

AChR-specific immunosuppressive therapy of myasthenia gravis.

Science.gov (United States)

Luo, Jie; Lindstrom, Jon

2015-10-15

Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by muscle fatigability. In most cases, it is mediated by autoantibodies targeting muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for MG, which is usually induced by immunization with AChR purified from fish electric organ. Pathological autoantibodies to AChRs are directed at the extracellular surface, especially the main immunogenic region (MIR). Current treatments for MG can help many but not all patients. Antigen-specific immunosuppressive therapy for MG that specifically suppresses the autoimmune response without affecting the entire immune system and avoids side effects of general immunosuppression is currently unavailable. Early attempts at antigen-specific immunosuppression for EAMG using AChR extracellular domain sequences that form epitopes for pathological autoantibodies risked provoking autoimmunity rather than suppressing it. We discovered a novel approach to specific immunosuppression of EAMG with a therapeutic vaccine consisting of bacterially-expressed human AChR cytoplasmic domains, which has the potential to specifically suppress MG without danger of causing exacerbation. This approach prevents development of chronic EAMG when initiated immediately after the acute phase of EAMG, and rapidly reverses established chronic EAMG when started during the chronic phase of EAMG. Successfully treated rats exhibited long-term resistance to re-induction of EAMG. In this review we also discuss the current understanding of the mechanisms by which the therapy works. Vaccination with AChR cytoplasmic domains in adjuvant is promising as a safe, antigen-specific, potent, effective, rapidly acting, and long lasting approach to therapy of MG. Copyright © 2015 Elsevier Inc. All rights reserved.

Alemtuzumab in the treatment of multiple sclerosis: patient selection and special considerations

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Dörr J

2016-10-01

Full Text Available Jan Dörr,1,2 Karl Baum1 1Multiple Sclerosis Center, Neurology Department, Klinik Hennigsdorf, Hennigsdorf, 2NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany Abstract: Multiple sclerosis (MS is among the most common chronic inflammatory diseases of the central nervous system. Although not curable, the constantly increasing armamentarium of disease-modifying drugs now allows control of disease activity in many patients. The humanized monoclonal antibody alemtuzumab is a powerful drug licensed for the treatment of MS. Upon binding to the CD52 surface protein on CD4+ and CD8+ T cells, B cells, and monocytes, circulating CD52+ cells are eliminated via antibody- and complement-mediated lysis, and a less autoreactive adaptive immune system is reconstituted. The efficacy of alemtuzumab in terms of both clinical and magnetic resonance imaging outcomes has been demonstrated in several phase II/III trials including long-term extensions and follow-up studies. Treatment response to alemtuzumab is strongest as long as active inflammation is the predominant pathophysiological feature, and it is becoming less efficacious in neurodegeneration-dominated later stages of the disease. Thus, the optimal placement of alemtuzumab within treatment algorithms of MS is crucial. The impressive efficacy of alemtuzumab is counteracted by a less favorable safety profile. Besides usually manageable infusion-associated side effects, development of secondary autoimmunity in almost half of treated patients is the most disconcerting risk of alemtuzumab. The high frequency, the delayed occurrence, and the potentially severe course of secondary autoimmune diseases require awareness and a close long-term monitoring of patients treated with alemtuzumab. Biomarkers that would allow prediction of treatment response to alemtuzumab on the one hand and identification of patients at risk for the development of secondary autoimmune diseases on

Persistent Hypotony Associated with Immunosuppressive Therapy in Glaucoma Drainage Implant Surgery

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Susana Duch

2016-09-01

Full Text Available Purpose: To describe the histopathology of non-valved implant capsules in three cases of persistent postoperative hypotony after the restrictive tube ligature was released in patients receiving immunosuppressive therapy. Observations: The macroscopic appearance of the capsules 3 and 4 months postoperatively was immature and loose. Microscopic examination disclosed extremely irregular thin tissue, with thicknesses ranging from 0.02 to 0.6 mm, depending on the capsular location studied. Withdrawal of immunosuppressive therapy did not facilitate rebuilding of new capsules. Replacement with a valved implant device was necessary in two cases; the third case recovered with tapering of prednisone. Conclusions and Importance: The use of chronic systemic immunosuppressive therapy might interfere with capsular formation around the plates of drainage devices inducing persistent hypotony. In these cases, the use of valved implants might be safer.

A Danish nationwide questionnaire study of hepatitis B virus screening before immunosuppressive therapy

DEFF Research Database (Denmark)

Bunyoz, Kristine Ifigenia; Krarup, Henrik; Weis, Nina

2017-01-01

INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation of immunos......INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation...... of immunosuppressive therapy and to explore HBV treatment strategies. METHODS: All Danish units of haematology, oncology, dermatology, rheumatology and gastroenterology using immunosuppressive agents were invited to fill out a questionnaire for The Danish Database for Hepatitis B and C. RESULTS: A total of 28 (53...

Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification.

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Seto, Wai-Kay

2015-04-28

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) positive individuals during therapies containing rituximab, anti-TNF or HSCT.For HBsAg-positive patients, prophylactic antiviral therapy is proven to the effective in preventing HBV reactivation. Recent evidence also demonstrated entecavir to be more effective than lamivudine in this aspect. For HBsAg-negative, anti-HBc positive individuals, the risk of reactivations differs with the type of immunosuppression. For rituximab, a prospective study demonstrated the 2-year cumulative risk of reactivation to be 41.5%, but prospective data is still lacking for other immunosupressive regimes. The optimal management in preventing HBV reactivation would involve appropriate risk stratification for different immunosuppressive regimes in both HBsAg-positive and HBsAg-negative, anti-HBc positive individuals.

A Danish nationwide questionnaire study of hepatitis B virus screening before immunosuppressive therapy

DEFF Research Database (Denmark)

Bunyoz, Kristine Ifigenia; Krarup, Henrik; Weis, Nina

2017-01-01

INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation...... of immunosuppressive therapy and to explore HBV treatment strategies. METHODS: All Danish units of haematology, oncology, dermatology, rheumatology and gastroenterology using immunosuppressive agents were invited to fill out a questionnaire for The Danish Database for Hepatitis B and C. RESULTS: A total of 28 (53......%) of the 53 included units answered the questionnaire, of which 25 (89.3%) had a guideline regarding screening for HBV serological markers prior to immunosuppressive therapy, but only ten (37%) had a guideline that is in line with the joint guidelines from the national Danish Societies of Infectious Diseases...

Alemtuzumab-induced elimination of HIV-1-infected immune cells.

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Ruxrungtham, Kiat; Sirivichayakul, Sunee; Buranapraditkun, Supranee; Krause, Werner

2016-01-01

Currently, there is no drug known that is able to eradicate either HIV or HIV-infected host cells. The effectiveness of all available treatments is based on the prevention of viral replication. We investigated whether the monoclonal, CD52 receptor-targeting antibody, alemtuzumab, which is currently approved for the treatment of multiple sclerosis, is able to eliminate HIV-infected immune cells. In blood samples from healthy donors and from HIV-1-infected subjects who were either treatment-naïve or resistant to HAART, we studied whether the CD52 expression on T cells and their subsets (CD3, CD4, CD8), B cells (CD19), dendritic cells (CD123) and monocytes (CD11c) is retained in HIV-1 infection and whether alemtuzumab is able to eradicate infected cells, using four-colour flow cytometry. We found that CD52 expression on immune cells is retained in HIV-1 infection regardless of CD4 cell count, viral load and treatment status, and is amenable to alemtuzumab-induced depletion. For the first time it could be shown in vitro that HIV-1-infected immune cells can be eliminated by using the monoclonal antibody alemtuzumab.

Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients

DEFF Research Database (Denmark)

Giovannoni, Gavin; Cohen, Jeffrey A; Coles, Alasdair J

2016-01-01

.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a...

Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro

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Havari, Evis; Turner, Michael J; Campos-Rivera, Juanita; Shankara, Srinivas; Nguyen, Tri-Hung; Roberts, Bruce; Siders, William; Kaplan, Johanne M

2014-01-01

Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon-β in relapsing–remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25hi T-cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell–cell contact and interleukin-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Treg cells may play a role in promoting the long-term efficacy of alemtuzumab in patients with multiple sclerosis. PMID:24116901

Remission induction using alemtuzumab can permit chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients to undergo allogeneic stem cell transplantation.

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Knauf, Wolfgang; Rieger, Kathrin; Blau, Wolfgang; Hegenbart, Ute; Von Gruenhagen, Ulrich; Niederwieser, Dietger; Thiel, Eckhard

2004-12-01

The outcome of allogeneic stem cell transplantation depends upon the disease status before transplantation. Patients with refractory disease are at high risk for relapse. To improve the curative potential of the transplant procedure, we treated 3 chemotherapy-refractory CLL patients with alemtuzumab before allogeneic stem cell transplantation. Prior to therapy, all patients suffered from B-symptoms, and had massive adenopathy, splenomegaly, thrombocytopenia, and anemia; two patients had hepatomegaly. Alemtuzumab greatly reduced tumor mass in blood and bone marrow, B-symptoms resolved, and organomegaly improved. Two patients became blood product independent. All patients proceeded to transplantation after conditioning with TBI 2 Gy (n=1) or Treosulfan (n=2) in combination with Fludarabine either from an HLA-matched sibling (n=2) or from an HLA-matched unrelated donor (n=1). All patients engrafted, and are alive and well. Two patients reached complete remission (CR); one patient attained stable partial remission (PR). These heavily pre-treated refractory patients gained substantial clinical benefit from alemtuzumab, and received successful allografts.

Malaria in immuno-suppressed individuals on antiretroviral therapy ...

African Journals Online (AJOL)

Malaria in immuno-suppressed individuals on antiretroviral therapy (ART) in north-central Nigeria. C.R. Pam, B.T. Abubakar, G.O. Inwang, G.A. Amuga. Abstract. The immune deficiency caused by HIV infection reduces the immune response to malaria parasitaemia and therefore leads to an increased frequency of clinical ...

Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

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Narita, Atsushi; Muramatsu, Hideki; Sekiya, Yuko; Okuno, Yusuke; Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Yoshida, Nao; Wang, Xinan; Xu, Yinyan; Kawashima, Nozomu; Doisaki, Sayoko; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Kobayashi, Masao; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

2015-12-01

Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972. Copyright© Ferrata Storti Foundation.

Intestinal strongyloidiasis in a psoriatic patient following immunosuppressive therapy: Seeing the unforeseen

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Poongodi Lakshmi Santhana Kumaraswamy

2016-01-01

Full Text Available Strongyloides stercoralis , an intestinal nematode, has a complicated life cycle. Mostly asymptomatic, if symptomatic it has nonspecific, transient clinical manifestations. The two aggressive forms of the disease are: Hyperinfection syndrome (HS or disseminated syndrome (DS. Several risk factors have been associated with strongyloidiasis including immunosuppressive therapy, human immunodeficiency virus (HIV infection, diabetes, alcoholism, tuberculosis, impaired bowel motility, surgically created intestinal blind loops, chronic obstructive pulmonary disease, and chronic renal failure. We describe a case of intestinal strongyloidiasis in a psoriatic patient treated with immunosuppressive therapy.

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

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E. A. Drozdova

2014-07-01

Full Text Available Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years who received low dose methotrexate — 7.5-20 mg once a week (n=79 cyclosporine A 3.5-5.0 mg/kg/d (n=21 with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% of patients with chronic uveitis. Control of acute inflammation was achived in 71.1% patients, who received methotrexate in combination with prednisolone. Cyclosporine A was more effective in controlling inflammatory of the eye: remission of uveitis was achived in 85.7% in combination with glucocorticoids. No significant side effects have been noted.Conclusion: Methotrexate and cyclosporine A with low dose of prednisolone are well tolerated immunosuppressive agents andrather effective in the treatment of non-infectious uveitis and retinovasculitis that fails to respond to conventional steroid treatment.

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

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E. A. Drozdova

2012-01-01

Full Text Available Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years who received low dose methotrexate — 7.5-20 mg once a week (n=79 cyclosporine A 3.5-5.0 mg/kg/d (n=21 with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% of patients with chronic uveitis. Control of acute inflammation was achived in 71.1% patients, who received methotrexate in combination with prednisolone. Cyclosporine A was more effective in controlling inflammatory of the eye: remission of uveitis was achived in 85.7% in combination with glucocorticoids. No significant side effects have been noted.Conclusion: Methotrexate and cyclosporine A with low dose of prednisolone are well tolerated immunosuppressive agents andrather effective in the treatment of non-infectious uveitis and retinovasculitis that fails to respond to conventional steroid treatment.

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

Science.gov (United States)

Rolla, Simona; De Mercanti, Stefania Federica; Bardina, Valentina; Horakova, Dana; Habek, Mario; Adamec, Ivan; Cocco, Eleonora; Annovazzi, Pietro; Vladic, Anton; Novelli, Francesco; Durelli, Luca; Clerico, Marinella

2017-12-15

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

OpenAIRE

E. A. Drozdova

2012-01-01

Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years) who received low dose methotrexate — 7.5-20 mg once a week (n=79) cyclosporine A 3.5-5.0 mg/kg/d (n=21) with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% o...

Does Pre-Operative Multiple Immunosuppressive Therapy Associate with Surgical Site Infection in Surgery for Ulcerative Colitis.

Science.gov (United States)

Uchino, Motoi; Ikeuchi, Hiroki; Bando, Toshihiro; Hirose, Kei; Hirata, Akihiro; Chohno, Teruhiro; Sasaki, Hirofumi; Takahashi, Yoshiko; Takesue, Yoshio; Hida, Nobuyuki; Hori, Kazutoshi; Nakamura, Shiro

2015-01-01

Almost all surgeries for ulcerative colitis (UC) are performed under immunosuppressive conditions. Immunomodulators or biologics, with the exception of corticosteroids, do not appear to be risk factors for post-operative infectious complications. However, many patients are on multiagent immunosuppressive therapy at the time of surgery. Therefore, we evaluated the influence of pre-operative multiple immunosuppressives on the occurrence of surgical site infection (SSI) in UC. We reviewed surveillance data from 181 patients who underwent restorative proctocolectomy between January 2012 and March 2014. The incidences of SSI and the possible risk factors among patients receiving different immunosuppressive therapies were compared and analyzed. The incidence of incisional (INC) SSI was 13.3% and that of organ/space (O/S) SSI was 7.2%. The number of immunosuppressives did not significantly correlate with each incidence. Total prednisolone administration ≥12,000 mg (OR 2.6) and an American Society of Anesthesiologists score ≥3 (OR 2.8) were shown to be independent risk factors for overall SSI, whereas corticosteroid use in INC SSI (OR 17.4) and severe disease (OR 5.2) and a large amount of blood loss (OR 3.9) in O/S SSI were identified as risk factors. Although a correlation between multiple immunosuppressive therapy and SSIs was not found, it is not recommended that all patients be treated with multiple immunosuppressive therapy. Treatment strategy should be applied based on the patient's condition. © 2015 S. Karger AG, Basel.

Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification

OpenAIRE

Seto, Wai-Kay

2015-01-01

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negati...

Immunosuppressive therapy in patients with aplastic anemia: a single-center retrospective study.

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Hasan Jalaeikhoo

Full Text Available Aplastic anemia (AA is a rare disease in which hematopoietic stem cells are severely diminished resulting in hypocellular bone marrow and pancytopenia. Etiology of AA includes auto immunity, toxins, infection, ionizing radiation, drugs and rare genetic disorders, but in the majority of cases no cause can be identified. In the present study we assessed response rate, survival, relapse and clonal evolution in patients with AA treated with immunosuppressive therapy.Patients with AA who received immunosuppressive therapy between May 1998 and September 2013 were included in this study. Patients with non-severe AA (NSAA were treated with cyclosporine (CsA and danazol while patients with severe AA (SAA as well as patients with NSAA who progressed to SAA after beginning of the treatment, were candidates for receiving antithymocyte globulin in addition to CsA and danazol.Among the 63 studied patients, 29 (46% had NSAA and 34 (54% had SAA. Three months after treatment, overall response was 58.6% in NSAA and 12.9% in patients with SAA. Survival of all patients at 5, 10 and 15 years were 73%, 55% and 49%, respectively. Survival rates were significantly higher in patients with NSAA compared to patients with SAA as well as in patients who responded at 6 months compared to non-responders. The relapse risk was 39.7% at 10 years. Relapse occurred in patients who discontinued the therapy more than those who continued taking CsA (p value<0.01. The risk of clonal evolution was 9.9% at 10 years and 22.8% at 15 years after treatment.This long-term retrospective study indicated that immunosuppressive therapy should be recommended to patients with AA. Also, our experience indicated that immunosuppressive therapy should not be discontinued after response to therapy in patients with both NSAA and SAA due to high risk of relapse. Low dose of CsA should be continued indefinitely.

CEFTRIAXONE EFFICIENCY AMONG PATIENTS, SUFFERING FROM JUVENILE ARTHRITIS AND RECEIVING IMMUNOSUPPRESSIVE THERAPY

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A.M. Chomakhidze

2007-01-01

Full Text Available The article is dedicated to diagnostics and treatment of infectious complications among children with juvenile rheumatoid arthritis, receiving immunosuppressive therapy. The research involves 92 children with different variants of the illness run, who received immunosuppressive therapy. All the patients showed development of the systemic inflammatory response manifestations. The researchers used the definition of the procalcytonine levels as a marker for the bacterial infectiondevelopment. All the patients showed it higher than 0,5 ng/ml, while 7 patients — higher than 10 ng/ml. keeping in mind several courses of the antibacterial therapy in the anamnesis and presence of the combined bacterial infection, ceftriaxone was prescribed to all the children. As a result of the ceftriaxone based therapy, reduction of the clinical and laboratory manifestations of the bacterial infection was noted among more than 90% of patients. The development of the allergic reaction was noted in 1 case, and leukopenia was also found in 1 patient.Key words: children, juvenile rheumatoid arthritis, ceftriaxone.

Outcomes of changing immunosuppressive therapy after treatment failure in patients with noninfectious uveitis.

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Joshi, Lavnish; Talat, Lazha; Yaganti, Satish; Sandhu, Sartaj; Taylor, Simon R J; Wakefield, Denis; McCluskey, Peter; Lightman, Susan

2014-05-01

To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure. Retrospective cohort study. Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom and Australia. Participants with a history of using immunosuppressive therapy were identified in clinics, and notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a therapy) was identified, and demographic details, clinical characteristics, drug used (second-line immunosuppressive agent [ISA] or biologicals), and drug doses were obtained. For each treatment episode, the reasons for changing therapy, corticosteroid-sparing effects, and control of inflammation were determined. A total of 147 patients were identified who underwent 309 different treatment episodes. Fifty-five percent of patients eventually required a change in treatment after their first treatment episode/course. Forty-five episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving "success" (prednisolone ≤10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53 episodes, with "success" being achieved in 50% to 71% of these patients. Biological agents were used in 45 episodes, the most common one being infliximab, which achieved success in 80% of patients. Our data suggest that control of inflammation can be achieved after switching or combining ISAs. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model

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Hu, Yanping; Turner, Michael J; Shields, Jacqueline; Gale, Matthew S; Hutto, Elizabeth; Roberts, Bruce L; Siders, William M; Kaplan, Johanne M

2009-01-01

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined and mechanism of action studies have been hampered by the lack of cross-reactivity between human and mouse CD52. To address this issue, a transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did not display any phenotypic abnormalities and were able to mount normal immune responses. The tissue distribution of hCD52 and the level of expression by various immune cell populations were comparable to those seen in humans. Treatment with alemtuzumab replicated the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte depletion was not as profound in lymphoid organs, providing a possible explanation for the relatively low incidence of infection in alemtuzumab-treated patients. Interestingly, both lymphocyte depletion and cytokine induction by alemtuzumab were largely independent of complement and appeared to be mediated by neutrophils and natural killer cells because removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the activity of alemtuzumab whereas removal of complement by treatment with cobra venom factor had no impact. The hCD52 transgenic mouse appears to be a useful model and has provided evidence for the previously uncharacterized involvement of neutrophils in the activity of alemtuzumab. PMID:19740383

Low incidence of lymphoproliferative disease post kidney transplantation with prevalent use of alemtuzumab

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John Fredy Nieto-Ríos

2014-01-01

Full Text Available Introduction: It is well known that the incidence of malignancy is significantly higher in transplanted patients than in general population. The incidence of lymphoproliferative disease post-transplantation (PTLD is approximately of 1% to 2% in kidney transplantation recipients. Objective: The main objective of this study was to evaluate the PTLD incidence when monitoring kidney transplanted patients between the years 2005 and 2010. Methods: Kidney transplanted patients’ data was retrospectively taken between the years 2005 to 2010 in order to determine the number of PTLD cases according to the inductor scheme used. Results: 425 patients were transplanted between 2005 and 2010. They received alemtuzumab 76.2%, daclizumab 10.7%, basiliximab 3.6% and thymoglobulin 2.4%. The 7% did not receive antibody induction. During this period 2 cases of PTLD ocurred: One with multiple myeloma and the other with lymphoma. One of them had been treated with alemtuzumab and the other with thymoglobulin. Conclusions: The PTLD incidence in our group, where alemtuzumab was used predominantly as inductor, was very low; this might suggest that alemtuzumab is a medication that does not increase the risk of this kind of neoplasia.

Immunosuppression following radiation therapy for carcinoma of the nasopharynx

International Nuclear Information System (INIS)

Wara, W.M.; Phillips, T.L.; Wara, D.W.; Ammann, A.J.; Smith, V.

1975-01-01

Eleven patients treated for nasopharyngeal carcinoma with standard radiation therapy were found to have depressed cell mediated immunity. Post-treatment their total lymphocyte count was decreased by 60 percent. Eight of 11 patients had depressed T-cell rosettes, and 9 of 10 had abnormal lymphocyte response to PHA. Immunosuppression was probably related to irradiation of large blood volumes, irradiation of the thymus, and malnutrition. (U.S.)

Immunosuppression in Graves' ophthalmopathy

International Nuclear Information System (INIS)

Tian Rong; Kuang Anren; Qin Weishi; Zhang Huimin

2000-01-01

Objective: Graves' ophthalmopathy (GO) is a disease that seriously threatens the health of patients. But up to now, no optimal therapies have been established. Immunosuppressive treatment is usually used in the management of GO, but they may cause side effects. Recently, 99 Tc-MDP, commercially named 'Yun Ke', is used in the management of autoimmune disease. Therefore, a randomized trial was done to compare the values in the treatment of GO with between Yun Ke and immunosuppression. Methods: 42 consecutive patients with moderate or severe GO were randomly assigned to receive either Yun Ke therapy or immunosuppressive therapy. The degree of ocular involvement and responses to the treatment were evaluated by numerical scoring (ophthalmopathy index, OI) and clinical assessment. Therapy outcome was assessed 4 months after the start of treatment by the change in the highest NOSPECS class and OI. Data analysis was performed with the SPASS statistic software. Chi-square test was used to compare percentages, logistic regression was performed to identify which variables might correlated with the treatment outcome. Results: The remarkably effective outcome was observed in 14 (67%) cases in immunosuppression treated group and 13 (62%) cases in Yun Ke treated group. There were no significant differences in the degree of improvements in ocular involvements. There was a marked decrease of thyroid antibody titres in both groups. The variables found to correlated significantly with treatment outcome were thyroid antibody titres and GO activity. Side effects were more frequent and severe during immunosuppressive therapy. No side effects were found during Yun Ke treatment. Conclusion: Yun Ke and immunosuppression appeared to be equally effective in the management of GO, but Yun Ke is safer for patients during treatment

The safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious uveitis in childhood.

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Little, Jessica A; Sen, Ethan S; Strike, Helen; Hinchcliffe, Annie; Guly, Catherine M; Lee, Richard W J; Dick, Andrew D; Ramanan, Athimalaipet V

2014-01-01

To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis. Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months. Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY). In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

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Gabardi, Steven; Catella, Jennifer; Martin, Spencer T; Perrone, Ronald; Chandraker, Anil; Magee, Colm C; McDevitt-Potter, Lisa M

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation. The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisolone 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m²) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m²) and no adverse events. The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting, long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAs have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2

First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy.

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Yoshida, Nao; Kobayashi, Ryoji; Yabe, Hiromasa; Kosaka, Yoshiyuki; Yagasaki, Hiroshi; Watanabe, Ken-Ichiro; Kudo, Kazuko; Morimoto, Akira; Ohga, Shouichi; Muramatsu, Hideki; Takahashi, Yoshiyuki; Kato, Koji; Suzuki, Ritsuro; Ohara, Akira; Kojima, Seiji

2014-12-01

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); Paplastic anemia. Copyright© Ferrata Storti Foundation.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

LENUS (Irish Health Repository)

Gabardi, Steven

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation.

Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy

Institute of Scientific and Technical Information of China (English)

Kohtaro Ooka; Joseph K.Lim

2016-01-01

With 185 million people chronically infected globally,hepatitis C is a leading bloodborne infection.All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable.However,trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation.Yet,these patients-most often suffering from malignancy or autoimmune diseases-could stand to benefit from these treatments.In this study,we systematically review the literature on the treatment of hepatitis C in these neglected populations.Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically.Our systematic review produced 2273 unique works,of which 56 met our inclusion criteria and were used in our review.The quality of data was low;only 3 of the 56 studies were randomized controlled trials.Sustained virologic response was reported sporadically.Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals.Severe adverse effects and death were rare.Data on all-oral regimens were sparse,but in the most robust study,rates of sustained virologic response were again comparable to immunocompetent individuals (40/41).Efficacy and safety of interferoncontaining regimens and all-oral regimens were similar to rates in immunocompetent individuals;however,there were few interventional trials.The large number of case reports and case series makes conclusions vulnerable to publication bias.While firm conclusions are challenging,given the dearth of high-quality studies,our results demonstrate that antiviral therapy can be safe and effective.The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects.Preliminary data reveal that these regimens may confer such benefits in immunosuppressed individuals as well

Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment - an hypothesis

DEFF Research Database (Denmark)

Vojdeman, Fie Juhl; Jurlander, Jesper; Van't Veer, Mars

2013-01-01

ABSTRACT In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in m...

Human Peripheral Blood Mononuclear Cells Exhibit Heterogeneous CD52 Expression Levels and Show Differential Sensitivity to Alemtuzumab Mediated Cytolysis

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Rao, Sambasiva P.; Sancho, Jose; Campos-Rivera, Juanita; Boutin, Paula M.; Severy, Peter B.; Weeden, Timothy; Shankara, Srinivas; Roberts, Bruce L.; Kaplan, Johanne M.

2012-01-01

Alemtuzumab is a monoclonal antibody that targets cell surface CD52 and is effective in depleting lymphocytes by cytolytic effects in vivo. Although the cytolytic effects of alemtuzumab are dependent on the density of CD52 antigen on cells, there is scant information regarding the expression levels of CD52 on different cell types. In this study, CD52 expression was assessed on phenotypically distinct subsets of lymphoid and myeloid cells in peripheral blood mononuclear cells (PBMCs) from normal donors. Results demonstrate that subsets of PBMCs express differing levels of CD52. Quantitative analysis showed that memory B cells and myeloid dendritic cells (mDCs) display the highest number while natural killer (NK) cells, plasmacytoid dendritic cells (pDCs) and basophils have the lowest number of CD52 molecules per cell amongst lymphoid and myeloid cell populations respectively. Results of complement dependent cytolysis (CDC) studies indicated that alemtuzumab mediated profound cytolytic effects on B and T cells with minimal effect on NK cells, basophils and pDCs, correlating with the density of CD52 on these cells. Interestingly, despite high CD52 levels, mDCs and monocytes were less susceptible to alemtuzumab-mediated CDC indicating that antigen density alone does not define susceptibility. Additional studies indicated that higher expression levels of complement inhibitory proteins (CIPs) on these cells partially contributes to their resistance to alemtuzumab mediated CDC. These results indicate that alemtuzumab is most effective in depleting cells of the adaptive immune system while leaving innate immune cells relatively intact. PMID:22761788

Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis.

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Sambasiva P Rao

Full Text Available Alemtuzumab is a monoclonal antibody that targets cell surface CD52 and is effective in depleting lymphocytes by cytolytic effects in vivo. Although the cytolytic effects of alemtuzumab are dependent on the density of CD52 antigen on cells, there is scant information regarding the expression levels of CD52 on different cell types. In this study, CD52 expression was assessed on phenotypically distinct subsets of lymphoid and myeloid cells in peripheral blood mononuclear cells (PBMCs from normal donors. Results demonstrate that subsets of PBMCs express differing levels of CD52. Quantitative analysis showed that memory B cells and myeloid dendritic cells (mDCs display the highest number while natural killer (NK cells, plasmacytoid dendritic cells (pDCs and basophils have the lowest number of CD52 molecules per cell amongst lymphoid and myeloid cell populations respectively. Results of complement dependent cytolysis (CDC studies indicated that alemtuzumab mediated profound cytolytic effects on B and T cells with minimal effect on NK cells, basophils and pDCs, correlating with the density of CD52 on these cells. Interestingly, despite high CD52 levels, mDCs and monocytes were less susceptible to alemtuzumab-mediated CDC indicating that antigen density alone does not define susceptibility. Additional studies indicated that higher expression levels of complement inhibitory proteins (CIPs on these cells partially contributes to their resistance to alemtuzumab mediated CDC. These results indicate that alemtuzumab is most effective in depleting cells of the adaptive immune system while leaving innate immune cells relatively intact.

Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia

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Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Hama, Asahito; Kawashima, Nozomu; Wang, Xinan; Narita, Atsushi; Doisaki, Sayoko; Xu, Yinyan; Muramatsu, Hideki; Yoshida, Nao; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Nakamura, Kazuhiro; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

2014-01-01

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5–16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41–69%) and 97% (95%CI: 87–99%), respectively. Median telomere length in responders was −0.4 standard deviation (SD) (−2.7 to +3.0 SD) and −1.5 SD (−4.0 to +1.6 (SD)) in non-responders (Paplastic anemia. PMID:24816243

Immunosuppressive strategies and management

Institute of Scientific and Technical Information of China (English)

Shi-hui PAN

2008-01-01

Advances in immunosuppressive therapy have significantly improved short-term allograft and patient survival.However,chronic allograft failure,antibody mediated rejection,recurrent diseases and immunosuppressive drug associated adverse effects remain serious barriers to long-term survival and quality of life.New immunosuppressive agents and protocols are being evaluated to combat these problems.Importantly,clinicians must work to manage post-transplant complications and avoid complex medication regimens,which will potentiate drug interactions and non.compliance.Different organs have different immunogenicities and each recipient has a unique clinical and immunologic profile.The clinician must recognize these variations and customize the immunosuppressive regimens and treatment protocols based on the individual condition.The general principles of an individualized immunosuppressive protocol should take the following factors into account:organ type,donor and recipient characteristics,quality of the donor organ,recipienVs medical history,recipient's undedying disease,immunologic risk for acute rejection,potential co-morbidity related to immunosuppression,significant druginteractions,medication costs and patient compliance.In addition,the combination of immunosuppressive drugs must have a pharmacologic rationale to achieve the desired goal of suppressing the individual's immune system to render the patient tolerant to the allograft while minimizing co-morbidities.For the past few years,many clinical strategies have been applied in an attempt to improve graft survival or to reduce immunsuppressants induced side-effects.Specific protocols include steroid or CNI avoidance,minimization or withdraw,desensitization,and treatment for antibody mediated rejection,disease specific,and pediatric specific.The short-term outcomes from these different strategies are promising but the long-term results remain to be determined.Unfortunately,current immunosuppressive agents or strategies

Nanoparticles and direct immunosuppression

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Ngobili, Terrika A

2016-01-01

Targeting the immune system with nanomaterials is an intensely active area of research. Specifically, the capability to induce immunosuppression is a promising complement for drug delivery and regenerative medicine therapies. Many novel strategies for immunosuppression rely on nanoparticles as delivery vehicles for small-molecule immunosuppressive compounds. As a consequence, efforts in understanding the mechanisms in which nanoparticles directly interact with the immune system have been overshadowed. The immunological activity of nanoparticles is dependent on the physiochemical properties of the nanoparticles and its subsequent cellular internalization. As the underlying factors for these reactions are elucidated, more nanoparticles may be engineered and evaluated for inducing immunosuppression and complementing immunosuppressive drugs. This review will briefly summarize the state-of-the-art and developments in understanding how nanoparticles induce immunosuppressive responses, compare the inherent properties of nanomaterials which induce these immunological reactions, and comment on the potential for using nanomaterials to modulate and control the immune system. PMID:27229901

Hyperbaric Oxygen Therapy as a Sole Agent Is Not Immunosuppressant in a Highly Immunogenic Mouse Model

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Adam Gassas

2011-01-01

Full Text Available Background. Hyperbaric oxygen (HBO therapy, which is used for many conditions, may also have immunosuppressive effects and could be used for prevention or treatment of graft-versus-host disease (GvHD. If HBO is immunosuppressant, then we hypothesize that HBO therapy will delay the T-cell mediated skin graft rejection. Methods. C57/BL6 black-coated (H2B mice received skin graft from CBA (H2D white-coated mice. Mice were treated with either 19 session of 240 kpa oxygen or 29 session of 300 kpa oxygen, for 90 minutes. Mice were housed either 4 per cage or separately, to prevent friction and mechanical factors that may affect graft survival. Skin grafts were assessed daily. Results. There was no difference in length of graft survival between mice that received either regimens of HBO therapy and mice that did not receive HBO therapy. Conclusions. HBO therapy, as a sole agent, did not delay skin graft rejection in a highly immunogenic mouse model.

Candidal carriage predicts candidiasis during topical immunosuppressive therapy: a preliminary retrospective cohort study.

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Tejani, Sara; Sultan, Ahmed; Stojanov, Ivan; Woo, Sook-Bin

2016-10-01

To determine (1) the prevalence of candidal carriage in patients with oral mucosal disease to be treated with topical immunosuppressive therapy, and (2) the incidence of oral candidiasis among carriers and noncarriers after initiation of therapy to assess any correlation between carriage and the development of candidiasis. Records of patients who underwent swab cultures for Candida between January 2009 and October 2014 at the Brigham and Women's Hospital in Boston, Massachusetts, were retrospectively reviewed. The prevalence of candidal carriage and incidence of candidiasis were determined by using descriptive statistics. Of 99 evaluable patients, 20 (20.2%) were Candida positive and 79 (79.8%) were Candida negative. Of 44 patients with follow-up, 7 (15.9%) were Candida positive and 37 (84.1%) were Candida negative; five (11.4%) developed candidiasis. Four of seven (57.1%) Candida-positive patients developed candidiasis, whereas only one of 37 (2.7%) Candida-negative patients developed candidiasis (P = .0012). The overall prevalence of candidal carriage was low (20.2%), and there was a significant difference in the incidence of candidiasis between carriers and noncarriers (P = .0012) after topical immunosuppressive therapy. Therefore, patients who are candidal carriers should be monitored closely for the development of secondary candidiasis and may be candidates for prophylactic antifungal therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation

DEFF Research Database (Denmark)

Kohno, M; Perch, M; Andersen, E

2011-01-01

of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory...

Richter transformation driven by Epstein-Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia.

Science.gov (United States)

García-Barchino, Maria J; Sarasquete, Maria E; Panizo, Carlos; Morscio, Julie; Martinez, Antonio; Alcoceba, Miguel; Fresquet, Vicente; Gonzalez-Farre, Blanca; Paiva, Bruno; Young, Ken H; Robles, Eloy F; Roa, Sergio; Celay, Jon; Larrayoz, Marta; Rossi, Davide; Gaidano, Gianluca; Montes-Moreno, Santiago; Piris, Miguel A; Balanzategui, Ana; Jimenez, Cristina; Rodriguez, Idoia; Calasanz, Maria J; Larrayoz, Maria J; Segura, Victor; Garcia-Muñoz, Ricardo; Rabasa, Maria P; Yi, Shuhua; Li, Jianyong; Zhang, Mingzhi; Xu-Monette, Zijun Y; Puig-Moron, Noemi; Orfao, Alberto; Böttcher, Sebastian; Hernandez-Rivas, Jesus M; Miguel, Jesus San; Prosper, Felipe; Tousseyn, Thomas; Sagaert, Xavier; Gonzalez, Marcos; Martinez-Climent, Jose A

2018-05-01

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV - tumours, EBV + DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV + DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV + DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2 -/- IL2γc -/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV + B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV + DLBCL in patients. Accordingly, clonally related and unrelated EBV + DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV + DLBCL. Copyright © 2018 Pathological

New Immunosuppressive Therapies in Uveitis Treatment

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Salvador Mérida

2015-08-01

Full Text Available Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines.

New Immunosuppressive Therapies in Uveitis Treatment

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Mérida, Salvador; Palacios, Elena; Navea, Amparo; Bosch-Morell, Francisco

2015-01-01

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. PMID:26270662

Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

KAUST Repository

Hill-Cawthorne, Grant A.

2011-11-05

Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

KAUST Repository

Hill-Cawthorne, Grant A.; Button, Tom; Tuohy, Orla C.; Jones, Joanne L.; May, Karen; Somerfield, Jennifer; Green, Alison J E; Giovannoni, Gavin; Compston, Alastair D.; Fahey, Michael T.; Coles, Alasdair J.

2011-01-01

Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

A longitudinal assessment of adherence with immunosuppressive therapy following kidney transplantation from the Mycophenolic Acid Observational REnal Transplant (MORE) study.

Science.gov (United States)

Tsapepas, Demetra; Langone, Anthony; Chan, Laurence; Wiland, Anne; McCague, Kevin; Chisholm-Burns, Marie

2014-04-17

Nonadherence with immunosuppressive therapy after renal transplantation is a major clinical concern, but longitudinal data are sparse. Adherence data were recorded during the Mycophenolic Acid Observational REnal Transplant (MORE) study to help inform compliance management decisions. Prospective data were analyzed from the four-year, observational MORE study of de novo adult renal transplant recipients receiving mycophenolic acid (MPA) as enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at 40 US sites under routine management. Adherence was assessed using the Immunosuppressant Therapy Adherence Scale (ITAS): total score 0-12 (12, adherence; adherent recipients (p=0.59); graft loss was 4.7% (19/402) vs. 3.0% (12/406) (p=0.20); death was 1.5% (6/402) vs. 4.7% (19/406) (p=0.013). Adherence to the immunosuppressive regimen decreases over time, highlighting the need to monitor and encourage adherence even in long-term maintenance kidney transplant patients. Other than African American race, demographic factors may be of limited value in predicting nonadherence.

Very late relapse of PTLD 10 yrs after allogeneic HSCT and nine yrs after stopping immunosuppressive therapy

DEFF Research Database (Denmark)

Helgestad, Jon; Rosthøj, Steen; Pedersen, Morten Høgild

2014-01-01

the fever settled, the PET scan normalized, and the M-component disappeared. Without any ongoing immunosuppressive therapy, PTLD relapsed nine yr later with large intra-abdominal lymph node masses causing ureteric obstruction with bilateral hydronephrosis. Pathological features were identical to the primary...

Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

Science.gov (United States)

Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

2014-07-01

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. © 2014 Wiley Periodicals, Inc.

Pemphigus vulgaris in a patient with arthritis and uveitis: successful treatment with immunosuppressive therapy and acyclovir.

Science.gov (United States)

Pranteda, G; Carlesimo, M; Bottoni, U; Di Napoli, A; Muscianese, M; Pimpinelli, F; Cordiali, P; Laganà, B; Pranteda, G; Di Carlo, A

2014-01-01

A case of pemphigus vulgaris in a 41-year-old man with undifferentiated arthritis and uveitis is described. Histology of labial mucosa showed acantholytic, necrotic, and multinucleated giant keratinocytes having some nuclear inclusions suggestive of a virus infection. Specific serological tests revealed IgG positivity for HSV-1, CMV, and EBV, while real-time polymerase chain reaction assay from a biopsy of the mucosal lesion showed the presence of HSV-1/2 DNA. Treatment with prednisone, methotrexate, and acyclovir induced the complete remission of mucosal and joint symptoms, which then relapsed after interruption of antiviral therapy or immunosuppressive therapy. Therefore, a combined treatment with low doses of prednisone, methotrexate, and acyclovir was restarted and during 18 months of follow-up no recurrence was registered. Correlations between pemphigus and the herpes virus infection and also between autoimmune arthritis and herpetic agents have been well documented, but the exact role of the herpes virus in these disorders still needs further discussion. Our case strongly suggests that when autoimmune disorders do not respond to immunosuppressive agents, a viral infection should be suspected, researched, and treated. © 2014 Wiley Periodicals, Inc.

[Correlation of SNP of IL-2-330T/G Gene with Genetic Susceptibility and Efficacy of Immunosuppressive Therapy in Patients with Aplastic Anemia].

Science.gov (United States)

Zeng, Qiang; Chang, Hong

2016-10-01

To investigate the correlation of single nucleotide polymorphism (SNP) of Interleukin-2(IL-2)-330T/G with genetic susceptibility and the efficacy of immunosuppressive therapy in patients with aplastic anemia. The peripheral blood samples from 103 patients with aplastic anemia in our hospital were collected. Out of 103 patients 46 received immuosuppressive therapy and were observed for 4 months, and 100 healthy adults were selected as control. The electrophoresis and DNA sequence were performed. The polymerase chain reaction(PCR) was used to amplify the polymorphic gene segment of IL-2 -330T/G from 103 aplastic anemia patients and 100 healthy adults. The frequencis of IL-2-330 GG genotype and G allele were a little higher in patients with aplastic anemia than that in the healthy adults(12.6% vs 12.0%, P>0.05; 27.7% vs 33.5%, P>0.05), but not statistically significant(P>0.05); in the 103 patients with aplastic anemia, 46 received immunosuppressive therapy, whereas 29 patients showed response, no significant difference was found between the responders and non-responders in the IL-2-330 GG genotype and G allele (31.0% vs 48.3%, P>0.05; 64.8% vs 61.8%, P>0.05). IL-2 -330T/G gene polymorphism may not correlate with the susceptibility of aplastic anemia or the efficacy of immunosuppressive therapy.

[Experience with high-dose immunosuppressive therapy followed by transplantation of autologous stem hematopoietic cells in patients with multiple sclerosis].

Science.gov (United States)

Rossiev, V A; Makarov, S V; Aleksandrova, I Ia; Dolgikh, G T; Lipshina, S R; Stukalova, T A; Trushina, O A; Fedorova, E Iu; Lipina, L N; Sivak, V F; Korenev, P P; Murashov, B F

2002-01-01

To assess efficiency of immunosuppressive therapy and subsequent autologous transplantation of stem blood cells (SBC) in patients with multiple sclerosis. The trial enrolled 23 patients (4 men and 19 women) with multiple sclerosis (MS) lasting for 3 to 12 years. The age of the patients ranged from 18 to 44 years. The index of the progression was above 1 in all the patients. A remitting, primary-progredient, secondary-progredient course was diagnosed in 3, 3 and 17 patients, respectively. Posttransplantation follow-up was 1 to 1.5 years. The degree of the neurological deficiency (0-6 scores) was estimated by the scale of functional systems damage. Lymphocyte subpopulations were evaluated by enzyme immunoassay according to expression of membrane antigens CD3, CD4, CD8, CD16, CD20, CD25, CD56, CD95 using monoclonal antibodies ICO (Biomedspectr), humoral immunity--by serum levels of IgA, IgM and IgG. SBC mobilization was conducted for 5 days by subcutaneous introduction of neipogen (Roche) in a dose 8.7-10 mcg/kg. Preparation of SBC was made on Haemonetics blood separator on mobilization day 4-5. Cryopreservation was carried out in programmed freezer (Cryomed) with 7% dimethylsulphoxide as a cryoprotector. Pretransplantation conditioning was conducted according to the schemes BEAM + antilymphocytic globulin (protocol N 1) and fludar + melfalan + ALG (protocol N 2). In posttransplantation period most of the patients achieved a fall in intensity of motor and coordination disorders. No recovery of cranial nerve function was observed. The protocols of pretransplantation preparation were compared by efficiency and organic toxicity. Indications to immunosuppressive therapy in MS patients were defined, pathogenetic validation of the immunosuppressive therapy was attempted.

Knowledge-based immunosuppressive therapy for kidney transplant patients--from theoretical model to clinical integration.

Science.gov (United States)

Seeling, Walter; Plischke, Max; de Bruin, Jeroen S; Schuh, Christian

2015-01-01

Immunosuppressive therapy is a risky necessity after a patient received a kidney transplant. To reduce risks, a knowledge-based system was developed that determines the right dosage of the immunosuppresive agent Tacrolimus. A theoretical model, to classify medication blood levels as well as medication adaptions, was created using data from almost 500 patients, and over 13.000 examinations. This model was then translated into an Arden Syntax knowledge base, and integrated directly into the hospital information system of the Vienna General Hospital. In this paper we give an overview of the construction and integration of such a system.

Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile.

Science.gov (United States)

Mauro, Francesca R; Molica, Stefano; Laurenti, Luca; Cortelezzi, Agostino; Carella, Angelo M; Zaja, Francesco; Chiarenza, Annalisa; Angrilli, Francesco; Nobile, Francesco; Marasca, Roberto; Musolino, Caterina; Brugiatelli, Maura; Piciocchi, Alfonso; Vignetti, Marco; Fazi, Paola; Gentile, Giuseppe; De Propris, Maria S; Della Starza, Irene; Marinelli, Marilisa; Chiaretti, Sabina; Del Giudice, Ilaria; Nanni, Mauro; Albano, Francesco; Cuneo, Antonio; Guarini, Anna; Foà, Robin

2014-02-01

In 45, ≤ 60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab(®)) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features. Copyright © 2013 Elsevier Ltd. All rights reserved.

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide.

Science.gov (United States)

Kanakry, Christopher G; Bolaños-Meade, Javier; Kasamon, Yvette L; Zahurak, Marianna; Durakovic, Nadira; Furlong, Terry; Mielcarek, Marco; Medeot, Marta; Gojo, Ivana; Smith, B Douglas; Kanakry, Jennifer A; Borrello, Ivan M; Brodsky, Robert A; Gladstone, Douglas E; Huff, Carol Ann; Matsui, William H; Swinnen, Lode J; Cooke, Kenneth R; Ambinder, Richard F; Fuchs, Ephraim J; de Lima, Marcos J; Andersson, Borje S; Varadhan, Ravi; O'Donnell, Paul V; Jones, Richard J; Luznik, Leo

2017-03-09

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

Efficacy of interventions for adherence to the immunosuppressive therapy in kidney transplant recipients: a meta-analysis and systematic review.

Science.gov (United States)

Zhu, Yichen; Zhou, Yifan; Zhang, Lei; Zhang, Jian; Lin, Jun

2017-10-01

Immunosuppressive treatment regimens are complex and require ongoing self-management. Medication adherence can be difficult to achieve for several reasons. The current meta-analysis and systematic review investigated whether adherence interventions improved immunosuppressive treatment adherence in kidney transplant recipients. Medline, Cochrane, EMBASE, and Google Scholar were searched until October 17, 2016 using the following search terms: kidney transplantation, compliance, adherence, and immunosuppressive therapy. Randomized controlled trials and two-arm prospective, retrospective, and cohort studies were included. The primary outcomes were adherence rate and adherence score. Eight studies were included with a total for 546 patients. Among participants receiving intervention, the adherence rate was significantly higher than the control group (pooled OR=2.366, 95% CI 1.222 to 4.578, p=0.011). Participants in the intervention group had greater adherence scores than those in the control group (pooled standardized difference in means =1.706, 95% CI 0.346 to 3.065, p=0.014). Sensitivity analysis indicated that findings for adherence rate were robust. However, for adherence score, the significance of the association disappeared after removing one of the studies indicating the findings may have been overly influenced by this one study. Intervention programs designed to increase immunosuppressive adherence in patients with kidney transplant improve treatment adherence. Copyright © 2017 American Federation for Medical Research.

In vivo T-cell depletion using alemtuzumab in family and unrelated donor transplantation for pediatric non-malignant disease achieves engraftment with low incidence of graft vs. host disease.

Science.gov (United States)

Saif, M A; Borrill, R; Bigger, B W; Lee, H; Logan, A; Poulton, K; Hughes, S; Turner, A J; Bonney, D K; Wynn, R F

2015-03-01

In vivo T-cell depletion, using alemtuzumab therapy prior to SCT, can reduce the incidence of GVHD. This treatment has a potential to delay immune reconstitution resulting in increased morbidity due to viral illnesses. We retrospectively analyzed data on all pediatric patients with non-malignant disorders who received alemtuzumab-based conditioning regimens in our center over the last 10 yr (n = 91). Our data show an OS of 91.2%. The incidence of acute (grade 2-4) GVHD was 18.7% and that of chronic GVHD 5.5%. Viremia due to adenovirus, EBV and CMV was seen in 19.8%, 64.8% and 39.6% patients, respectively, with only two deaths attributed to viral infection (adenovirus). Chimerism level at three month was predictive of graft outcome. Nine patients, who had graft failure after first SCT, were salvaged with a second SCT using RIC and same donor (if available). Based on these results, we conclude that the use of in vivo T-cell depletion is safe, achieves good chimerism and does not lead to increased morbidity and mortality due to viral infections. It is associated with a reduced incidence of chronic GVHD. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immunosuppressive therapy for transplant-ineligible aplastic anemia patients.

Science.gov (United States)

Schrezenmeier, Hubert; Körper, Sixten; Höchsmann, Britta

2015-02-01

Aplastic anemia is a rare life-threatening bone marrow failure that is characterized by bicytopenia or pancytopenia in the peripheral blood and a hypoplastic or aplastic bone marrow. The patients are at risk of infection and hemorrhage due to neutropenia and thrombocytopenia and suffer from symptoms of anemia. The main treatment approaches are allogeneic stem cell transplantation and immunosuppression. Here, we review current standard immunosuppression and the attempts that have been made in the past two decades to improve results: review of recent developments also reveals that sometimes not only the advent of new drugs, good ideas and well-designed clinical trials decide the progress in the field but also marketing considerations of pharmaceutical companies. Aplastic anemia experts unfortunately had to face the situation that efficient drugs were withdrawn simply for marketing considerations. We will discuss the current options and challenges in first-line treatment and management of relapsing and refractory patients with an emphasis on adult patients. Some promising new approaches are currently under investigation in prospective, randomized trials.

Association of time under immunosuppression and different immunosuppressive medication on periodontal parameters and selected bacteria of patients after solid organ transplantation.

Science.gov (United States)

Schmalz, G; Berisha, L; Wendorff, H; Widmer, F; Marcinkowski, A; Teschler, H; Sommerwerck, U; Haak, R; Kollmar, O; Ziebolz, D

2018-05-01

Aim of this study was to investigate the association of the time under immunosuppression and different immunosuppressive medication on periodontal parameters and selected periodontal pathogenic bacteria of immunosuppressed patients after solid organ transplantation (SOT). 169 Patients after SOT (lung, liver or kidney) were included and divided into subgroups according their time under (0-1, 1-3, 3-6, 6-10 and >10 years) and form of immunosuppression (Tacrolimus, Cyclosporine, Mycophenolate, Glucocorticoids, Sirolimus and monotherapy vs. combination). Periodontal probing depth (PPD) and clinical attachment loss (CAL) were assessed. Periodontal disease severity was classified as healthy/mild, moderate or severe periodontitis. Subgingival biofilm samples were investigated for eleven selected potentially periodontal pathogenic bacteria using polymerasechainreaction. The mean PPD and CAL as well as prevalence of Treponema denticola and Capnocytophaga species was shown to be different but heterogeneous depending on time under immunosuppression (pperiodontal condition compared to patients without Cyclosporine (pperiodontal and microbiological parameters of patients after SOT. Patients under Cyclosporine medication should receive increased attention. Differences in subgingival biofilm, but not in clinical parameters were found for Glucocorticoids, Mycophenolate and combination therapy, making the clinical relevance of this finding unclear.

Efficiency of Photodynamic Therapy in the Treatment of Diffuse Facial Viral Warts in an Immunosuppressed Patient: Towards a Gold Standard

Directory of Open Access Journals (Sweden)

M. Caucanas

2010-12-01

Full Text Available A 64-year-old man with a pulmonary transplant developed diffuse verrucae vulgares of the neck. After the failure of multiple cryotherapy treatments, 3 sessions of photodynamic therapy resulted in rapid therapeutic clinical success. This moderately painful and well-tolerated treatment is reproducible and can be very useful in treating papillomavirus infections in the immunosuppressed patient.

Management of HBV Infection During Immunosuppressive Treatment

OpenAIRE

Marzano, Alfredo

2009-01-01

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and refers mainly to the pre-antivirals era. Currently, a rational approach to the problem of hepatitis B in these patients provides for: a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), b) the treatment with antivirals (therapy) of active carriers, c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if...

Side Effects of Transplant Immunosuppressive Therapy in Post Renal Transplant Recipients, Mazandaran, Northern Iran

Directory of Open Access Journals (Sweden)

Abazar Akbarzadeh Pasha

2017-04-01

Full Text Available Background Post-kidney transplant survival relies on patient adherence to the intake of immunosuppressive medication. This study was performed to investigate complications associated with immunosuppressive therapy in renal transplantation. Methods This cross-sectional study was conducted on 188 transplanted patients in Shahid Beheshti hospital of Babol in 2013. Check list and demographic questionnaire for data collecting were used. Then the data using were analyzed in SPSS.18 software by using chi-square test. Results A total of 188 transplanted patients, 115 (61.2% was male and mean age was 12.9 ± 42.9 years. 181 (96.3% of the subjects had at least one complication. The most common complication in 142 cases (75.5% was “excessive hair growth” and after this complication “increased blood sugar” had higher frequency and 119 (63.3% had this complication. Severe form of gingival overgrowth in women was significantly that more than men (22 (30.1, 14 (12.2, P = 0.004, and the other side effect was not significant difference between men and women or different age groups (P > 0.05 Conclusions Finding show that nearly all transplanted recipients suffered from one complication which need to recognize, control and treatment. It suggested that period visiting for early diagnosis and education to patient was recommend.

Varicella-zoster virus immunity in dermatological patients on systemic immunosuppressant treatment.

LENUS (Irish Health Repository)

Hackett, C B

2012-02-01

BACKGROUND: Primary varicella infection is caused by varicella-zoster virus (VZV). It is a common childhood infection, which is usually benign but can occasionally cause morbidity and mortality. In immunosuppressed adults, atypical presentation and disseminated disease can occur with significant morbidity and mortality. A VZV vaccine is available. OBJECTIVES: This study was designed to measure the prevalence of immunity to VZV and to determine the predictive value of a self-reported history of varicella infection in a population of dermatological patients receiving systemic immunosuppressant therapy. We sought to assess the need for routine serological testing for varicella-zoster immunity in this cohort. METHODS: Serological testing for VZV immunity was done on 228 patients receiving systemic immunosuppressive treatment for a dermatological condition. Information regarding a history of previous primary VZV infection was obtained from each patient. RESULTS: Two hundred and twenty-eight patients had VZV serology performed. The mean age of the patients was 49.6 years. The prevalence of VZV seropositivity in this cohort was 98.7%. One hundred and two patients (44.7%) reported having a definite history of primary VZV. The sensitivity of a self-reported history of VZV infection was 45.3% with a specificity of 100%. The positive and negative predictive values of a self-reported history of VZV for serologically confirmed immunity were 100% and 2.3%, respectively. CONCLUSIONS: The prevalence of VZV IgG antibodies in our cohort of Irish dermatology patients receiving immunosuppressive therapy is 98.7%. A recalled history of varicella infection is a good predictor of serological immunity. This study has shown that there are VZV-susceptible individuals within our cohort. These patients did not have a clear history of previous infection. We recommend serological testing of patients without a clear history of infection prior to the commencement of immunosuppressive therapy and

Differences in Attitudes Toward Immunosuppressant Therapy in a Multi-ethnic Sample of Kidney Transplant Recipients.

Science.gov (United States)

Constantiner, Melissa; Rosenthal-Asher, Deborah; Tedla, Fasika; Salifu, Moro; Cukor, Judith; Wyka, Katarzyna; Hartono, Choli; Serur, David; de Boccardo, Graciela; Cukor, Daniel

2018-03-01

Barriers for renal transplant patients to immunosuppressant medication adherence are poorly understood, despite the high rate and toll of non-adherence. We sought to assess factors that contribute to barriers to immunosuppressive medication adherence in an ethnically diverse sample of 312 renal transplant patients recruited from three transplant centers across New York City. Transplant patients who were at least 6 months post-transplant completed questionnaires while waiting for their medical appointment. Ethnic differences were observed on barriers to immunosuppressant adherence. Black and Hispanic participants reported significantly more barriers to adherence compared to Caucasian participants. Differences in perception about the potential harm and necessity of immunosuppressant medications also were present. Using hierarchical multiple regression, age and income were significant predictors of reported barriers to adherence, even while controlling for ethnicity. The most robust predictor of reported barriers was the perception of the medication cost-benefit differential, i.e., the balance between concerns about immunosuppressant medications and their perceived helpfulness (B = - 0.5, p adherence. Future interventions targeting non-adherence should aim to reduce the barriers to adherence by addressing perceived risks and benefits of taking immunosuppressant medication.

[Therapy of intermediate uveitis].

Science.gov (United States)

Doycheva, D; Deuter, C; Zierhut, M

2014-12-01

Intermediate uveitis is a form of intraocular inflammation in which the vitreous body is the major site of inflammation. Intermediate uveitis is primarily treated medicinally and systemic corticosteroids are the mainstay of therapy. When recurrence of uveitis or side effects occur during corticosteroid therapy an immunosuppressive treatment is required. Cyclosporine A is the only immunosuppressive agent that is approved for therapy of uveitis in Germany; however, other immunosuppressive drugs have also been shown to be effective and well-tolerated in patients with intermediate uveitis. In severe therapy-refractory cases when conventional immunosuppressive therapy has failed, biologics can be used. In patients with unilateral uveitis or when the systemic therapy is contraindicated because of side effects, an intravitreal steroid treatment can be carried out. In certain cases a vitrectomy may be used.

Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.

Science.gov (United States)

Cui, Xin; Morales, Renee-Tyler Tan; Qian, Weiyi; Wang, Haoyu; Gagner, Jean-Pierre; Dolgalev, Igor; Placantonakis, Dimitris; Zagzag, David; Cimmino, Luisa; Snuderl, Matija; Lam, Raymond H W; Chen, Weiqiang

2018-04-01

altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Factors that determine self-reported immunosuppressant adherence in kidney transplant recipients: a correlational study.

Science.gov (United States)

Weng, Li-Chueh; Yang, Ya-Chen; Huang, Hsiu-Li; Chiang, Yang-Jen; Tsai, Yu-Hsia

2017-01-01

To determine the factors related to immunosuppressant therapy adherence in kidney transplant recipients in Taiwan. Adherence to immunosuppressant treatment is critical after kidney transplantation. Thus, the factors associated with self-reported medication adherence in kidney transplant recipients warrant investigation. The study used a cross-sectional and correlation design. A convenience sample of 145 kidney transplant recipients was included. Structured questionnaires were used to collect data during 2012-2013. Multivariate linear regression was used to examine the factors related to immunosuppressant therapy adherence. Over half of the participants were female (54·5%), mean age was 45·5 years, and mean year after transplant was 7·4. The mean score for medication adherence was 29·73 (possible score range 7-35). The results of the multivariate linear regression analysis showed that gender (male), low income with a high school or college education, years after transplantation and concerns about medication taking were negatively associated with adherence. Medication self-efficacy was positively associated with adherence. Therapy-related factors, partnerships with healthcare professionals and having private healthcare insurance did not significantly relate to immunosuppressant therapy adherence. Kidney transplant recipients demonstrated a high level of adherence. Strategies to enhance patients' self-efficacy and alleviate concerns about medication may promote medication adherence. Male patients, those with a lower income and those with a higher education level, should be a focus of efforts to maintain adherence to the medication regimen. © 2016 John Wiley & Sons Ltd.

Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy.

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Letko, Erik; Yeh, Steven; Foster, C Stephen; Pleyer, Uwe; Brigell, Mitchell; Grosskreutz, Cynthia L

2015-05-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis. Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial. Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy. Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose). Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening. Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared

Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells

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Zent, Clive S.; Taylor, Ronald P.; Lindorfer, Margaret A.; Beum, Paul V.; LaPlant, Betsy; Wu, Wenting; Call, Timothy G.; Bowen, Deborah A.; Conte, Michael J.; Frederick, Lori A.; Link, Brian K.; Blackwell, Sue E.; Veeramani, Suresh; Baig, Nisar A.; Viswanatha, David S.; Weiner, George J.; Witzig, Thomas E.

2014-01-01

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation.

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Martin, Spencer T; Tichy, Eric M; Gabardi, Steven

2011-04-01

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as

Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.

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Vargas-Hitos, J A; Sabio, J M; Navarrete-Navarrete, N; Arenas-Miras, M del M; Zamora-Pasadas, M; Jiménez-Alonso, J

2016-03-01

Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant. © The Author(s) 2015.

Awareness of memory impairment increases the adherence to immunosuppressants in kidney transplant recipients.

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Cheng, C-Y; Lin, B Y-J; Chang, K-H; Shu, K-H; Wu, M-J

2012-04-01

Nonadherence to immunosuppressive drugs is a concern among kidney transplantation recipients (KTRs). The adverse effects of immunosuppressive drugs can trigger nonadherence and lead to a great impact on the allograft survival. The aim of this prospective controlled study is to determine the major adverse effects of immunosuppressive drugs and their correlation with the nonadherence in kidney transplantation recipients. All data were collected from medical and pharmacy records. We use modified Immunosuppressant Therapy Adherence Scale combined with Modified Transplant Symptom Occurrence and Symptom Distress scale to explore the relationship between symptom experience related to side effects of immunosuppressants and adherence. The risk of nonadherence was estimated by stepwise logistic regression while controlling for age, gender, education, and immunosuppressive medications. Multivariable analysis was performed using a single random effect of P adherence increased in patients with awareness of memory impairment (odds ratio 2.320, 95% confidence interval: 1.259-4.274, P = .007). There was no significant difference in the incidence of acute rejection, gender, age, and education between adherent and nonadherent patients. In summary, these results indicate a significant prevalence of nonadherence to immunosuppressive drugs in kidney transplantation recipients. Awareness of memory impairment significantly affected adherence to immunosuppressive drugs. Copyright © 2012 Elsevier Inc. All rights reserved.

Genetic factors for individual administration of immunosuppressants in organ transplantation

Institute of Scientific and Technical Information of China (English)

Song-Feng Yu; Li-Hua Wu; Shu-Sen Zheng

2006-01-01

BACKGROUND: The immunosuppressive drugs used worldwide have a narrow therapeutic index, which results in a need to individualize the dose regimen for different recipients. The oxidative enzymes cytochrome P450 (CYP)3A and the drug eflfux pump P-glycoprotein (P-gp) are two potential factors in the processes of metabolism. Pharmacogenetic study of immunosuppressive drugs has focused on these two enzymes. This review was undertaken to assess the role of single nuclear polymorphisms (SNPs) of these two enzymes in the individual administration of immunosuppressive drugs. DATA SOURCES: An English-language literature search was made using MEDLINE for articles on CYP3A and P-gp in organ transplantation. RESULTS: The SNPs of CYP3A and P-gp are closely correlated to the large variations of cyclosporine and tacrolimus dosage between different patients, although conlficting results were obtained by some authors. CONCLUSIONS: More studies should be conducted to elucidate further the pharmacogenetics of immuno-suppressive drugs in organ transplantation, a deep understanding of which would provide an important step toward drug regimen individualization in the posttransplant therapy.

Pneumonia in immunosuppressed patients; Pneumonien bei immunsupprimierten Patienten

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Solyanik, O.; Gaass, T.; Hellbach, K. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Campus Grosshadern, Institut fuer klinische Radiologie, Muenchen (Germany); Dinkel, J. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Campus Grosshadern, Institut fuer klinische Radiologie, Muenchen (Germany); Comprehensive Pneumology Center Munich (CPC-M), Muenchen (Germany)

2017-01-15

Pulmonary infections are a common complication in immunosuppressed patients with a frequently fatal prognosis despite modern prophylactic therapy. An early and correct diagnosis is important for initiation of the appropriate therapy. Chest radiography is the preferred initial imaging examination but is not accurate enough for the detection of pulmonary infections in immunosuppressed patients. Pneumonia is caused by a broad spectrum of pathogens in immunocompromised patients. In addition to imaging, the clinical history and epidemiology also play an important role in the diagnostics. Using epidemiological and anamnestic information, computed tomography (CT) shows a significantly better sensitivity and specificity particularly for the diagnosis of atypical forms of pneumonia. Due to the exact imaging of the different infiltration patterns CT provides an increased sensitivity with respect to the etiological classification of pulmonary infections. This article reviews in particular the radiological findings of commonly occurring pulmonary infections in immunosuppressed patients. (orig.) [German] Pneumonien bei immunsupprimierten Patienten sind haeufige Komplikationen, die trotzt moderner Prophylaxe toedlich verlaufen koennen. Eine korrekte Diagnose ist daher von entscheidender Bedeutung, um die richtige Therapie einleiten zu koennen. Die Roentgenthoraxaufnahme ist selten spezifisch genug fuer die genaue Einordnung atypischer Pneumonien in Folge einer Immunsuppression. Pneumonien unter Immunsuppression werden durch ein sehr breites Erregerspektrum verursacht. Eine wichtige Rolle bei der Diagnosefindung spielen neben der Bildgebung auch die klinische Anamnese und Epidemiologie. Mithilfe der klinischen Anamnese und Epidemiologie bietet die Computertomographie (CT) bei immunsupprimierten Patienten zum einen eine erhoehte Sensitivitaet bei der Detektion insbesondere atypischer Pneumonien. Zum anderen weist die CT durch die exakte Abbildung unterschiedlicher Infiltratmuster

The clinical value of immunosuppression in Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism

International Nuclear Information System (INIS)

Chen Yue; Qiu Ling; Zhang Chunying; Long Shuiqing; Gan Xilun

2001-01-01

Objective: The chief clinical characteristics of Graves disease are hyperthyroidism and ophthalmopathy. To assess the values of using immunosuppression in Graves ophthalmopathy. Method: 415 patients with Graves hyperthyroidism were studied. They were randomly assigned to receive radioiodine, methimazole from 1.5 to 2 years, radioiodine followed by a 3-month course of prednisone. The changes in thyroid function and progression of ophthalmopathy were evaluated. Results: Among the 138 patients treated with radioiodine, 19 patients had new or worsening ophthalmopathy; 117 had no changes in their eyes; 2 patients had improvement in their eye disease. Among the 138 patients treated with methimazole, 3 patients had new or worsening ophthalmopathy; 133 had no changes in their eyes; 2 patients had improvement in their eye disease. Among the 139 patients treated with radioiodine and prednisone, no patient had new or worsening ophthalmopathy; 107 had no changes in their eyes; 32 patients had improvement in their eye disease. The frequency of improvement of ophthalmopathy was significantly higher in the radioiodine-prednisone group than in either the radioiodine group or the methimazole group (P<0.001 for both comparisons). Conclusions: The administration of prednisone after radioiodine therapy was associated with improvement of ophthalmopathy. Worsening of ophthalmopathy after radioiodine therapy is often transient and can be prevented by the administration of prednisone

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis.

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Aly, Lilian; Hemmer, Bernhard; Korn, Thomas

2017-01-01

Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide. Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy. Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression

OpenAIRE

MCCANN, SHAUN

2002-01-01

PUBLISHED Background: Aplastic anemia may develop during pregnancy and sometimes improves spontaneously after delivery. The effects of pregnancy on aplastic anemia after immunosuppressive treatment and of aplastic anemia on the outcome of pregnancy have not been described. Objective: To determine the outcome of pregnancy and the disease course among women with aplastic anemia who received immunosuppressive therapy. Design: Retrospective multicenter study. Setting: Twelve cen...

Pancreatic islet allograft in spleen with immunosuppression with cyclosporine. Experimental model in dogs.

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Waisberg, Jaques; Neff, Charles Benjamin; Waisberg, Daniel Reis; Germini, Demetrius; Gonçalves, José Eduardo; Zanotto, Arnaldo; Speranzini, Manlio Basilio

2011-01-01

To study the functional behavior of the allograft with immunosuppression of pancreatic islets in the spleen. Five groups of 10 Mongrel dogs were used: Group A (control) underwent biochemical tests; Group B underwent total pancreatectomy; Group C underwent total pancreatectomy and pancreatic islet autotransplant in the spleen; Group D underwent pancreatic islet allograft in the spleen without immunosuppressive therapy; Group E underwent pancreatic islet allograft in the spleen and immunosuppression with cyclosporine. All of the animals with grafts received pancreatic islets prepared by the mechanical-enzymatic method - stationary collagenase digestion and purification with dextran discontinuous density gradient, implanted in the spleen. The animals with autotransplant and those with allografts with immunosuppression that became normoglycemic showed altered results of intravenous tolerance glucose (p < 0.001) and peripheral and splenic vein plasmatic insulin levels were significantly lower (p < 0.001) in animals that had allografts with immunosuppression than in those with just autotransplants. In the animals with immunosuppression with cyclosporine subjected to allograft of pancreatic islets prepared with the mechanical-enzymatic preparation method (stationary collagenase digestion and purification with dextran discontinuous density gradient), the production of insulin is decreased and the response to intravenous glucose is altered.

The role of immunosuppression of mesenchymal stem cells in tissue repair and tumor growth

OpenAIRE

Han Zhipeng; Jing Yingying; Zhang Shanshan; Liu Yan; Shi Yufang; Wei Lixin

2012-01-01

Abstract Mesenchymal stem cells (MSCs) have acquired great interests for their potential use in the clinical therapy of many diseases because of their functions including multiple lineage differentiation, low immunogenicity and immunosuppression. Many studies suggest that MSCs are strongly immunosuppressive in vitro and in vivo. MSCs exert a profound inhibitory effect on the proliferation of T cells, B cells, dendritic cells and natural killer cells. In addition, several soluble factors have ...

Menopause in women with chronic immunosuppressive treatment - how to help those patients.

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Cyganek, Anna; Pietrzak, Bronisława; Wielgoś, Mirosław; Grzechocińska, Barbara

2016-03-01

Women after organ transplantation with chronic immunosuppressive therapy or after bone marrow transplantation without such therapy are a growing group of patients. Although their problems in the peri- and postmenopausal period are the same as in healthy women, due to the primary disease and treatment applied they represent a huge challenge from the point of view of their hormonal treatment of menopause. Transplanted women have no particular contraindications for hormonal therapy use. General contraindications, however, such as arterial hypertension, thrombosis in medical history, diabetes, endometriosis, myomas, or active neoplastic disease, have a higher incidence in this group of patients than in healthy women, which significantly influences the possibility of using hormonal therapy. On the other hand, taking into consideration the predisposition for premature menopause in this group, in combination with chronic immunosuppression, it predisposes these patients for higher cardiovascular disease incidence and bone density loss, so hormonal therapy would be highly advisable. Therapy management in transplanted patients requires special care and close monitoring of the transplanted organ. Saving lives with organ transplantation is one of the greatest achievements of contemporary medicine. For long-term improvement of their quality of life, emphasis should be put on regular diagnostic examinations, early detection of abnormalities, and introduction of effective treatment.

Menopause in women with chronic immunosuppressive treatment ? how to help those patients

OpenAIRE

Cyganek, Anna; Pietrzak, Bronis?awa; Wielgo?, Miros?aw; Grzechoci?ska, Barbara

2016-01-01

Women after organ transplantation with chronic immunosuppressive therapy or after bone marrow transplantation without such therapy are a growing group of patients. Although their problems in the peri- and postmenopausal period are the same as in healthy women, due to the primary disease and treatment applied they represent a huge challenge from the point of view of their hormonal treatment of menopause. Transplanted women have no particular contraindications for hormonal therapy use. General ...

Immunosuppressive therapy in glomerular diseases: major accomplishment of Tadeusz Orłowski and his school.

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Smogorzewski, Mirosław J; Lao, Mieczysław; Gradowska, Liliana; Rowińska, Danuta; Rancewicz, Zofia

2009-05-01

Glomerulopathies are the third most common cause of end-stage renal failure. Immunosuppressive treatment of glomerulonephritis in a systematic way was introduced in Poland by Professor Tadeusz Orłowski in the early 1960s. The studies were conducted at the First Department of Medicine and at the Transplantation Institute of the Medical Academy in Warsaw in the years 1962-1988. This paper critically reviews the results of studies on the use of combined, triple-drug (prednisone/chlorambucil/azathioprine), immunosuppressive protocol in various pathological forms of glomerulopathies. We conclude that immunosuppressive protocols pioneered by Tadeusz Orłowski continue to be the backbone of the treatment of glomerulonephritis, especially the one with nephrotic syndrome, progressive impairment of kidney function and poor prognosis.

ATG-Fresenius S combined with cyclosporine a: an effective immunosuppressive therapy for children with aplastic anemia.

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Luo, Cheng-Juan; Gao, Yi-Jin; Tang, Jing-Yan; Zhu, Xiao-Hua; Xue, Hui-Liang; Lu, Feng-Juan; Pan, Ci; Jiang, Hua; Luo, Chang-Ying; Ye, Qi-Dong; Zhou, Min; Chen, Jing

2014-07-01

For the first time, we conducted a 2-center retrospective study to show the efficacy of antithymocyte globulin (ATG)-Fresenius S plus cyclosporine treatment of children with severe aplastic anemia. From March 1997 to May 2011, a total of 124 patients (median age, 7.5 y; range, 1.5 to 16 y) from 2 centers with acquired AA treated with an immunosuppressive therapy (IST) regimen, consisting of ATG-Fresenius S (5 mg/kg per day for 5 d) and cyclosporine, were enrolled. The response rate was 55.6%. The median time between IST and response was 6 (0.5 to 18) months. After a median follow-up time of 29 (6 to 153) months, the rates of relapse and clonal evolution were 3.2% and 0.8%, respectively. Overall, 17 patients (13.7%) died in this study: 14 resulted from sepsis, 1 resulted from intracranial hemorrhage, 1 occurred after hematopoietic stem cell transplantation, and 1 resulted from clonal disease progression. The 5-year overall survival rate for the entire cohort was 74.7%. IST responders had a better survival rate (100%) than nonresponders (70.7%). The use of ATG-Fresenius S plus cyclosporine as a first-line immunosuppressive treatment appeared to be effective for children with severe aplastic anemia in our study. ATG-Fresenius S could be another option in the treatment arsenal, especially in countries where the other ATG products are harder to acquire.

Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?

OpenAIRE

Passweg, Jakob R.; Tichelli, André

2009-01-01

The combination of antithymocyte globulin of horse origin and cyclosporine A is the standard treatment for aplastic anemia in patients not eligible for bone marrow transplantation. In this perspective article, Drs. Passweg and Tichelli discuss the current immunosuppressive therapy of aplastic anemia. See related article on page 348.

Immunosuppressants

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... Brain Death HIV and Kidney Transplantation/Donation Incompatible Blood Types and Paired Exchange Programs Knowing Your Immunosuppressive (anti-rejection) Medications Organ and Tissue Donation The National Kidney ...

Menopause in women with chronic immunosuppressive treatment – how to help those patients

Directory of Open Access Journals (Sweden)

Anna Cyganek

2016-03-01

Full Text Available Women after organ transplantation with chronic immunosuppressive therapy or after bone marrow transplantation without such therapy are a growing group of patients. Although their problems in the peri- and postmenopausal period are the same as in healthy women, due to the primary disease and treatment applied they represent a huge challenge from the point of view of their hormonal treatment of menopause. Transplanted women have no particular contraindications for hormonal therapy use. General contraindications, however, such as arterial hypertension, thrombosis in medical history, diabetes, endometriosis, myomas, or active neoplastic disease, have a higher incidence in this group of patients than in healthy women, which significantly influences the possibility of using hormonal therapy. On the other hand, taking into consideration the predisposition for premature menopause in this group, in combination with chronic immunosuppression, it predisposes these patients for higher cardiovascular disease incidence and bone density loss, so hormonal therapy would be highly advisable. Therapy management in transplanted patients requires special care and close monitoring of the transplanted organ. Saving lives with organ transplantation is one of the greatest achievements of contemporary medicine. For long-term improvement of their quality of life, emphasis should be put on regular diagnostic examinations, early detection of abnormalities, and introduction of effective treatment.

Progressive outer retinal necrosis and immunosuppressive therapy in myasthenia gravis.

Science.gov (United States)

Coisy, Solène; Ebran, Jean-Marc; Milea, Dan

2014-01-01

Progressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss. A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.

Surveillance of polyomavirus BK in relation to immunosuppressive therapy in kidney transplantation

Directory of Open Access Journals (Sweden)

Cristina Costa

2012-03-01

Full Text Available Introduction. Reactivation of polyomavirus BK in kidney transplant recipients has been associated to the development of nephropathy (polyomavirus-associated nephropathy, PVAN, possibly leading to the loss of the transplanted organ. Immunosuppression is the condicio sine qua non for the onset of PVAN; however, a lower incidence of BK viremia has been reported with low-level tacrolimus based immunosuppressive protocols in comparison to cyclosporine A.Aim of this study was to compare the two immunosuppressive protocols. Methods. Virological monitoring of BK was performed in 468 consecutive renal transplant patients over a period of 3 years (2370 urine e 2370 serum specimens: in particular, 1780 specimens from 362 patients treated with tacrolimus and 590 from 106 treated with cyclosporine A. Results. BK viremia was evidenced in 124 (7.0% and 12 (2.0% specimens from 40 (11.0% and 11 (10.4% patients treated with tacrolimus and cyclosporine A, respectively; similarly, BK viruria in 289 (16.2% and 58 (9.8% specimens from 67 (18.5% and 27 (25.5% patients, being the difference of incidence highly significant (p <0.0001 for both viremia and viruria at comparison between specimens and not significant for patients. No case of PVAN was diagnosed at histophatology evaluation. Conclusions. The incidence of viremia and viruria was similar to that previously reported. Our results evidenced that with low-level tacrolimus-based protocols the overall incidence of reactivation in renal transplant patients is not significantly different and there is no increased risk of PVAN, nevertheless the higher incidence of episodes of reactivation.

The Use of Immunosuppressant Therapy for Multiple Sclerosis in Italy: A Multicenter Retroprospective Study.

Directory of Open Access Journals (Sweden)

Emanuele D'Amico

Full Text Available Immunosuppressive agents (ISA have been used in multiple sclerosis (MS for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS?We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use.Out of 6,447 MS patients, 2,034 (31.6% were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary of the disease (RRR 5.82, 95% CI 4.14-8.16, p<0.0001, had higher EDSS (RRR 3.69, 95% CI 2.61-5.21, p<0.0001, higher assignment age (RRR 1.04, 95% CI 1.03-1.06, p<0.0001 than patients treated with only disease modifying drugs (DMDs.Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population.

CD54-Mediated Interaction with Pro-inflammatory Macrophages Increases the Immunosuppressive Function of Human Mesenchymal Stromal Cells

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Nicolas Espagnolle

2017-04-01

Full Text Available Summary: Mesenchymal stromal cells (MSCs sense and modulate inflammation and represent potential clinical treatment for immune disorders. However, many details of the bidirectional interaction of MSCs and the innate immune compartment are still unsolved. Here we describe an unconventional but functional interaction between pro-inflammatory classically activated macrophages (M1MΦ and MSCs, with CD54 playing a central role. CD54 was upregulated and enriched specifically at the contact area between M1MФ and MSCs. Moreover, the specific interaction induced calcium signaling and increased the immunosuppressive capacities of MSCs dependent on CD54 mediation. Our data demonstrate that MSCs can detect an inflammatory microenvironment via a direct and physical interaction with innate immune cells. This finding opens different perspectives for MSC-based cell therapy. : Mesenchymal stromal cells (MSCs are promising for cell-based therapy in inflammatory disorders by switching off the immune response. Varin and colleagues demonstrate that MSCs and inflammatory macrophages communicate via an unconventional but functional interaction that strongly increases the immunosuppressive capacities of MSCs. This new communication between the innate immune system and MSCs opens new perspectives for MSC-based cell therapy. Keywords: macrophages, bone marrow mesenchymal stromal cells, functional interaction, CD54, immunosuppression, indoleamine 2,3-dioxygenase, cell therapy

Candida albicans gastrointestinal colonization and invasion in the mouse: effect of antibacterial dosing, antifungal therapy and immunosuppression.

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Kinsman, O S; Pitblado, K

1989-12-01

Infant mice infected with Candida albicans by the oral-intragastric route became colonized in the gut and were persistently colonized into adulthood. Faecal levels of Candida were correlated with total gastrointestinal Candida and provided a useful means of detecting yeast overgrowth or elimination. Antibacterial agents promoting Candida overgrowth when given by the oral or parenteral route included ceftriaxone, augmentin and cefoperazone. Ceftizoxime had less effect. Ceftazidime and latamoxef produced raised levels only by the oral route. Gentamicin, vancomycin and metronidazole did not affect the Candida levels. Dosing with some antibacterials promoted an increase in gastrointestinal Candida and invasion to a greater extent than immunosuppression. Antifungal therapy to reduce gastrointestinal colonization was investigated using amphotericin B, nystatin, ketoconazole, intraconazole and fluconazole. Fluconazole was most effective at reducing faecal Candida.

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

Science.gov (United States)

Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

2012-07-05

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Progressive Outer Retinal Necrosis and Immunosuppressive Therapy in Myasthenia Gravis

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Solène Coisy

2014-04-01

Full Text Available Introduction: Progressive outer retinal necrosis (PORN is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV and responsible for severe visual loss. Case Report: A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. Conclusion: VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.

Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report.

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Schultze, Detlev; Mani, Bernhard; Dollenmaier, Günter; Sahli, Roland; Zbinden, Andrea; Krayenbühl, Pierre Alexandre

2015-10-29

Hepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA). A 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy. In immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended--as in our case--if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.

EFFECTIVENESS AND SAFETY OF RECOMBINANT HUMAN GRANULOCYTIC COLONY-STIMULATING FACTOR IN TREATMENT OF GRANULOCYTOPENIA DEVELOPED DURING IMMUNOSUPPRESSIVE THERAPY IN PATIENTS WITH JUVENILE RHEUMATOID ARTHRITIS

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E.I. Alexeeva

2010-01-01

Full Text Available Treatment of patients with severe clinical course of juvenile rheumatoid arthritis (JRA is difficult problem. During the last years genetically engineered biological drugs are used equally with traditional immunosuppressive agents in treatment of severe forms of juvenile arthritis. High effectiveness of these drugs can be accompanied with development of unfavorable effects, for example, febrile neutropenia. The article presents results of a study of effectiveness and safety of recombinant human granulocytic colony-stimulating factor — filgrastim (Leucostim — in treatment of granulocytopenia developed during immunosuppressive therapy in 16 patients with JRA. It was shown that administration of filgrastim arrests leucopenia in 100% of patients and granulocytopenia — in 93% of patients in 24 hours after first injection. High effectiveness of drug was combined with good tolerability and safety.Key words: children, treatment, granulocytopenia, filgrastim, juvenile rheumatoid arthritis.(Voprosy sovremennoi pediatrii — Current Pediatrics. – 2010;9(4:94-100

Endolymphatic irradiation. A useful method for immunosuppression in renal transplantation

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Galvao, M.M.; Ianhez, L.E.; Sabbaga, E. (Sao Paulo Univ. (Brazil). Faculdade de Medicina)

1982-02-01

The authors analysed the clinical evolution and the result of renal transplantation some years after irradiation in 24 patients (group I) who received endolymphatic /sup 131/I as a pre-transplantation immunosuppresive measure. The control group (group II) consisted of 24 non-irradiated patients comparable to group I in age, sex, primary disease, type of donor and immunosuppressive therapy. Significant differences were observed between the two groups regarding such factors as incidence and reversibility of rejection crises in the first 60 post-transplantation days, loss of kidney due to rejection, and dosage of azathioprine. The authors conclude that this method, besides being harmless, has prolonged immunosuppressive action, its administration being advised for receptors of cadaver kidneys, mainly those who show positive cross-match against HLA antigens for painel.

A Rationale for Age-Adapted Immunosuppression in Organ Transplantation.

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Krenzien, Felix; ElKhal, Abdallah; Quante, Markus; Rodriguez Cetina Biefer, Hector; Hirofumi, Uehara; Gabardi, Steven; Tullius, Stefan G

2015-11-01

Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older than 50 years, and organs from elderly donors are more frequently used. Nevertheless, the benefit of transplantation in older patients is well recognized, whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants.Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections, and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients, whereas the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus after transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors.This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly.

Immunosuppressant-Associated Neurotoxicity Responding to Olanzapine

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James A. Bourgeois

2014-01-01

Full Text Available Immunosuppressants, particularly tacrolimus, can induce neurotoxicity in solid organ transplantation cases. A lower clinical threshold to switch from tacrolimus to another immunosuppressant agent has been a common approach to reverse this neurotoxicity. However, immunosuppressant switch may place the graft at risk, and, in some cases, continuation of the same treatment protocol may be necessary. We report a case of immunosuppressant-associated neurotoxicity with prominent neuropsychiatric manifestation and describe psychiatric intervention with olanzapine that led to clinical improvement while continuing tacrolimus maintenance.

Cutaneous lymphoproliferative disorder complicating infectious mononucleosis in an immunosuppressed patient.

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Owen, Cindy England; Callen, Jeffrey P; Bahrami, Soon

2011-01-01

Infectious mononucleosis is the syndrome produced by primary infection with Epstein-Barr virus during adolescence or early adulthood. In immunosuppressed individuals, depressed T-cell function allows the Epstein-Barr virus-driven B-cell proliferation to continue unabated, potentially leading to a lymphoproliferative disorder. A 15-year-old girl with a history of ulcerative colitis treated with 6-mercaptopurine and mesalamine presented with the acute onset of a rapidly enlarging, ulcerative nodule on her left lower eyelid 4 weeks following recovery from infectious mononucleosis. The biopsy revealed an Epstein-Barr virus-positive lymphoproliferative disorder. Systemic disease was absent. Following discontinuation of 6-mercaptopurine, the patient was treated with two courses of intravenous cyclophosphamide. The lesion resolved completely and she remains disease free at 14 months following diagnosis. We report a solitary cutaneous lesion of an immunosuppression-related lymphoproliferative disorder (IR-LPD) occurring as a complication of infectious mononucleosis, and review the pathogenesis and reported cases of Epstein-Barr virus-related immunosuppression-related lymphoproliferative disorder arising in the setting of inflammatory bowel disease. It is important for dermatologists and dermatopathologists to be aware of the occurrence of IR-LPD in patients being treated for inflammatory conditions, including inflammatory bowel disease. Given the role of primary infection with Epstein-Barr virus in the development of IR-LPD, consideration may be given to assessing Epstein-Barr virus status prior to initiating immunosuppressive therapy in young patients. © 2010 Wiley Periodicals, Inc.

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

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Aron Badin, R; Vadori, M; Vanhove, B; Nerriere-Daguin, V; Naveilhan, P; Neveu, I; Jan, C; Lévèque, X; Venturi, E; Mermillod, P; Van Camp, N; Dollé, F; Guillermier, M; Denaro, L; Manara, R; Citton, V; Simioni, P; Zampieri, P; D'avella, D; Rubello, D; Fante, F; Boldrin, M; De Benedictis, G M; Cavicchioli, L; Sgarabotto, D; Plebani, M; Stefani, A L; Brachet, P; Blancho, G; Soulillou, J P; Hantraye, P; Cozzi, E

2016-07-01

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Clinical aspects of immunosuppression in poultry.

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Hoerr, Frederic J

2010-03-01

Chickens, turkeys, and other poultry in a production environment can be exposed to stressors and infectious diseases that impair innate and acquired immunity, erode general health and welfare, and diminish genetic and nutritional potential for efficient production. Innate immunity can be affected by stressful physiologic events related to hatching and to environmental factors during the first week of life. Exposure to environmental ammonia, foodborne mycotoxins, and suboptimal nutrition can diminish innate immunity. Infectious bursal disease (IBD), chicken infectious anemia (CIA), and Marek's disease (MD) are major infectious diseases that increase susceptibility to viral, bacterial, and parasitic diseases and interfere with acquired vaccinal immunity. A shared feature is lymphocytolytic infection capable of suppressing both humoral and cell-mediated immune functions. Enteric viral infections can be accompanied by atrophic and depleted lymphoid organs, but the immunosuppressive features are modestly characterized. Some reoviruses cause atrophy of lymphoid organs and replicate in blood monocytes. Enteric parvoviruses of chickens and turkeys merit further study for immunosuppression. Hemorrhagic enteritis of turkeys has immunosuppressive features similar to IBD. Other virulent fowl adenoviruses have immunosuppressive capabilities. Newcastle disease can damage lymphoid tissues and macrophages. Avian pneumovirus infections impair the mucociliary functions of the upper respiratory tract and augment deeper bacterial infections. Recognition of immunosuppression involves detection of specific diseases using diagnostic tests such as serology, etiologic agent detection, and pathology. Broader measurements of immunosuppression by combined noninfectious and infectious causes have not found general application. Microarray technology to detect genetic expression of immunologic mediators and receptors offers potential advances but is currently at the developmental state. Control

Cancer immunotherapy by immunosuppression

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Prehn Liisa M

2010-12-01

Full Text Available Abstract We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis.

Current methods of the analysis of immunosuppressive agents in clinical materials: A review.

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Mika, Adriana; Stepnowski, Piotr

2016-08-05

More than 100000 solid organ transplantations are performed every year worldwide. Calcineurin (cyclosporine A, tacrolimus), serine/threonine kinase (sirolimus, everolimus) and inosine monophosphate dehydrogenase inhibitor (mycophenolate mofetil), are the most common drugs used as immunosuppressive agents after solid organ transplantation. Immunosuppressive therapy, although necessary after transplantation, is associated with many adverse consequences, including the formation of secondary metabolites of drugs and the induction of their side effects. Calcineurin inhibitors are associated with nephrotoxicity, cardiotoxicity and neurotoxicity; moreover, they increase the risk of many diseases after transplantation. The review presents a study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation and excretion, and also their accompanying side effects. Therefore, there is a necessity to monitor immunosuppressants, especially because these drugs are characterised by narrow therapeutic ranges. Their incorrect concentrations in a patient's blood could result in transplant rejection or in the accumulation of toxic effects. Immunosuppressive pharmaceuticals are macrolide lactones, peptides, and high molecular weight molecules that can be metabolised to several metabolites. Therefore the two main analytical methods used for their determination are high performance liquid chromatography with various detection methods and immunoassay methods. Despite the rapid development of new analytical methods of analysing immunosuppressive agents, the application of the latest generation of detectors and increasing sensitivity of such methods, there is still a great demand for the development of highly selective, sensitive, specific, rapid and relatively simple methods of immunosuppressive drugs analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Successful Immunosuppressive Therapy for Severe Infectious Mononucleosis in a Patient with Clonal Proliferation of EBV-infected CD8-positive Cells.

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Hosoi, Hiroki; Sonoki, Takashi; Murata, Shogo; Mushino, Toshiki; Kuriyama, Kodai; Nishikawa, Akinori; Hanaoka, Nobuyoshi; Ohshima, Koichi; Imadome, Ken-Ichi; Nakakuma, Hideki

2015-01-01

A 30-year-old woman was diagnosed with severe infectious mononucleosis (IM). The Epstein-Barr virus (EBV) had infected both CD19- and CD8-positive cells, and clonal proliferation of EBV-infected cells and T-cells was detected. Although we suspected malignant lymphoma, her condition improved following immunosuppressive therapy. A similar case was recently reported; therefore, this case is the second case of IM with EBV-infected CD8-positive cells and clonal proliferation of EBV-infected cells. Our results demonstrate that the clonal proliferation of EBV-infected cells is not always an indication for chemotherapy in the primary infection phase and that monitoring the EBV viral load is useful for therapeutic decision-making.

Exploring risk factors of non-adherence to immunosuppressive medication in kidney transplant recipients : improving methodology & reorienting research goals

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Denhaerynck, Kris

2006-01-01

8.1. Background and aim of the research program Non-adherence to the immunosuppressive therapy is an important issue in kidney transplant patients. About 20% of the kidney transplant patients are non-adherent to the immunosuppressive regimen. Non-adherence contributes to 20% of late acute rejection episodes and 16% of the graft losses, and results in a decreased number of quality adjusted life years. A strategy to increase long-term successful outcome after transplantation i...

Endogenous nocardial endophthalmitis in an immunosuppressed patient: A serious warning of an underlying life threatening and blinding disorder

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Hemant Trehan

2017-01-01

Conclusion: Ocular nocardiosis is a serious vision and life threatening disorder, particularly in patients on immunosuppressive therapy. A high index of suspicion is required for successful treatment.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial

NARCIS (Netherlands)

Khanna, Reena; Bressler, Brian; Levesque, Barrett G.; Zou, Guangyong; Stitt, Larry W.; Greenberg, Gordon R.; Panaccione, Remo; Bitton, Alain; Paré, Pierre; Vermeire, Séverine; D'Haens, Geert; MacIntosh, Donald; Sandborn, William J.; Donner, Allan; Vandervoort, Margaret K.; Morris, Joan C.; Feagan, Brian G.; Anderson, Frank; Atkinson, Kenneth; Bacchus, Rahman; Berezny, Gary; Borthistle, Bruce; Buckley, Alan; Chiba, Naoki; Cockeram, Alan; Elkashab, Magdy; Fashir, Baroudi; Gray, James; Hemphill, Douglas; Hoare, Connie; Holland, Stephen; Hurowitz, Eric; Kaal, Nuri; Laflamme, Pierre; Borromee, Saint-Charles; Lau, Helena; McMullen, William; Memiche, Reshat; Menon, Krishna; Miller, D. Alexander; O'Hara, William; Oravec, Michael; Penner, Robert; Petrunia, Denis; Pluta, Henryk; Prabhu, Umesh; Prest, Marcia; Shaaban, Hani; Sheppard, Duane; Shulman, Scott

2015-01-01

Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of

Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus.

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Sindhi, R; Webber, S; Venkataramanan, R; McGhee, W; Phillips, S; Smith, A; Baird, C; Iurlano, K; Mazariegos, G; Cooperstone, B; Holt, D W; Zeevi, A; Fung, J J; Reyes, J

2001-09-15

The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease. Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21). SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.

Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy

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Hiroyuki Horiguchi

2018-04-01

Full Text Available Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI, defined as ≥14 days requiring intensive care unit (ICU resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS, and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients.

Immunosuppressive drugs and fertility.

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Leroy, Clara; Rigot, Jean-Marc; Leroy, Maryse; Decanter, Christine; Le Mapihan, Kristell; Parent, Anne-Sophie; Le Guillou, Anne-Claire; Yakoub-Agha, Ibrahim; Dharancy, Sébastien; Noel, Christian; Vantyghem, Marie-Christine

2015-10-21

Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs.

Patient survey to identify reasons for non-adherence and elicitation of quality of life concepts associated with immunosuppressant therapy in kidney transplant recipients.

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Muduma, Gorden; Shupo, Francis C; Dam, Sophie; Hawken, Natalia A; Aballéa, Samuel; Odeyemi, Isaac; Toumi, Mondher

2016-01-01

Renal transplantation (RT) is considered the treatment of choice for end-stage renal disease compared to dialysis, offering better health-related quality of life (HRQoL) and higher survival rates. However, immunosuppressants are essential for the long-term survival of kidney grafts and patients' non-adherence to their medication leads to poor outcomes. Immunosuppressants can also significantly alter patients' HRQoL because of their side effects and the complex chronic medication regimen they represent. To elicit key concepts related to adherence to immunosuppressant therapy (IT) and reasons for non-adherence in terms of patient reported outcomes, side effects, and the impact of the medication on HRQoL in RT population, including patient preference of once daily over twice-daily immunosuppressive regimen. Results were used to develop an IT-specific conceptual framework and provide suggestions for improving patients' adherence to IT. Interviews were conducted with three clinical experts to determine key concepts related to RT and immunosuppressants. Thirty-seven participants in four focus groups were asked to cite important concepts related to adherence and impact of IT on HRQoL and to rate them. Qualitative analysis was conducted to code participants' responses. Non-adherence among participants where admitted was unintentional. The reason for this included forgetfulness, interference with lifestyle, being asleep at the time the medication should be taken, change in routine, and impact of side effects. Overall, participants reported that the evening dose was more problematic to remember and that the exclusion of this dose could make them more adherent. Participants also reported that IT impacted on their HRQoL in a number of ways including: placing restrictions on their lifestyle, causing anxiety, or impairing their ability to work. This study provides qualitative evidence about the barriers to IT adherence and the components of HRQoL that are important from the

Immunosuppressive drugs and fertility

OpenAIRE

Leroy, Clara; Rigot, Jean-Marc; Leroy, Maryse; Decanter, Christine; Le Mapihan, Kristell; Parent, Anne-Sophie; Le Guillou, Anne-Claire; Yakoub-Agha, Ibrahim; Dharancy, Sébastien; Noel, Christian; Vantyghem, Marie-Christine

2015-01-01

Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior ...

6-methylprednisolone does not impair anti-thymocyte globulin (ATG) immunosuppressive activity in non-human primates

NARCIS (Netherlands)

Preville, [No Value; Sick, E; Beauchard, S; Ossevoort, M; Tiollier, J; Revillard, JP; Jonker, Margreet

2001-01-01

Background: Induction treatments with anti-thymocyte globulin (ATG) in solid organ transplantation may enhance the efficacy of maintenance immunosuppressive therapy. Since ATG can trigger Fas (CD95) mediated T cell apoptosis, a process antagonized in vitro by corticosteroids, an important issue is

Ocular toxoplasmosis in immunosuppressed nonhuman primates

International Nuclear Information System (INIS)

Holland, G.N.; O'Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

1988-01-01

To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease

Ocular toxoplasmosis in immunosuppressed nonhuman primates

Energy Technology Data Exchange (ETDEWEB)

Holland, G.N.; O' Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

1988-06-01

To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease.

Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells.

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Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-Ichiro

2016-10-15

The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy. Cancer Res; 76(20); 6030-42. ©2016 AACR. ©2016 American Association for Cancer Research.

Established and novel disease-modifying treatments in multiple sclerosis.

Science.gov (United States)

Cross, A H; Naismith, R T

2014-04-01

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e

Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis

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Sotsiou Florentia

2005-12-01

Full Text Available Abstract Background Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β1 is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β1 levels in patients with crescentic nephritis could be used as a marker of response to treatment. Methods Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β1 was estimated in biopsy sections by immunohistochemistry and urinary TGF-β1 levels were determined by quantitative sandwich enzyme immunoassay (EIA. TGF-β1 levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange. Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. Results Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively. In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β1 levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p 1 was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β1 immunostaining with the presence

Reactivation of tuberculosis during immunosuppressive treatment in a patient with a positive QuantiFERON-RD1 test

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Ravn, Pernille; Munk, Martin E; Andersen, Ase Bengaard

2004-01-01

A patient with polymyositis developed tuberculosis during immunosuppressive treatment. Tuberculin Skin Test and chest X-ray failed to demonstrate latent tuberculosis, whereas a blood sample that was tested with a modified QuantiFERON-TB-assay, using the recombinant ESAT-6 and CFP-10, was positive...... indicating that this patient was latently infected before immunosuppressive therapy. This case indicates the risk of progressing from latent to active tuberculosis given that the subject is RD1 responsive, and we believe that preventive anti-tuberculous treatment could have prevented this case...

Immunomodulator, immunosuppression of radiation and immune reconstruction

International Nuclear Information System (INIS)

Mao Jianping; Fang Jing; Zhou Ying; Cui Yufang; Jiang Zhujun; Du Li; Ma Qiong

2010-01-01

There is a refined and complicated regulatory network between immune cells, and between immune cells and secretory factors. The immune system is kept in a homeostasis and equilibrium by positive activation and negative inhibition. In recent years, the mechanisms of immunosuppression in depth for successful allograft transplantation were studied, and many immunosuppressants and immunosuppressive drugs have been developed for clinical use. Most of them are targeting T cell receptors and three kinds of singnal pathways. The receptors of the immunosuppression were either found highly expressed in immune cells after irradiation. To relieve the suppression by regulating the receptors could help the immune reconstruction out of radiation damage. Many new immunoenhancers have been discovered to improve the immune system function for radiation by Toll-like receptors. The search for new immunoenhancers and agents for relieving immunosuppression is of great importance to immune construction for radiation sickness. (authors)

Predominant or complete recipient T-cell chimerism following alemtuzumab-based allogeneic transplantation is reversed by donor lymphocytes and not associated with graft failure.

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Mohamedbhai, Sajir G; Edwards, Noha; Morris, Emma C; Mackinnon, Stephen; Thomson, Kirsty J; Peggs, Karl S

2012-02-01

The clinical significance of mixed chimerism following allogeneic haematopoietic stem cell transplantation (HSCT) remains controversial. Its relevance and incidence are probably influenced by the conditioning regimen and incorporation of T-cell depletion. The presence of recipient chimerism levels >40-50% following T-cell replete reduced intensity transplantation correlates with a high risk of graft rejection, regardless of donor-lymphocyte infusions, but it is unclear whether this finding translates to T-cell depleted transplants. We conducted a retrospective single-institution analysis of patients receiving alemtuzumab-based HSCT. 27/152 (18%) evaluable cases had predominantly recipient T-cell chimerism at 3 months or beyond. By contrast, coincident chimerism in the granulocyte lineage was predominantly of donor origin (median 100%) in all but one patient. Donor lymphocyte infusion effectively converted predominantly recipient T-cell chimerism to ful donor chimerism in all evaluable cases including three cases with no detectable donor T cells. The only graft failure occurred in the patient with predominantly recipient myeloid chimerism in whom rejection occurred rapidly before donor lymphocytes could be administered. We conclude that predominant or complete recipient T-cell chimerism following alemtuzumab-based regimens does not have the same clinical implications as that following T-cell replete transplants and can be effectively converted with donor lymphocytes without the need for lympho-depleting agents or re-conditioning. © 2011 Blackwell Publishing Ltd.

Perioperative single high dose ATG-Fresenius S administration as induction immunosuppressive therapy in cadaveric renal transplantation--preliminary results.

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Samsel, R; Chmura, A; Włodarczyk, Z; Wyzgał, J; Cieciura, T; Lagiewska, B; Pliszczyński, J; Korczak, G; Lazowski, T; Paczek, L; Wałaszewski, J; Lao, M; Rowiński, W

1999-01-01

Monoclonal and polyclonal antilymphocyte antibodies have been used successfully in organ transplantation as induction therapy and in the treatment of acute graft rejection. Used for induction the medication is generally given for the first 7-10 days. The aim of this study was to assess the safety and efficacy of single high dose (9 mg/kg) ATG Fresenius S given perioperatively, before revascularization, to kidney allograft recipients. During last twelve months seventy six, first cadaveric kidney adult recipients were included into the study in two centers (center A-64, center B-12). All patients received triple drug immunosuppression (Neoral, steroids and Cellcept which was replaced by azathioprine after 4 months), and were randomized to receive ATG or not. The follow-up period ranged from 1 month up to 1 year. The preliminary results are very promising, the rejection rate in bolus group was significantly lower than in control. No significant side effects or serious adverse events in both groups were observed.

Cost utility analysis of immunosuppressive regimens in adult renal transplant recipients in England and Wales

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Muduma G

2014-11-01

Full Text Available Gorden Muduma,1 Jane Shaw,2 Warren M Hart,3 Abayomi Odeyemi,3 Isaac Odeyemi21Astellas Pharma Europe Limited, Chertsey, UK; 2Astellas Pharma Limited, Chertsey, UK; 3EcoStat Consulting UK Limited, London, UKBackground: End-stage renal disease is the irreversible final stage of chronic kidney disease and is fatal when not managed by either transplantation or dialysis. Transplantation is generally preferred over dialysis. However, to prevent graft rejection or loss, lifelong immunosuppression is required. Tacrolimus is currently the cornerstone of post-transplantation immunosuppression. The study aim was to carry out an economic evaluation of immunosuppression, including more recent agents such as a once-daily prolonged-release formulation of tacrolimus (Advagraf™ and belatacept, relative to a twice-daily immediate-release formulation of tacrolimus (Prograf™.Methods: A model was constructed comprising six states: onset of biopsy-confirmed acute rejection, functioning graft with or without a biopsy-confirmed acute rejection, non-functioning graft (dialysis, re-transplantation, and death. Data on clinical effectiveness were derived from a systematic literature review and the model captured the effects of patient adherence to immunosuppressant therapy on graft survival using relative risk of graft survival and published data on adherence in patients using Advagraf and Prograf. In the base case, the time horizon was 25 years and one-way and probabilistic sensitivity analyses were conducted.Results: The analysis demonstrated that Prograf was cost-effective when compared with cyclosporin and belatacept and was more effective than sirolimus, but would not be considered cost-effective against sirolimus. The modeled improvement in the adherence profile of patients using Advagraf relative to Prograf resulted in both improved clinical outcomes and reduced costs. Conclusion: Prograf was more clinically effective than cyclosporin, belatacept, and sirolimus

Patient survey to identify reasons for non-adherence and elicitation of quality of life concepts associated with immunosuppressant therapy in kidney transplant recipients

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Muduma G

2016-01-01

Full Text Available Gorden Muduma,1 Francis C Shupo,2 Sophie Dam,3 Natalia A Hawken,3 Samuel Aballéa,3 Isaac Odeyemi,1 Mondher Toumi4 1Astellas Pharma Europe Ltd, Chertsey, 2Creativ-Ceutical Ltd, London, UK; 3Creativ-Ceutical Ltd, Paris, 4Public Health (EA 3279, Faculty of Medicine, Aix-Marseille University, Marseille, France Background: Renal transplantation (RT is considered the treatment of choice for end-stage renal disease compared to dialysis, offering better health-related quality of life (HRQoL and higher survival rates. However, immunosuppressants are essential for the long-term survival of kidney grafts and patients’ non-adherence to their medication leads to poor outcomes. Immunosuppressants can also significantly alter patients’ HRQoL because of their side effects and the complex chronic medication regimen they represent. Purpose: To elicit key concepts related to adherence to immunosuppressant therapy (IT and reasons for non-adherence in terms of patient reported outcomes, side effects, and the impact of the medication on HRQoL in RT population, including patient preference of once daily over twice-daily immunosuppressive regimen. Results were used to develop an IT-specific conceptual framework and provide suggestions for improving patients’ adherence to IT. Materials and methods: Interviews were conducted with three clinical experts to determine key concepts related to RT and immunosuppressants. Thirty-seven participants in four focus groups were asked to cite important concepts related to adherence and impact of IT on HRQoL and to rate them. Qualitative analysis was conducted to code participants’ responses. Results: Non-adherence among participants where admitted was unintentional. The reason for this included forgetfulness, interference with lifestyle, being asleep at the time the medication should be taken, change in routine, and impact of side effects. Overall, participants reported that the evening dose was more problematic to remember

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression.

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Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-06-02

To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Retrospective multicenter study using the Swiss Pediatric Rheumatology registry. Children with rheumatic diseases followed in a Swiss center for pediatric rheumatology and treated with cDMARD and/or bDMARD with a clinical diagnosis of varicella or herpes zoster between January 2004 and December 2013 were included. Twenty-two patients were identified, of whom 20 were treated for juvenile idiopathic arthritis, 1 for a polyglandular autoimmune syndrome type III, and 1 for uveitis. Of these 22 patients, 16 had varicella and 6 had herpes zoster. Median age at VZV disease was 7.6 years (range 2 to 17 years), with 6.3 years (range 2 to 17 years) for those with varicella and 11.6 years (range 5 to 16 years) for those with herpes zoster. The median interval between start of immunosuppression and VZV disease was 14.1 months (range 1 to 63 months). Two patients had received varicella vaccine (1 dose each) prior to start of immunosuppression. Concomitant immunosuppressive therapy was methotrexate (MTX) monotherapy (n = 9) or bDMARD monotherapy (n = 2), or a combination of bDMARD with prednisone, MTX or Leflunomide (n = 11). Four patients experienced VZV related complications: cellulitis in 1 patient treated with MTX, and cellulitis, sepsis and cerebellitis in 3 patients treated with biological agents and MTX combination therapy. Six children were admitted to hospital (range of duration: 4 to 9 days) and 12 were treated with valaciclovir or aciclovir. The clinical course of varicella and herpes zoster in children under

Adherence to immunosuppressive therapy following liver transplantation: an integrative review.

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Oliveira, Ramon Antônio; Turrini, Ruth Natália Teresa; Poveda, Vanessa de Brito

2016-08-29

to investigate the evidence available in the literature on non-adherence to immunosuppressive therapy among patients undergoing liver transplantation. integrative literature review, including research whose sample consisted of patients aged over 18 years undergoing liver transplantation. It excluded those containing patients undergoing multiple organ transplants. For the selection of articles, Medline / Pubmed, CINAHL, LILACS, Scopus and Embase were searched. The search period corresponded to the initial date of indexation of different bases, up to the deadline of February 10, 2015, using controlled and uncontrolled descriptors: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance and patient compliance. were located 191 investigations, 10 of which met the objectives of the study and were grouped into four categories, namely: educational process and non-adherence; non-adherence related to the number of daily doses of immunosuppressive medications; detection methods for non-adherence and side effects of therapy. there were risk factors related to the health service, such as control and reduction of the number of doses; related to the individual, such as being male, divorced, alcohol or other substances user, exposed to low social support and being mentally ill. investigar as evidências disponíveis na literatura sobre a não adesão à terapêutica imunossupressora entre pacientes submetidos ao transplante de fígado. revisão integrativa da literatura, que incluiu investigações cuja amostra era composta por pacientes com idade igual ou superior a 18 anos, submetidos a transplante de fígado. Excluíram-se as que continham pacientes submetidos a transplantes de múltiplos órgãos. Para a seleção dos artigos foram consultadas as bases Medline/Pubmed, CINAHL, LILACS, Scopus e Embase. O período de busca determinado correspondeu à data inicial de indexação das

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

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Gianluigi Zaza

Full Text Available The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group, and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group.A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05. Flagellar motor switch protein (fliNY and type IV pilus assembly protein pilM (pilM were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

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Zaza, Gianluigi; Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

2017-01-01

The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen

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Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

2017-01-01

Background The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. Methods We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). Results A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Conclusions Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this

First-Line Matched Related Donor Hematopoietic Stem Cell Transplantation Compared to Immunosuppressive Therapy in Acquired Severe Aplastic Anemia

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Peinemann, Frank; Grouven, Ulrich; Kröger, Nicolaus; Bartel, Carmen; Pittler, Max H.; Lange, Stefan

2011-01-01

Introduction Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. Methods A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. Results 26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. Conclusions Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. PMID:21541024

Monitoring the patient off immunosuppression. Conceptual framework for a proposed tolerance assay study in liver transplant recipients.

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Thomson, A W; Mazariegos, G V; Reyes, J; Donnenberg, V S; Donnenberg, A D; Bentlejewski, C; Zahorchak, A F; O'Connell, P J; Fung, J J; Jankowska-Gan, E; Burlingham, W J; Heeger, P S; Zeevi, A

2001-10-27

The mission of the recently established Immune Tolerance Network includes the development of protocols for the induction of transplant tolerance in organ allograft recipients and the development of assays that correlate with and may be predictive of the tolerant state. The state of clinical organ transplant tolerance seems to already exist in a small minority of conventionally immunosuppressed liver and, more rarely, kidney transplant patients. Immunosuppressive drug therapy has been withdrawn from these patients for a variety of reasons, including protocolized weaning for a uniquely large group of liver patients at the University of Pittsburgh. In this study, we propose to evaluate the validity of a variety of in vitro immunologic and molecular biologic tests that may correlate with, and be predictive of, the state of organ transplant tolerance in stable liver patients off immunosuppression. Only peripheral blood will be available for the execution of these tests. Both adult and pediatric liver graft recipients will be studied, in comparison to appropriate controls. We shall examine circulating dendritic cell (DC) subsets [precursor (p) DC1 and p DC2] including cells of donor origin, and assess both the frequency and function of donor-reactive T cells by ELISPOT and by trans-vivo delayed-type hypersensitivity analysis in a surrogate murine model. Cytokine gene polymorphism and alloantibody titers will also be investigated. It is anticipated that the results obtained may provide physicians with a tolerance assay "profile" that may determine those patients from whom immunosuppressive therapy may be safely withdrawn.

Generic immunosuppression in transplantation: current evidence and controversial issues.

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El Hajj, Sandra; Kim, Miae; Phillips, Karen; Gabardi, Steven

2015-05-01

The overall success of organ transplantation in the 21st century has been predicated, in part, on the use of newer, more potent, and selective immunosuppressive agents. However, the high cost of lifelong immunosuppression represents a financial burden for many patients. In the past 15 years, regulatory agencies in Europe and America have approved several generic immunosuppressants. One concern is whether the conversion between innovator and generic immunosuppressants will prove to be problematic. This manuscript aims to compare and contrast the bioequivalence requirements among regulatory authorities in the USA, Europe, and Canada, evaluate published studies of generic immunosuppressants in transplant recipients, summarize consensus statements made by transplant organizations and discuss how to engage patients in discussion regarding the choice between innovator and generic immunosuppressants.

Early Introduction of Everolimus Immunosuppressive Regimen in Liver Transplantation with Extra-Anatomic Aortoiliac-Hepatic Arterial Graft Anastomosis

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Emanuele Felli

2014-01-01

Full Text Available Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

Rat allotransplantation of epigastric microsurgical flaps: a study of rejection and the immunosuppressive effect of cyclosporin A

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Carramaschi Fábio R.

2000-01-01

Full Text Available The rejection of allotransplantation of epigastric microsurgical flaps and the effect of immunosuppression have been studied in 58 rats. Three sets of experiments were planned: (1 Wistar Furth isogenic donors and receptors (control set; (2 Brown Norway donors and Wistar Furth receptors (rejection set; and (3 Brown Norway donors and Wistar Furth immunosuppressed receptors (cyclosporin A set. Cyclosporin A (10 mg/kg/d treated rats had a transplantation survival rate of up to 30 days: 83.3% among isogenic animals and 60% among allogeneic. There was 100% rejection by the 9th day after the transplantation in allogeneic non-immunosuppressed rats. Biopsies embedded with historesin were taken from the flap and normal contralateral skin (used as control on the 3rd, 7th, 15th, and 30th days after the surgery. A quantitative study of infiltrating lymphocytes in the flaps, with and without cyclosporin A, was done by evaluating the local inflammatory infiltrate. A significant increase in the number of lymphocytes among the rejection and immunosuppressed groups was seen, as compared to the isogenic set. Local lymphocytosis in allogeneic non-immunosuppressed transplantations reached its highest level on the 3rd day after surgery, before gross findings of rejection, which could only be seen by naked eye on the 5th or 6th day. Therefore, we conclude that cyclosporin A is effective in preserving allogenic transplantation in rats. Biopsies of transplanted areas may contribute to earlier diagnosis of the need for immunosuppressive therapy.

Budget impact analysis of conversion from cyclosporine to sirolimus as immunosuppressive medication in renal transplantation therapy

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Foroutan N

2013-10-01

Full Text Available Naghmeh Foroutan,1 Hamid R Rasekh,1 Jamshid Salamzadeh,1 Hamid R Jamshidi,1 Mohsen Nafar2 1Department of Pharmacoeconomics and Pharmaceutical Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, 2Department of Kidney Transplantation, Urinary Nephrology Research Center (UNRC, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Objectives: The aim of this study was to determine budget impact of conversion from cyclosporine (CsA to sirolimus (SRL in renal transplant therapy (RTT from the perspective of insurance organizations in Iran. Methods: An Excel-based model was developed to determine cost of RTT, comparing current CsA based therapy to an mTOR inhibitor-based therapy regimen. Total cost included both cost of immunosuppressive agents and relative adverse events. The inputs were derived from database of Ministry of Health and insurance organizations, hospital and pharmacy based registries, and available literature that were varied through a one-way sensitivity analysis. According to the model, there were almost 17,000 patients receiving RTT in Iran, out of which about 2,200 patients underwent the operation within the study year. The model was constructed based on the results of a local RCT, in which test and control groups received CsA, SRL, and steroids over the first 3 months posttransplantation and, from the fourth month on, CsA, mycophenolate mofetil (MMF, and steroids were used in the CsA group and SRL, MMF, and steroids were administered in the SRL group, respectively. Results: The estimated cost of RTT with CsA was US$4,850,000 versus US$4,300,000 receiving SRL. These costs corresponded to the cost saving of almost US$550,000 for the payers. Conclusion: To evaluate the financial consequence of adding mTOR inhibitors to the insurers’ formulary, in the present study, a budget impact analysis was conducted on sirolimus. Fewer cases of costly adverse events along with

Reactivation of tuberculosis during immunosuppressive treatment in a patient with a positive QuantiFERON-RD1 test

DEFF Research Database (Denmark)

Ravn, Pernille; Munk, Martin E; Andersen, Ase Bengaard

2004-01-01

A patient with polymyositis developed tuberculosis during immunosuppressive treatment. Tuberculin Skin Test and chest X-ray failed to demonstrate latent tuberculosis, whereas a blood sample that was tested with a modified QuantiFERON-TB-assay, using the recombinant ESAT-6 and CFP-10, was positive...... indicating that this patient was latently infected before immunosuppressive therapy. This case indicates the risk of progressing from latent to active tuberculosis given that the subject is RD1 responsive, and we believe that preventive anti-tuberculous treatment could have prevented this case...... of tuberculosis. We suggest that RD1 based tests are evaluated further in immunocompromised patients....

Immunosuppressive medication adherence in kidney transplant patients.

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Lalić, Jelena; Veličković-Radovanović, Radmila; Mitić, Branka; Paunović, Goran; Cvetković, Tatjana

2014-01-01

To assess the degree of immunosuppressive medication adherence in kidney transplant patients (KTPs) and to determine if there is a difference in the rate of adherence to tacrolimus (Tac), cyclosporine (CsA) and sirolimus (Sir). From a total of 63 KTPs treated at the Clinic of Nephrology, Clinical Centre Niš, Serbia, 60 participated in the study by responding to questionnaires. They were divided into the adherence group (n = 43) and the nonadherence group (n = 17) according to their degree of adherence which was measured using a validated survey form, the simplified medication adherence questionnaire. The KTP adherence to the different immunosuppressive regimens (Tac, CsA and Sir) was compared. Statistical analysis was performed using the Student t test. Adherence was observed in 43 (71.7%) patients, and only 17 (28.3%) did not follow the prescribed therapy. The estimated glomerular filtration rate was significantly lower in the nonadherence group (38.52 ± 18.22 ml/min) than in the adherence group (52.43 ± 16.91 ml/min, p adherers and the nonadherers (6.30 ± 2.06 vs. 5.0 ± 1.52 ng/ml, p adherence. Nonadherence was associated with worse graft function and a lower Tac level. Knowledge about the degree of adherence could help the early identification of nonadherent patients and the development of strategies to improve this. © 2014 S. Karger AG, Basel

EBV-associated post-transplantation B-cell lymphoproliferative disorder following allogenic stem cell transplantation for acute lymphoblastic leukaemia: tumor regression after reduction of immunosuppression - a case report

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Niedobitek Gerald

2010-03-01

Full Text Available Abstract Epstein-Barr virus (EBV-associated B-cell post-transplantation lymphoproliferative disorder (PTLD is a severe complication following stem cell transplantation. This is believed to occur as a result of iatrogenic immunosuppression leading to a relaxation of T-cell control of EBV infection and thus allowing viral reactivation and proliferation of EBV-infected B-lymphocytes. In support of this notion, reduction of immunosuppressive therapy may lead to regression of PTLD. We present a case of an 18-year-old male developing a monomorphic B-cell PTLD 2 months after receiving an allogenic stem cell transplant for acute lymphoblastic leukemia. Reduction of immunosuppressive therapy led to regression of lymphadenopathy. Nevertheless, the patient died 3 months afterwards due to extensive graft-vs.-host-disease and sepsis. As a diagnostic lymph node biopsy was performed only after reduction of immunosuppressive therapy, we are able to study the histopathological changes characterizing PTLD regression. We observed extensive apoptosis of blast cells, accompanied by an abundant infiltrate comprising predominantly CD8-positive, Granzyme B-positive T-cells. This observation supports the idea that regression of PTLD is mediated by cytotoxic T-cells and is in keeping with the observation that T-cell depletion, represents a major risk factor for the development of PTLD.

Listeria monocytogenes Meningitis in an Immunosuppressed Patient with Autoimmune Hepatitis and IgG4 Subclass Deficiency

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Shahin Gaini

2015-01-01

Full Text Available A 51-year-old Caucasian woman with Listeria monocytogenes meningitis was treated and discharged after an uncomplicated course. Her medical history included immunosuppressive treatment with prednisolone and azathioprine for autoimmune hepatitis. A diagnostic work-up after the meningitis episode revealed that she had low levels of the IgG4 subclass. To our knowledge, this is the first case report describing a possible association between autoimmune hepatitis and the occurrence of Listeria monocytogenes meningitis, describing a possible association between Listeria monocytogenes meningitis and deficiency of the IgG4 subclass and finally describing a possible association between Listeria monocytogenes meningitis and immunosuppressive therapy with prednisolone and azathioprine.

Listeria monocytogenes Meningitis in an Immunosuppressed Patient with Autoimmune Hepatitis and IgG4 Subclass Deficiency

DEFF Research Database (Denmark)

Gaini, Shahin

2015-01-01

A 51-year-old Caucasian woman with Listeria monocytogenes meningitis was treated and discharged after an uncomplicated course. Her medical history included immunosuppressive treatment with prednisolone and azathioprine for autoimmune hepatitis. A diagnostic work-up after the meningitis episode...... revealed that she had low levels of the IgG4 subclass. To our knowledge, this is the first case report describing a possible association between autoimmune hepatitis and the occurrence of Listeria monocytogenes meningitis, describing a possible association between Listeria monocytogenes meningitis...... and deficiency of the IgG4 subclass and finally describing a possible association between Listeria monocytogenes meningitis and immunosuppressive therapy with prednisolone and azathioprine....

The influence of immunosuppressive treatment on the progression of Graves' disease after radioiodine

International Nuclear Information System (INIS)

Jurca, T.; Pirnat, E.; Hojker, S.; Avcin, J.

1994-01-01

Radioiodine therapy (RIT) for Graves' disease could produce a rise in autoimmune activity expressed as elevation of antibody against TSH receptors (TSI). In our retrospective study the influence of different immunosuppressive therapy on autoimmune activity was studied. Patients, treated with radioiodine or surgery for the first time, between January 1989 and March 1992 were included in the study, divided in the 5 groups (patients after thyroidectomy, and patients after RIT divided into groups according to treatment with different combinations of corticosteroids and cyclosporine A). Patients were examined and TT 4 , TT 3 TSH and TSI were collected before and 3, 6 and 9 months after treatment. There was no differences between groups before and according to the thyroid status the patients of all groups received antithyroid drugs or substitution therapy after the RIT or surgery. Immunosuppressive therapy was indicated because of Graves' ophthalmopathy. After surgery, the progressive fall of TSI and no relapses of the disease were stated. After first 3 months the situation was very similar in group of patients treated with cyclosporine A after RIT, later after the cessation of treatment, there were a slight elevation of TSI. In all other groups of patients after RIT there was a constant positive trend of TSI and the significant correlation was found between TSI before and after treatment. We conclude, that autoimmune response after RIT is a consequence of activity of T cells and therefore cyclosporine A could be taken in mind when we want to prevent it. Corticosteroids on the other hand had no such an effect. (author)

Chlorphenesin: an antigen-associated immunosuppressant.

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Whang, H Y; Neter, E

1970-07-01

Chlorphenesin (3-p-chlorophenoxy-1,2-propanediol), when injected intravenously together with either of two common bacterial antigens, inhibits the antibody response of the rabbit. The antigens studied are those common to Enterobacteriaceae and to gram-positive bacteria. The immunosuppression is contingent upon incubation of chlorphenesin and antigen in vitro prior to administration, since separate injection of antigen and inhibitor or of mixtures without prior incubation yields undiminished antibody response. Chlorphenesin, as shown by hemagglutination-inhibition tests, does not alter the antigenic determinants, because antibody neutralization occurs in the presence or absence of the drug. The immunosuppressive effect is reversible, since precipitation of chlorphenesin at 4 C substantially restores immunogenicity. Animals immunized with antigen-drug mixtures, which fail to respond with significant antibody production, nonetheless are immunologically primed. It is concluded that chlorphenesin represents another example of antigen-associated immunosuppressants.

Fractionated total lymphoid irradiation as preparative immunosuppression in high risk renal transplantation

International Nuclear Information System (INIS)

Najarian, J.S.; Ferguson, R.M.; Sutherland, D.E.; Slavin, S.; Kim, T.; Kersey, J.; Simmons, R.L.

1982-01-01

Twenty-two patients at high risk to reject renal allografts have been treated with fractionated total lymphoid irradiation (FTLI) prior to transplantation of primary (2), secondary (16) or tertiary (4) renal allografts. All patients undergoing retransplantation had rapidly rejected previous grafts. At 24 months following transplantation, 72% of grafts were functioning in the TLI group compared with a 38% graft function in an historical control group of recipients receiving secondary or tertiary grafts and treated with conventional immunosuppression. Important variables in determining success of transplantation following fractionated TLI include the dose of TLI, the interval from radiation to transplantation, and maintenance post-transplant immunosuppressive therapy. Optimal results were achieved with 2500 rads delivered in 100 rad fractions followed by transplantation within two weeks, and a tapering prednisone schedule and maintenance azathioprine post-transplantation. Seventeen patients had significant complications of the radiation treatment and there was one death, prior to transplantation, associated with pneumonitis. In vitro assessment of immune function demonstrated marked peripheral T cell depletion and loss of in vitro responsiveness to mitogen and allogeneic stimulation following FTLI. The administration of donor bone marrow at the time of transplantation did not produce chimerism. The results suggest that when properly utilized FTLI can produce effective adjunctive immunosuppression for clinical transplantation

Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

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Yuan Cao

2015-01-01

Full Text Available Objective: To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants. Data Sources: We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators. The following terms were used: "inflammatory bowel disease (IBD" OR "Crohn′s disease" OR "ulcerative colitis" AND ("vaccination" OR "vaccine" AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]" AND "immunomodulators." Study Selection: The inclusion criteria of articles were that the studies: (1 Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria; (2 exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3 exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents. The exclusion criteria of articles were that the studies: (1 History of hepatitis B virus (HBV, influenza or streptococcus pneumoniae infection; (2 patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3 any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection; (4 individuals with positive hepatitis markers or liver cirrhosis; (5 patients with a known allergy to eggs or other components of the vaccines and (6 pregnancy. Results: Patients treated with immunomodulators were associated with lower response rates to

Primer trasplante de intestino en Chile: Caso clínico

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Buckel G,Erwin; Ferrario B,Mario; Uribe M,Mario; González G,Gloria; Godoy L,Jorge; Fluxá G,Fernando; Quera P,Rodrigo; Codoceo R,Verner; Morales B,Jorge; Benavente M,David; Santander D,María Teresa; Herzog O,Cristina

2009-01-01

Small bowel transplantation is associated with a patient survival at one and five years, of 80% and 63%, respectively. We repon a 36 year-old female with short bowel syndrome, subjected to the first small bowel transplantation performed in Chile. A cadaveric gran was used. Immunosuppression was achieved by means of alemtuzumab, tacrolimus, sirolimus, micofenolate mofetil and steroids. Serial endoscopies and biopsies were performed during seven months after transplantation. The most important ...

Post-therapeutic recovery of serum interleukin-35 level might predict positive response to immunosuppressive therapy in pediatric aplastic anemia.

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Huang, Zhen; Tong, Hongfei; Li, Yuan; Zhou, Haixia; Qian, Jiangchao; Wang, Juxiang; Ruan, Jichen

2017-08-01

The predictive value of interleukin-35 (IL-35) on efficacy of immunosuppressive therapy (IST) in aplastic anemia (AA) has not been well investigated. The aim of the study was to evaluate the association between serum IL-35 level and response to IST in pediatric AA. A total of 154 children with AA and 154 controls were included between January 2012 and December 2013. Blood and bone marrow fluid specimens were collected. Serum level of IL-35 was determined by enzyme-linked immunosorbent assay. Patients were treated with IST, and response to therapy was evaluated during 180-day follow-up period after starting therapy. Serum levels of IL-35 at admission decreased significantly in patients compared with that in controls (10.9 ± 5.5 pg ml -1 and 45.3 ± 8.8 pg ml -1 , p < 0.001). After starting IST, serum levels of IL-35 in patients recovered 30.7 ± 9.7 pg ml -1 in the first 28 days (p < 0.001). During the follow-up period, increased range of serum IL-35 level ≥30.7 pg ml -1 in the first 28 days was associated with effective response to therapy (odds ratio 7.97, 95% confidence interval 3.82-16.79). In addition, Fas/FasL protein expression in bone marrow mononuclear cells dropped significantly in the same group of patients in the first 28 days (p < 0.05). The study revealed that post-therapeutic recovery of circulating IL-35 concentration might be an independent predictor for effective response to IST in pediatric AA. Moreover, apoptosis might be involved in such a forecasting process.

Merkel Cell Carcinoma in Immunosuppressed Patients

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Ma, Janice E. [Mayo Clinic College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (United States); Brewer, Jerry D., E-mail: brewer.jerry@mayo.edu [Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (United States)

2014-06-27

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients.

Merkel Cell Carcinoma in Immunosuppressed Patients

International Nuclear Information System (INIS)

Ma, Janice E.; Brewer, Jerry D.

2014-01-01

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients

Phase I-II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints.

Science.gov (United States)

Winqvist, Maria; Mozaffari, Fariba; Palma, Marzia; Eketorp Sylvan, Sandra; Hansson, Lotta; Mellstedt, Håkan; Österborg, Anders; Lundin, Jeanette

2017-01-01

This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3-4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67 + ) CD8 + T cells was increased at week 4, with further increase in both the CD4 + and CD8 + subsets (p cells increased at week 4 as the frequency of effector memory cells increased in the CD8 + subset (p cells decreased in both the CD8 + and CD4 + subsets (p regulatory T cells was reduced (p T cells decreased, and effector memory T cells increased (p T cells increased at 30-week follow-up (p T cells, including increased proliferative activity and cytotoxic potential.

Is there an association between immunosuppressant therapy medication adherence and depression, quality of life, and personality traits in the kidney and liver transplant population?

Science.gov (United States)

Gorevski, Elizabeth; Succop, Paul; Sachdeva, Jyoti; Cavanaugh, Teresa M; Volek, Paul; Heaton, Pamela; Chisholm-Burns, Marie; Martin-Boone, Jill E

2013-01-01

To measure the association of transplant patients' personality, depression, and quality of life with medication adherence in kidney and liver transplant recipients. A cross-sectional study of liver and kidney transplant recipients greater than 1 year post-transplant was conducted. Patients' adherence with medications was assessed using the Immunosuppressive Therapy Adherence Scale. Personality and depression were assessed using the NEO Five-Factor Inventory Scale and Patient Health Questionnaire 9, respectively. Quality of life was assessed using the Short Form-36, and functional status was determined using the Karnofsky Performance Status Scale. A total of 86 kidney and 50 liver transplant patients completed the surveys. Logistic regression analysis demonstrated an association between depression and adherence with immunosuppressive medications in kidney transplant recipients. Kidney transplant patients who exhibited "low openness" scores were 91% more likely to be nonadherent. Kidney transplant patients' physical functional status was strongly associated with nonadherence, and for each point increase in functionality the patients' adherence increased by 4%. In the liver sample, age was associated with adherence. For every year increase in age, adherence increased by 7%. The presence of low openness as a personality trait, poor physical functional status, and depression were associated with adherence in the kidney transplant population. In the liver transplant population, younger age was associated with nonadherence.

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

Science.gov (United States)

Pasadhika, Sirichai; Rosenbaum, James T

2014-01-01

Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. PMID:24600203

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients.

Science.gov (United States)

Meaney, Calvin J; Arabi, Ziad; Venuto, Rocco C; Consiglio, Joseph D; Wilding, Gregory E; Tornatore, Kathleen M

2014-06-12

After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse

From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases

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Raghavan Chinnadurai

2013-01-01

Full Text Available The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS, linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs.

Effects and Predictive Factors of Immunosuppressive Therapy Combined with Umbilical Cord Blood Infusion in Patients with Severe Aplastic Anemia.

Science.gov (United States)

Zhang, Xia; Li, Zhangzhi; Geng, Wei; Song, Bin; Wan, Chucheng

2018-07-01

To investigate the efficacy and safety of umbilical cord blood (UCB) infusion (UCBI) plus immunosuppressive therapy (IST) treatment in comparison to IST treatment, as well as predictive factors for clinical responses, in severe aplastic anemia (SAA) patients. Totally, 93 patients with SAA were enrolled in this cohort study. In the IST group, rabbit antithymocyte globulin (r-ATG) combined with cyclosporine A (CsA) was administered, while in the IST+UBCI group, r-ATG, CsA, and UCB were used. After 6 months of treatment, UCBI+IST achieved a higher complete response (CR) rate (p=0.002) and an elevated overall response rate (ORR) (p=0.004), compared to IST. Regarding hematopoietic recovery at month 6, platelet responses in the UCBI+IST group were better than those in the IST group (p=0.002), and UCBI+IST treatment facilitated increasing trends in absolute neutrophil count (ANC) response (p=0.056). Kaplan-Meier curves illuminated UCBI+IST achieved faster ANC response (paplastic anemia (VSAA) and ANC could predict clinical responses as well. However, Cox proportional hazard regression indicated that VSAA (p=0.003), but not UCBI+IST, affected OS. Safety profiles showed that UCBI+IST therapy did not elevate adverse events, compared with IST treatment. UCBI+IST achieved better clinical responses and hematopoietic recovery than IST, and was well tolerated in SAA patients. © Copyright: Yonsei University College of Medicine 2018.

Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications.

Science.gov (United States)

Subramaniam, K; Cherian, M; Jain, S; Latimer, M; Corbett, M; D'Rozario, J; Pavli, P

2013-12-01

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Incidence of herpes zoster amongst adults varies by severity of immunosuppression.

Science.gov (United States)

Schröder, Carsten; Enders, Dirk; Schink, Tania; Riedel, Oliver

2017-09-01

We examined the incidence of herpes zoster in immunocompromised adults (≥18 years) with different severities of immunosuppression and assessed the prevalence of complications and of various kinds of healthcare resource utilisation. German claims data from more than ten million adults were used to calculate annual incidence rates of herpes zoster for the years 2006-2012 and to analyse the prevalence of complications, physician visits, hospitalisations, and antiviral and analgesic treatments using a cohort design. The analyses were stratified by age, sex, and severity of immunosuppression, defined by immunocompromising conditions and drug therapies. The incidence rate per 1000 person-years of herpes zoster was almost twice as high in immunocompromised patients (11.5 (95% confidence interval (CI): 11.4-11.6)) compared to immunocompetent subjects (5.9 (95% CI: 5.8-5.9)). The incidence rate was higher in highly immunocompromised patients (13.4 (95% CI: 13.2-13.6)) than in patients with a low severity of immunosuppression (10.0 (95% CI: 9.8-10.1)). These differences were observed for both sexes and in all age groups. Complications, outpatient physician visits, hospitalisations, and analgesic treatments occurred more frequently in immunocompromised patients as well. Our results show that immunocompromised individuals are affected by the disease in particular and that the burden of herpes zoster is highest in severely immunocompromised patients. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Generation of Human Immunosuppressive Myeloid Cell Populations in Human Interleukin-6 Transgenic NOG Mice

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Asami Hanazawa

2018-02-01

Full Text Available The tumor microenvironment contains unique immune cells, termed myeloid-derived suppressor cells (MDSCs, and tumor-associated macrophages (TAMs that suppress host anti-tumor immunity and promote tumor angiogenesis and metastasis. Although these cells are considered a key target of cancer immune therapy, in vivo animal models allowing differentiation of human immunosuppressive myeloid cells have yet to be established, hampering the development of novel cancer therapies. In this study, we established a novel humanized transgenic (Tg mouse strain, human interleukin (hIL-6-expressing NOG mice (NOG-hIL-6 transgenic mice. After transplantation of human hematopoietic stem cells (HSCs, the HSC-transplanted NOG-hIL-6 Tg mice (HSC-NOG-hIL-6 Tg mice showed enhanced human monocyte/macrophage differentiation. A significant number of human monocytes were negative for HLA-DR expression and resembled immature myeloid cells in the spleen and peripheral blood from HSC-NOG-hIL-6 Tg mice, but not from HSC-NOG non-Tg mice. Engraftment of HSC4 cells, a human head and neck squamous cell carcinoma-derived cell line producing various factors including IL-6, IL-1β, macrophage colony-stimulating factor (M-CSF, and vascular endothelial growth factor (VEGF, into HSC-NOG-hIL-6 Tg mice induced a significant number of TAM-like cells, but few were induced in HSC-NOG non-Tg mice. The tumor-infiltrating macrophages in HSC-NOG-hIL-6 Tg mice expressed a high level of CD163, a marker of immunoregulatory myeloid cells, and produced immunosuppressive molecules such as arginase-1 (Arg-1, IL-10, and VEGF. Such cells from HSC-NOG-hIL-6 Tg mice, but not HSC-NOG non-Tg mice, suppressed human T cell proliferation in response to antigen stimulation in in vitro cultures. These results suggest that functional human TAMs can be developed in NOG-hIL-6 Tg mice. This mouse model will contribute to the development of novel cancer immune therapies targeting immunoregulatory/immunosuppressive

Mesenchymal Stem Cells Attenuate the Adverse Effects of Immunosuppressive Drugs on Distinct T Cell Subopulations

Czech Academy of Sciences Publication Activity Database

Hájková, Michaela; Heřmánková, Barbora; Javorková, Eliška; Boháčová, Pavla; Zajícová, Alena; Holáň, Vladimír; Krulová, Magdaléna

2017-01-01

Roč. 13, č. 1 (2017), s. 104-115 ISSN 1550-8943 R&D Projects: GA ČR(CZ) GA14-12580S; GA MŠk(CZ) LO1508; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : mesenchymal stem cells * immunosuppressive drugs * stem cell therapy Subject RIV: FF - HEENT, Dentistry OBOR OECD: Immunology Impact factor: 2.967, year: 2016

Immunosuppression by non-ionising and ionising radiation - are there similarities?

International Nuclear Information System (INIS)

Reeves, V.

2003-01-01

Solar UV radiation, the ubiqitous environmental non-ionising radiation, initiates its immunomodulating effects almost entirely in the skin. In direct contrast, ionising radiation penetrates much more efficiently, and has a multitude of internal targets throughout the body. As a consequence, the mechanisms underlying UV-induced immunosuppression have been more readily characterised, whereas surprisingly little is known about immunosuppression resulting from ionising radiation. Photoimmunological studies in mice during the past 20-30 years have established the action spectrum for UV-induced immunosuppression, implicating the UVB waveband, 290-320 nm. Controversy rages over the immunosuppressive potential of the UVA waveband, 320-400 nm, but we demonstrate that environmentally relevant doses of UVA not only are immunologically innocuous, but provide protection against UVB-immunosuppression. Increasingly larger UVA exposures increasingly immunosuppress mice. The UVA immunoprotective effect is strongly dependent on the induction of a cutaneous redox-regulated enzyme, haem oxygenase (heat shock protein 32) that is known to protect cells from oxidative stress, and it is consistent that a number of exogenous antioxidants (vitamin E, vitamin C, green tea polyphenols, isoflavones) can protect effectively from photoimmuno-suppression. Thus the UV-immunosuppressed state is promoted by oxidative damage and depletion of endogenous antioxidant molecules. It is also associated with cutaneous cytokine derangements, such that Th-2 cytokines (IL-4, IL-10) are increased at the expense of Th-1 cytokines (IFN-gamma, IL-12), and with histamine and inflammatory prostaglandin activity. In contrast, immunoprotective UVA irradiation protects the cutaneous cytokine array, inhibits IL-10 upregulation and increases IFN-gamma and IL-12 expression. On the other hand, while ionising radiation is known to cause immunosuppression, large doses target the bone marrow and haemopoiesis lethally and

Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression

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Viktor Fleming

2018-03-01

Full Text Available The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME, which inhibits antitumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an antitumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches, and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various preclinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.

Tuberculin Skin Test and Quantiferon in BCG Vaccinated, Immunosuppressed Patients with Moderate-to-Severe Inflammatory Bowel Disease.

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Kurti, Zsuzsanna; Lovasz, Barbara Dorottya; Gecse, Krisztina Barbara; Balint, Anita; Farkas, Klaudia; Morocza-Szabo, Agnes; Gyurcsanyi, Andras; Kristof, Katalin; Vegh, Zsuzsanna; Gonczi, Lorant; Kiss, Lajos Sandor; Golovics, Petra Anna; Lakatos, Laszlo; Molnar, Tamas; Lakatos, Peter Laszlo

2015-12-01

There are few data available on the effect of immunomodulator/biological therapy on the accuracy of the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) in BCG-vaccinated immunosuppressed patients with inflammatory bowel disease (IBD). Our aim was to define the accuracy, predictors and agreement of TST and IGRA in a BCG-vaccinated immunosuppressed referral IBD cohort. 166 consecutive moderate-to-severe IBD patients (122 Crohn's disease, CD and 44 ulcerative colitis, UC) were enrolled in a prospective study from three centers. Patients were treated with immunosuppressives and/or biologicals. IGRA and TST were performed on the same day. Both in- and outpatient records were collected and comprehensively reviewed. TST positivity rate was 23.5%, 21.1%,14.5% and 13.9% when cut-off values of 5, 10, 15 and 20mm were used. IGRA positivity rate was 8.4% with indeterminate result in 0.6%. Chest X-ray was suggestive of latent tuberculosis in 2 patients. Correlation between TST and IGRA was moderate (kappa: 0.39-0.41, p15mm) should be considered to identify patients at risk for latent TB. Accuracy is satisfactory in BCG-vaccinated, immunosuppressed IBD patients. Smoking is a risk factor for TST positivity.

What is the best frontline therapy for patients with CLL and 17p deletion?

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Badoux, Xavier C; Keating, Michael J; Wierda, William G

2011-03-01

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with significant variation in disease progression, response to therapy, and survival outcome. Deletions of 17p or mutations of TP53 have been identified as one of the poorest prognostic factors, being predictive of short time for disease progression, lack of response to therapy, short response duration, and short overall survival. The treatment of patients with CLL has improved significantly with the development of chemoimmunotherapy, but this benefit was not pronounced in patients with 17p deletion. We compare various treatment strategies used in these patients, including FCR-like chemoimmunotherapy, alemtuzumab, other antibody combinations, or novel targeted therapies with promising results. Allogeneic stem cell transplantation offers the possibility for long-term disease control in these patients and should be considered early in younger, transplant-eligible patients. The current state of therapy is far from optimal and resources should be applied to studying therapeutic options for patients who have CLL with loss of p53 function.

Putative bronchopulmonary flagellated protozoa in immunosuppressed patients.

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Kilimcioglu, Ali Ahmet; Havlucu, Yavuz; Girginkardesler, Nogay; Celik, Pınar; Yereli, Kor; Özbilgin, Ahmet

2014-01-01

Flagellated protozoa that cause bronchopulmonary symptoms in humans are commonly neglected. These protozoal forms which were presumed to be "flagellated protozoa" have been previously identified in immunosuppressed patients in a number of studies, but have not been certainly classified so far. Since no human cases of bronchopulmonary flagellated protozoa were reported from Turkey, we aimed to investigate these putative protozoa in immunosuppressed patients who are particularly at risk of infectious diseases. Bronchoalveolar lavage fluid samples of 110 immunosuppressed adult patients who were admitted to the Department of Chest Diseases, Hafsa Sultan Hospital of Celal Bayar University, Manisa, Turkey, were examined in terms of parasites by light microscopy. Flagellated protozoal forms were detected in nine (8.2%) of 110 cases. Metronidazole (500 mg b.i.d. for 30 days) was given to all positive cases and a second bronchoscopy was performed at the end of the treatment, which revealed no parasites. In conclusion, immunosuppressed patients with bronchopulmonary symptoms should attentively be examined with regard to flagellated protozoa which can easily be misidentified as epithelial cells.

Influence of genetic polymorphisms of IL23R, STAT3, IL12B, and STAT4 on the risk of aplastic anemia and the effect of immunosuppressive therapy.

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Zhao, Li; Zhu, Huanling; Han, Bing; Wang, Lixin; Sun, Yuming; Lu, Xiaojun; Huang, Chunyan; Tan, Bin; Chen, Chunxia; Qin, Li

2018-04-01

Studies have suggested that IL-23/STAT3 and IL-12/STAT4 signaling pathways associate with aplastic anemia (AA) occurrence. Polymorphisms in pathway-related genes may contribute to AA risk. In the current study, we investigated the association between polymorphisms in genes of IL23R, STAT3, IL12B, and STAT4 and occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China. In the current 164 AA cases and 211 controls study, we found T allele and TT genotype of rs7574865 were more frequent in the cases than that in the controls. In the additive model, individual carrying rs7574865 T allele demonstrated a 37% (OR (95% CI) = 1.37 (1.02-1.85), Pper = 0.036) increased AA risk. In the recessive model, carrier with rs7574865 TT genotype showed a 2.08-fold increased AA risk (OR (95% CI) = 2.08 (1.14-3.70), Pper = 0.017). Additionally, we showed that G allele and GG genotype of rs11209032 were more frequent in the 88 non-severe AA cases than that in the 76 severe AA ones. Our study also found G allele and GG genotype of rs11209032, and GG-genotype of rs744166 associated with the immunosuppressive therapy outcome in AA patients. Current study results support that functional STAT4 (rs7574865), IL23R (rs11209032), and STAT3 (rs744166) variants may associate with occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

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Lorf Thomas

2010-04-01

Full Text Available Abstract Background Immunosuppression with calcineurin inhibitors (CNI increases the risk of renal dysfunction after orthotopic liver transplantation (OLT. Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods/Design A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate, liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT, treatment failure, (i. e., re-introduction of CNI, incidence of adverse events, and mortality up to one year after OLT. Discussion This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation of this phase III trial. Trial registration number NCT00890253 (clinicaltrials.gov

Nonadherence to immunosuppressive therapy in kidney transplant recipients: can technology help?

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Nerini, Erika; Bruno, Fulvio; Citterio, Franco; Schena, Francesco P

2016-10-01

End-stage kidney disease is a life-threatening condition that compels patients to accept either dialysis or transplant. Kidney transplantation is the best choice for patients with end-stage kidney disease because it ensures higher quality of life and longer survival rates than other choices, with less cost for the healthcare system. However, in order for renal recipients to maintain the functioning graft they must take lifelong immunosuppressive medications, with possible side effects and low medication adherence. It is known that low medication adherence in kidney transplant recipients may cause poor outcomes, chronic graft rejection, and graft failure. In this review, the authors give an overview of nonadherence in the transplant setting. In addition, they analyze the role of different technologies as an aid to improve adherence, with a focus on mobile-phone based solutions to monitor and enhance kidney transplant recipient compliance.

Modified immunosuppressive therapy with porcine antilymphocyte globulin plus delayed cyclosporine A in children with severe aplastic anemia.

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Cui, Qingya; Sha, Pingping; Chen, Haifei; Shen, Hongshi; Qin, Longmei; Li, Zhengyang; Wu, Tianqin; Wang, Zhaoyue

2018-01-01

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) is the standard treatment for children with severe aplastic anemia (SAA) with no human leukocyte antigen-matched siblings. Due to the unavailability of horse ATG in China, porcine antilymphocyte globulin (p-ALG), which is less expensive and more effective than rabbit ATG, is widely used. We sought to evaluate the efficacy and safety profile of modified IST with p-ALG plus delayed CsA at day 21 in 50 SAA children. Eighteen SAA patients who progressed from nonsevere aplastic anemia (NSAA) were classified as SAA-II; the other 32 patients were classified as SAA-I. Overall response (OR) rates at 3, 6 and 12 months were 56, 64 and 62%, respectively. The 10-year overall survival (OS) rate and disease-free survival (DFS) rate were 80 and 56%. The OR, OS and DFS rates in the SAA-I group were clearly better than those in the SAA-II group. Death rate from infection within 30 days was 4%. Modified IST with p-ALG plus delayed CsA is a reliable and well-tolerated treatment for children with SAA, and reduces early death due to infection. Modified IST is more suitable for children with SAA-I.

Cytomegalovirus retinitis after central retinal vein occlusion in a patient on systemic immunosuppression: does venooclusive disease predispose to cytomegalovirus retinitis in patients already at risk?

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Welling JD

2012-04-01

Full Text Available John D Welling, Ahmad B Tarabishy, John ChristoforidisDepartment of Ophthalmology, Havener Eye Institute, Ohio State University, Columbus, OH, USAAbstract: Cytomegalovirus (CMV retinitis remains the most common opportunistic ocular infection in immunocompromised patients. Patients with immunocompromising diseases, such as acquired immunodeficiency syndrome, inherited immunodeficiency states, malignancies, and those on systemic immunosuppressive therapy, are known to be at risk. Recently, it has been suggested that patients undergoing intravitreal injection of immunosuppressive agents may also be predisposed. One previous case report speculated that there may be an additional risk for CMV retinitis in acquired immunodeficiency syndrome patients with venoocclusive disease. This case study presents a case of CMV retinitis following central retinal vein occlusion in a patient on systemic immunosuppressants.Keywords: cytomegalovirus retinitis, central retinal vein occlusion, immunosuppression, solid organ transplant, venous stasis, risk factor

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

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Pasadhika S

2014-02-01

Full Text Available Sirichai Pasadhika,1 James T Rosenbaum2 1Department of Ophthalmology, Southern Arizona Veterans Administration Health Care System, Tucson, AZ, USA; 2Legacy Devers Eye Institute, Portland, OR, USA Abstract: Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet's disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet's disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present

Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

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Michaud L

2016-12-01

Full Text Available Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20 might have lower medication adherence than noncomplex patients (INTERMED≤20. Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20. Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11 and noncomplex patients (N=21 were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value. Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly

A tacrolimus-related immunosuppressant with reduced toxicity.

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Dumont, F J; Koprak, S; Staruch, M J; Talento, A; Koo, G; DaSilva, C; Sinclair, P J; Wong, F; Woods, J; Barker, J; Pivnichny, J; Singer, I; Sigal, N H; Williamson, A R; Parsons, W H; Wyvratt, M

1998-01-15

Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility. Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity. Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intracellular FK506 binding protein-12 than tacrolimus or ASC. Further evaluation of indolyl-ASC revealed that it is threefold less potent than tacrolimus in inducing hypothermia, a response that may reflect neurotoxicity, and in causing gastrointestinal transit alterations in mice. Moreover, indolyl-ASC was at least twofold less nephrotoxic than tacrolimus upon 3-week oral treatment in rats. Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.

[Clinical views from the forefront of immunosuppressive drugs].

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Kobayashi, Eiji

2005-11-01

Recently, many immunosuppressants have been developed and some of them have already been introduced in clinical organ transplantation. With a new concept of immunoregulation, which focuses on prevention of rejection and over-immunosuppression, the latest protocol has been conducted. Chimeric or humanized antibodies targeting the lymphocyte surface molecule such as CD19, 20, 25, 40, and 52 are administrated in the induction phase, and calcineurin inhibitors (cyclosporin and tacrolimus) are used as key drugs. For tapering the doses of them, the combined application of anti-metabolic agents of azathioprine, mizoribine, or mycophenolate mofetil (MMF) has been proved effective. Lymphocyte forming drugs induce unique immunoregulation, targeting at sphingosine 1-phosphate (SlP) receptors. FTY720 is now in the procedure of clinical trial to compare with MMF. KRP203 is also a candidate for more specific SIP receptor agonist. In this issue, I reviewed the recent immunosuppressive strategy and focused on the advance of novel immunosuppressive drugs.

Immunosuppressive agents are associated with peptic ulcer bleeding.

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Tomizawa, Minoru; Shinozaki, Fuminobu; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

2017-05-01

Peptic ulcer bleeding can be fatal. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents are administered for long-term usage. The present study assessed the association between peptic ulcer bleeding and administration of NSAIDs, corticosteroids and immunosuppressive agents. Furthermore, the efficacy of lowering the risk of peptic ulcer bleeding with proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was evaluated. Medical records were retrospectively analyzed for patients subjected to an upper gastrointestinal (GI) endoscopy performed at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from October 2014 to September 2015. During this period, a total of 1,023 patients underwent an upper GI endoscopy. A total of 1,023 patients, including 431 males (age, 68.1±12.9 years) and 592 females (age, 66.4±12.3 years), who had been administered NSAIDs, corticosteroids, immunosuppressive agents, PPIs and H2RAs, were respectively enrolled. Endoscopic findings of the patients were reviewed and their data were statistically analyzed. Logistic regression analysis was used to determine the odds ratio of peptic ulcer bleeding for each medication; immunosuppressive agents had an odds ratio of 5.83, which was larger than that for NSAIDs (4.77). The Wald test was applied to confirm the correlation between immunosuppressive agents and peptic ulcer bleeding. Furthermore, χ 2 tests were applied to the correlation between peptic ulcer bleeding and administration of PPIs or H2RAs. Immunosuppressive agents had the largest χ 2 , and the P-value was 0.03. Administration of PPIs was significantly correlated with non-peptic ulcer bleeding (P=0.02); furthermore, a tendency toward non-peptic ulcer bleeding with administration of H2RA was indicated, but it was not statistically significant (P=0.12). In conclusion, immunosuppressive agents were correlated with peptic ulcer bleeding and PPIs were effective at

Unusual Case Report of Thrombotic Microangiopathy of the Small Bowel Following Liver Transplantation, a Possible Immunosuppressant-Induced Disease with Histological and Ultrastructural Findings

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Domenico Piscitelli

2009-01-01

Full Text Available Cyclosporin-A (CsA and tacrolimus (FK-506 are immunomodulating agents used to prevent rejection in organ transplantation. They are both associated with several side effects, including nephrotoxicity and severe hypertension due to vascular injury, which often appears as a microvascular occlusive disorder (thrombotic microangiopathy, TMA. We report the first case of a microvascular occlusive disorder with the features of TMA in the small bowel of an orthotopic liver transplant (OLT patient after immunosuppressive therapy with CsA and FK506. The patient presented with severe recurrent abdominal colics and distal subocclusion, requiring aggressive surgical treatment. Histological and ultrastructural analysis of the resected specimen disclosed intestinal TMA. Although rare, such a complication should be considered in the differential diagnosis of abdominal colics in patients undergoing immunosuppressant therapy after OLT.

Immunosuppressive T-cell antibody induction for heart transplant recipients

DEFF Research Database (Denmark)

Penninga, Luit; Møller, Christian H; Gustafsson, Finn

2013-01-01

Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required...... to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation....

Cutaneous toxoplasmosis in an immunosuppressed dog

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T.S. Oliveira

2014-06-01

Full Text Available A seven-year-old female spayed Schnauzer was presented with cutaneous ulcerated nodular lesions shortly after the beginning of an immunosuppressive treatment for immune-mediated hemolytic disease. Cytology was performed and a great number of neutrophils and banana-shaped organisms were observed. Biopsy showed a neutrophilic and histiocytic dermatitis and panniculitis with myriads of intralesional bradyzoites cysts and tachyzoites. PCR analysis was positive for Toxoplasma gondii and negative for Neospora caninum. Immunohistochemistry confirmed intralesional T. gondii antigens. This study reports a rare case of cutaneous toxoplasmosis in an immunosuppressed dog.

Cutaneous Alternaria infectoria infection in a dog in association with therapeutic immunosuppression for the management of immune-mediated haemolytic anaemia

NARCIS (Netherlands)

Dedola, C.; Stuart, A.P.G.; Ridyard, A.E.; Else, R.W.; Van den Broek, T.; Choi, J.S.; de Hoog, G.S.; Thoday, K.L.

2010-01-01

A 4-year-old, ovariohysterectomized, English springer spaniel on immunosuppressive therapy was re-examined for the review of its immune-mediated haemolytic anaemia and the recent development of skin lesions. For the 3 months since hospital discharge, the dog had been receiving 1.3 mg/kg prednisolone

Screening and Monitoring for Infectious Complications When Immunosuppressive Agents Are Studied in the Treatment of Autoimmune Disorders.

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Loechelt, Brett J; Green, Michael; Gottlieb, Peter A; Blumberg, Emily; Weinberg, Adriana; Quinlan, Scott; Baden, Lindsey R

2015-09-01

Significant progress has been made in the development, investigation, and clinical application of immunosuppressive agents to treat a variety of autoimmune disorders. The expansion of clinical applications of these new agents requires the performance of large multicenter clinical trials. These large clinical trials are particularly important as one considers these agents for the treatment of type 1 diabetes, which although autoimmune in its pathogenesis, is not classically treated as an autoimmune disorder. Although these agents hold promise for amelioration or cure of this disease, they have the potential to facilitate infectious complications. There are limited data regarding the prospective assessment of infectious risks with these agents in trials of this nature. Pediatric subjects may be at greater risk due to the higher likelihood of primary infection. A subgroup of experts associated with TrialNet (a National Institutes of Health [NIH]-funded Type 1 diabetes mellitus research network) with expertise in infectious diseases, immunology, and diagnostics developed an approach for screening and monitoring of immunosuppression-associated infections for prospective use in clinical trials. The goals of these recommendations are to provide a structured approach to monitor for infections, to identify specific laboratory testing and surveillance methods, and to consider therapies for treatment of these potential complications. Prospective evaluations of these infectious risks allow for greater scientific rigor in the evaluation of risk, which must be balanced with the potential benefits of these therapies. Our experience supports an important role for investigators with expertise in infections in immunocompromised individuals in protocol development of immunosuppressive trials in type 1diabetes and potentially other autoimmune diseases.

Sternoclavicular Osteomyelitis in an Immunosuppressed Patient: A Case Report and Review of the Literature.

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Khan, Kamran; Wozniak, Susan E; Mehrabi, Erfan; Giannone, Anna Lucia; Dave, Mitul

2015-12-28

BACKGROUND Sternoclavicular osteomyelitis is a rare disease, with less than 250 cases identified in the past 50 years. We present a rare case of sternoclavicular osteomyelitis in an immunosuppressed patient that developed from a conservatively treated dislocation. CASE REPORT A 62-year-old white man with a history of metastatic renal cell carcinoma presented to the emergency department (ED) with a dislocated left sternoclavicular joint. He was managed conservatively and subsequently discharged. However, over subsequent days he began to experience pain, fever, chills, and night sweats. He presented to the ED again and imaging revealed osteomyelitis. In the operating room, the wound was aggressively debrided and a wound vac (vacuum-assisted closure) was placed. He was diagnosed with sternoclavicular osteomyelitis and placed on a 6-week course of intravenous Nafcillin. CONCLUSIONS Chemotherapy patients who sustain joint trauma normally associated with a low risk of infection should be monitored thoroughly, and the option to discontinue immunosuppressive therapy should be considered if signs of infection develop.

Relationship between Post-kidney Transplantation Antithymocyte Globulin Therapy and Wound Healing Complications

OpenAIRE

Pourmand, G. R.; Dehghani, S.; Saraji, A.; Khaki, S.; Mortazavi, S. H.; Mehrsai, A.; Sajadi, H.

2012-01-01

Background: Wound healing disorders are probably the most common post-transplantation surgical complications. It is thought that wound healing disturbance occurs due to antiproliferative effects of immunosuppressive drugs. On the other hand, success of transplantation is dependent on immunosuppressive therapies. Antihuman thymocyte globulin (ATG) has been widely used as induction therapy but the impact of this treatment on wound healing is not fully understood. Objective: To investigate wound...

Immunosuppressive effect of total lymphoid irradiation

International Nuclear Information System (INIS)

Bendel, V.; Medizinische Hochschule Hannover

1981-01-01

Contrary to the immunosuppression by means of wholebody irradiation which is known for a long while but connected with considerable side effects and risks, the total lymphoid irradiation (TLI) is a new possibility of immunosuppression the tolerance of which by man is known by virtue of long-standing experiences with the treatment of malignant lymphatic system diseases. In connexion with organ transplantations, TLI might possibly soon be important for the radiotherapeutist. In the experimentation on animals, the unspecific immunosuppression induced by TLI causes a prolonged survival time of allogeneic skin and organ grafts in certain mammals. Furthermore, a formation of blood chimeras combined with specific, permanent tolerance of organ grafts from the bone marrow donor can be caused by bone marrow transplantation after TLI. First experiences with man have been made. In the German literature, TLI has not been mentioned yet. In the present study, a summary is given on the Anglo-Saxon literature, and the first own experiments with regard to the problem of irradiation dose and transplantation interval are presented. (orig.) [de

Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation.

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Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H Joachim

2014-12-01

A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients. Copyright© Ferrata Storti Foundation.

Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment.

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Salinas-Carmona, Mario Cesar; Rosas-Taraco, Adrian Geovanni; Welsh, Oliverio

2012-10-01

Human diseases produced by pathogenic actinomycetes are increasing because they may be present as opportunistic infections. Some of these microbes cause systemic infections associated with immunosuppressive conditions, such as chemotherapy for cancer, immunosuppressive therapy for transplant, autoimmune conditions, and AIDS; while others usually cause localized infection in immunocompetent individuals. Other factors related to this increase in incidence are: antibiotic resistance, not well defined taxonomy, and a delay in isolation and identification of the offending microbe. Examples of these infections are systemic disease and brain abscesses produced by Nocardia asteroides or the located disease by Nocardia brasiliensis, named actinomycetoma. During the Pathogenic Actinomycetes Symposium of the 16th International Symposium on Biology of Actinomycetes (ISBA), held in Puerto Vallarta, Mexico, several authors presented recent research on the mechanisms by which N. brasiliensis modulates the immune system to survive in the host and advances in medical treatment of human actinomycetoma. Antibiotics and antimicrobials that are effective against severe actinomycetoma infections with an excellent therapeutic outcome and experimental studies of drugs that show promising bacterial inhibition in vivo and in vitro were presented. Here we demonstrate a systemic strong acquired immune response in humans and experimental mice at the same time of a local dominance of anti inflammatory cytokines environment. The pathogenic mechanisms of some actinomycetes include generation of an immunosuppressive micro environment to evade the protective immune response. This information will be helpful in understanding pathogenesis and to design new drugs for treatment of actinomycetoma.

Function of external respiration in patients after kidney transplantation under conditions of immunosuppressive therapy.

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O. V. Kuryata

2018-04-01

Full Text Available The aim of our study was to evaluate the changes in the parameters of the function of external respiration in patients after kidney transplantation due to chronic kidney disease and to assess the relationship between the level of cyclosporin A and tacrolimus in the blood with FVD indices. The study included 37 patients after kidney transplantation. The first group included 27 patients who received cyclosporine at an average dose of 225 [175-350] mg/day under the immunosuppressive therapy regimen, the second group included 10 patients who received tacrolimus at an average dose of 8.25 [5.0-9.0] mg/day. A significant difference (p˂0.05 between the indicators of the VCmax (78 [71-90]% and 76.5 [72-78]%, FVC (93 [85-99]% and 95 [91-98]%, PEF (82 [64-94]% and 80 [69-84]%, MEF25-75 (75 [66-112]% and 82.5 [67-90]% was found in patients of the first and second groups relative to the FVD of the comparison group: VCmax (102.5 [98-113]%, FVC (107.5 [105.5-124]%, PEF (99.5 [95-102.5]%, MEF25-75 (98.5 [97.5-101.5]%. In both groups, a statistically significant negative correlation between the indicators of the VCmax, FVC and the level of cyclosporin A (R=-0.69, p<0.0001 and R=-0.4, p<0.037 in the blood in the first group and FVC and tacrolimus (R=-0.72, p<0.018 in the second group was found. A moderate decrease in the VCmax values in patients after kidney transplantation requires monitoring of the function of external respiration and managing such patients by nephrologists together with specialists in the pulmonological profile.

Increased risk of histologically defined cancer subtypes in human immunodeficiency virus-infected individuals: clues for possible immunosuppression-related or infectious etiology.

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Shiels, Meredith S; Engels, Eric A

2012-10-01

Malignancies that occur in excess among human immunodeficiency virus (HIV)-infected individuals may be caused by immunosuppression or infections. Because histologically defined cancer subtypes have not been systematically evaluated, their risk was assessed among people with acquired immunodeficiency syndrome (AIDS). Analyses included 569,268 people with AIDS from the HIV/AIDS Cancer Match Study, a linkage of 15 US population-based HIV/AIDS and cancer registries during 1980 to 2007. Standardized incidence ratios (SIRs) were estimated to compare cancer risk in people with AIDS to the general population overall, and stratified by age, calendar period (a proxy of changing HIV therapies), and time since onset of AIDS (a proxy of immunosuppression). Sixteen individual cancer histologies or histology groupings manifested significantly elevated SIRs. Risks were most elevated for adult T cell leukemia/lymphoma (SIR = 11.3), neoplasms of histiocytes and accessory lymphoid cells (SIR = 10.7), giant cell carcinoma (SIR = 7.51), and leukemia not otherwise specified (SIR = 6.69). SIRs ranged from 1.4 to 4.6 for spindle cell carcinoma, bronchioloalveolar adenocarcinoma, adnexal and skin appendage neoplasms, sarcoma not otherwise specified, spindle cell sarcoma, leiomyosarcoma, mesothelioma, germ cell tumors, plasma cell tumors, immunoproliferative diseases, acute lymphocytic leukemia, and myeloid leukemias. For several of these cancer subtypes, significant declines in SIRs were observed across calendar periods (consistent with decreasing risk with improved HIV therapies) or increase in SIRs with time since onset of AIDS (ie, prolonged immunosuppression). The elevated risk of certain cancer subtypes in people with AIDS may point to an etiologic role of immunosuppression or infection. Future studies are needed to further investigate these associations and evaluate candidate infectious agents. Copyright © 2012 American Cancer Society.

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

Directory of Open Access Journals (Sweden)

Helio Tedesco-Silva Jr

2011-01-01

Full Text Available Helio Tedesco-Silva Jr, Claudia Rosso Felipe, Tainá Veras de Sandes Freitas, Marina Pontello Cristeli, Carolina Araújo Rodrigues, José Osmar Medina PestanaNephrology Division, Hospital do Rim e Hipertensão, Universidade Federal de São Paulo, BrazilAbstract: Everolimus is an immunosuppressive agent used for the prophylaxis of acute rejection after kidney transplantation. Everolimus inhibits the activity of the serine/threonine kinase mammalian target of rapamycin (mTOR, a key enzyme that controls cell growth and metabolism, producing cell cycle arrest from the G1 to S phase. As a consequence, everolimus has antiproliferative and antineoplastic effects. Everolimus is a drug with a narrow therapeutic index. The pharmacokinetics of everolimus indicates a need for twice-daily dosing. Intra- and interindividual variability and drug–drug interactions suggest the need for therapeutic drug monitoring to maximize the efficacy/toxicity ratio. The good correlation between exposure (area under the concentration–time curve and trough concentration indicates that monitoring of everolimus trough concentrations is an adequate strategy after kidney transplantation. Everolimus is indicated for low- to moderate-risk de novo kidney transplant candidates. There are no conclusive studies thus far indicating that everolimus can be used in high-risk patients, such as sensitized patients, retransplants, and African Americans. In de novo kidney transplant recipients, the recommended initial dose of everolimus is 0.75 mg twice daily, adjusted to maintain blood trough concentrations of 3–8 ng/mL, in combination with progressive reduction in blood trough cyclosporine concentrations to 25–50 ng/mL. In combination with reduced trough blood tacrolimus concentrations of 4–7 ng/mL the recommended initial dose of everolimus is 1.5 mg twice daily, adjusted to maintain trough blood concentrations of 3–8 ng/mL. Everolimus can also be used as a conversion strategy

Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine

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Gianluigi Zaza

2015-02-01

Full Text Available Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.

Selective immunosuppression by radiation

International Nuclear Information System (INIS)

Chanana, A.D.; Cronkite, E.P.; Joel, D.D.

1976-01-01

The historical aspects of selective irradiation of lymphocytes are reviewed as well as the problems concerned with dosimetry and the radiosensitivity of circulating blood elements other than lymphocytes. The possibilities of perturbations in steady-state lymphocytopoiesis which might be triggered by products of radiation-induced cell death are presented; however, the parameters investigated thus far, such as the degree of lymphocytopenia, thoracic duct lymphocyte output, and cell-cycle times of thoracic duct lymphocytes, have failed to reveal any such perturbations. Studies in adrenalectomized calves have failed to confirm the notion that lymphocytopenia after extracorporeal irradiation of blood and lymph might primarily be accounted for by stress-induced corticosteroid hormonal activity. Of the various techniques, only local-graft irradiation and extracorporeal irradiation of blood (ECIB) have found clinical application. The results obtained are encouraging and indicate a need for additional, well-controlled clinical trials, especially concerning the role of ECIB as an adjunct to standard immunosuppressive therapy. The experimental results with extracorporeal irradiation of lymph have also established the potential of this technique for clinical application. There is an urgent need for studying the influence of irradiation on various subpopulations of lymphocytes with regard to their functional capabilities and in particular with regard to their reproductive potential. Possible influence of selective blood irradiation on circulating stem cells in blood needs to be evaluated

Fecal Bacteriotherapy: A Case Report in an Immunosuppressed Patient with Ulcerative Colitis and Recurrent  Clostridium difficile Infection

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Hadeel Zainah

2012-01-01

Full Text Available We report a case of ulcerative colitis (UC and recurrent Clostridium difficile infection (CDI where the patient was on immunomodulatory therapy and had successful CDI eradication after fecal transplantation. This is the first case report in the literature documenting successful C. difficile eradication in an immunosuppressed patient. We feel that fecal transplantation should be studied as a treatment option in these patients.

Amniotic membrane transplantation ineffective as additional therapy in patients with aggressive Mooren's ulcer.

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Schallenberg, Maurice; Westekemper, Henrike; Steuhl, Klaus-Peter; Meller, Daniel

2013-12-17

Mooren's ulcer is a severe ulcerative inflammation of the cornea. The exact pathogenesis remains unclear. Therefore many therapies of Mooren's ulcer are recommended in literature. To shed more light on the ongoing question of optimal treatment of severe progressive Mooren's ulcer, we here report on a retrospective case series of patients treated with systemic immunosuppressive therapy and additional amniotic membrane transplantation. Medical records from seven patients (eleven eyes), 4 male and 3 female, with severe progressive Mooren's ulcer were analysed retrospectively. The mean follow up was 88.4 ± 80.8 months (range 12-232 month). A HLA-typing was performed in all patients. A systemic immunosuppressive therapy was administered in all patients. The amniotic membrane was transplanted after the base of the ulcer was resected. Multiple amniotic membrane transplantations were necessary in six patients. The visual outcome of all patients was poor. No patient achieved a visual acuity better than 20/630 Snellen chart. Five patients were positive for HLA-DQ2 and four patients were positive for HLA-DR17(3). The aggressive and highly inflammatory form of Mooren's ulcer is difficult to treat and the progression of the disease is hard to influence positively even under systemic immunosuppressive therapy. Therefore, the main intention of therapy is to achieve a stable epithelialized corneal surface without the risk of perforation. Amniotic membrane transplantation is not able to cure severe forms of Mooren's ulcer. However it supports the immunosuppressive therapy in acute situations as in critical corneal thinning.

Is there an association between immunosuppressant therapy medication adherence and depression, quality of life, and personality traits in the kidney and liver transplant population?

Directory of Open Access Journals (Sweden)

Gorevski E

2013-04-01

Full Text Available Elizabeth Gorevski,1 Paul Succop,1 Jyoti Sachdeva,1 Teresa M Cavanaugh,1 Paul Volek,1 Pamela Heaton,1 Marie Chisholm-Burns,2 Jill E Martin-Boone1 1University of Cincinnati, Cincinnati, OH, USA, 2University of Tennessee College of Pharmacy, Memphis, TN, USA Objectives: To measure the association of transplant patients' personality, depression, and quality of life with medication adherence in kidney and liver transplant recipients. Methods: A cross-sectional study of liver and kidney transplant recipients greater than 1 year post-transplant was conducted. Patients’ adherence with medications was assessed using the Immunosuppressive Therapy Adherence Scale. Personality and depression were assessed using the NEO Five-Factor Inventory Scale and Patient Health Questionnaire 9, respectively. Quality of life was assessed using the Short Form-36, and functional status was determined using the Karnofsky Performance Status Scale. Results: A total of 86 kidney and 50 liver transplant patients completed the surveys. Logistic regression analysis demonstrated an association between depression and adherence with immunosuppressive medications in kidney transplant recipients. Kidney transplant patients who exhibited “low openness” scores were 91% more likely to be nonadherent. Kidney transplant patients’ physical functional status was strongly associated with nonadherence, and for each point increase in functionality the patients adherence increased by 4%. In the liver sample, age was associated with adherence. For every year increase in age, adherence increased by 7%. Conclusion: The presence of low openness as a personality trait, poor physical functional status, and depression were associated with adherence in the kidney transplant population. In the liver transplant population, younger age was associated with nonadherence. Keywords: adherence, transplant, liver, kidney

Low Adherence to Immunosuppressants Is Associated With Symptom Experience Among Kidney Transplant Recipients.

Science.gov (United States)

Lee, S Y; Chu, S H; Oh, E G; Huh, K H

2015-11-01

The purpose of this study was to investigate the relationship between immunosuppressant-related symptom experience (SE) and adherence to immunosuppressant regimens among kidney transplant (KT) recipients. A total of 239 KT recipients on an immunosuppressant regimen who were followed up after transplantation participated in this study. Data was collected through a self-reported questionnaire survey (medication adherence, SE, and quality of life) and medical record review. Low adherence in the immunosuppressant group was associated with longer time since KT, less comorbidity (adherence among KT recipients showed significantly greater overall symptom occurrence (P = .001) and symptom distress (P = .002) levels than patients with high or medium adherence after adjusting for a number of covariates. The most common symptom both in terms of occurrence (96.4%) and distress (91.1%) among poorly adherent KT recipients was tiredness. Low adherence to an immunosuppressant regimen was significantly associated with high SE among KT recipients. Strategies to decrease immunosuppressant-related SE are needed to improve adherence to immunosuppressants. Copyright © 2015 Elsevier Inc. All rights reserved.

Dietary Chlorella vulgaris Ameliorates Altered Immunomodulatory Functions in Cyclophosphamide-Induced Immunosuppressive Mice

Science.gov (United States)

Cheng, Dai; Wan, Zhaodong; Zhang, Xinyu; Li, Jian; Li, He; Wang, Chunling

2017-01-01

Based on the well-known toxicity of cyclophosphamide (CYP) on the immune system, this research investigated the modulating effects of the long-term dietary Chlorella vulgaris (CV) supplementation on the immunosuppression induced by CYP in mice, in order to provide a novel dietary design to mitigate the side effects of CYP therapy. Control, CYP-treated, CYP + CV (6%), CYP + CV (12%) and CYP + CV (24%) were used for 6 weeks, CV supplement in diet recovered the significantly reduced immunological function in CYP treated mice. As CV may have a modulating function through the inducible expression of cytokines, we assayed the expressions of interleukin-2 (IL-2), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Our results suggested that CYP significantly reduced the lymphocytes proliferation and phagocytic activities of macrophages, and stimulated the production of IL-2, IL-12, TNF-α and IFN-γ and that this impairment has been successfully adjusted by CV supplementation. Treatment with the algae also enhanced the natural killer (NK) cells cytotoxicity, and ameliorate histological changes of the spleen in CYP-treated mice. Therefore, as we found in this study, a diet supplemented with whole CV has beneficial effects on CVP-induced immunosuppression, through its immunomodulatory potential. PMID:28684674

Therapeutic applications of nanomedicine in autoimmune diseases: from immunosuppression to tolerance induction.

Science.gov (United States)

Gharagozloo, Marjan; Majewski, Slawomir; Foldvari, Marianna

2015-05-01

Autoimmune diseases are chronic, destructive diseases that can cause functional disability and multiple organ failure. Despite significant advances in the range of therapeutic agents, especially biologicals, limitations of the routes of administration, requirement for frequent long-term dosing and inadequate targeting options often lead to suboptimal effects, systemic adverse reactions and patient non-compliance. Nanotechnology offers promising strategies to improve and optimize autoimmune disease treatment with the ability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we focus on nanomedicine-based delivery strategies of biological immunomodulatory agents for the treatment of autoimmune disorders including psoriasis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, multiple sclerosis and type 1 diabetes. This comprehensive review details the concepts and clinical potential of novel nanomedicine approaches for inducing immunosuppression and immunological tolerance in autoimmune diseases in order to modulate aberrant and pathologic immune responses. The treatment of autoimmune diseases remains a significant challenge. The authors here provided a comprehensive review, focusing on the current status and potential of nanomedicine-based delivery strategies of immunomodulatory agents for the treatment of autoimmune disorders including psoriasis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, multiple sclerosis, and type 1 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA-identical siblings.

Science.gov (United States)

Kobayashi, Ryoji; Yabe, Hiromasa; Hara, Junichi; Morimoto, Akira; Tsuchida, Masahiro; Mugishima, Hideo; Ohara, Akira; Tsukimoto, Ichiro; Kato, Koji; Kigasawa, Hisato; Tabuchi, Ken; Nakahata, Tatsutoshi; Ohga, Shoichi; Kojima, Seiji

2006-12-01

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte-globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16.6, P = 0.001). Patients who received ATG and CsA had a significantly lower probability of failure-free survival than those who did not (69.7 +/- 6.2% vs. 87.9 +/- 8.0%, P = 0.044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen-identical siblings.

Cyclosporine A-loaded and stem cell-seeded electrospun nanofibers for cell-based therapy and local immunosuppression

Czech Academy of Sciences Publication Activity Database

Holáň, Vladimír; Chudíčková, Milada; Trošan, Peter; Svobodová, Eliška; Krulová, Magdalena; Kubinová, Šárka; Syková, Eva; Širc, Jakub; Michálek, Jiří; Juklíčková, M.; Munzarová, M.; Zajícová, Alena

2011-01-01

Roč. 156, č. 3 (2011), s. 406-412 ISSN 0168-3659 R&D Projects: GA AV ČR KAN200520804; GA ČR GAP304/11/0653; GA ČR(CZ) GAP301/11/1568; GA ČR GD310/08/H077; GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z40500505; CEZ:AV0Z50520514 Keywords : nanofibers * immunosuppression * cell transfer Subject RIV: EC - Immunology Impact factor: 5.732, year: 2011

Generic maintenance immunosuppression in solid organ transplant recipients.

Science.gov (United States)

Ensor, Christopher R; Trofe-Clark, Jennifer; Gabardi, Steven; McDevitt-Potter, Lisa M; Shullo, Michael A

2011-11-01

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immunosuppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.

Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia

Energy Technology Data Exchange (ETDEWEB)

Schuster, F R; Hubner, B [Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Düsseldorf (Germany); Führer, M [Department of Pediatric Oncology and Hematology, Dr von Haunersches Children' s Hospital, University of Munich, Munich (Germany); Eckermann, O; Gombert, M [Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Düsseldorf (Germany); Dornmair, K [Department for Clinical Neuroimmunology, University of Munich, Munich (Germany); Binder, V; Reuther, S; Krell, P [Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Düsseldorf (Germany); Keller, T [Acomed, statistical analysis GmbH, Leipzig (Germany); Borkhardt, A [Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Düsseldorf (Germany)

2011-03-01

One of the major obstacles of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) comes from the often months-long unpredictability of bone-marrow (BM) recovery. In this prospective study in children with newly diagnosed very severe AA (n=10), who were enrolled in the therapy study SAA-BFM 94, we found a dramatically reduced diversity of both CD4+ and CD8+ BM cells, as scored by comprehensive V-beta chain T-cell receptor (TCR) analysis. Strongly skewed TCR V-beta pattern was highly predictive for good or at least partial treatment response (n=6, CD8+ complexity scoring median 35.5, range 24–73). In contrast, IST in patients with rather moderate reduction of TCR V-beta diversity (n=4, CD8+ complexity scoring median 109.5, range 82–124) always failed (P=0.0095). If confirmed in a larger series of patients, TCR V-beta repertoire in BM may help to assign children with SAA up-front either to IST or to allogeneic stem-cell transplantation.

Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia

International Nuclear Information System (INIS)

Schuster, F R; Hubner, B; Führer, M; Eckermann, O; Gombert, M; Dornmair, K; Binder, V; Reuther, S; Krell, P; Keller, T; Borkhardt, A

2011-01-01

One of the major obstacles of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) comes from the often months-long unpredictability of bone-marrow (BM) recovery. In this prospective study in children with newly diagnosed very severe AA (n=10), who were enrolled in the therapy study SAA-BFM 94, we found a dramatically reduced diversity of both CD4+ and CD8+ BM cells, as scored by comprehensive V-beta chain T-cell receptor (TCR) analysis. Strongly skewed TCR V-beta pattern was highly predictive for good or at least partial treatment response (n=6, CD8+ complexity scoring median 35.5, range 24–73). In contrast, IST in patients with rather moderate reduction of TCR V-beta diversity (n=4, CD8+ complexity scoring median 109.5, range 82–124) always failed (P=0.0095). If confirmed in a larger series of patients, TCR V-beta repertoire in BM may help to assign children with SAA up-front either to IST or to allogeneic stem-cell transplantation

Immunity and immunosuppression in experimental visceral leishmaniasis

Directory of Open Access Journals (Sweden)

Goto H.

2004-01-01

Full Text Available Leishmaniasis is a disease caused by protozoa of the genus Leishmania, and visceral leishmaniasis is a form in which the inner organs are affected. Since knowledge about immunity in experimental visceral leishmaniasis is poor, we present here a review on immunity and immunosuppression in experimental visceral leishmaniasis in mouse and hamster models. We show the complexity of the mechanisms involved and differences when compared with the cutaneous form of leishmaniasis. Resistance in visceral leishmaniasis involves both CD4+ and CD8+ T cells, and interleukin (IL-2, interferon (IFN- gamma, and IL-12, the latter in a mechanism independent of IFN- gamma and linked to transforming growth factor (TGF-ß production. Susceptibility involves IL-10 but not IL-4, and B cells. In immune animals, upon re-infection, the elements involved in resistance are different, i.e., CD8+ T cells and IL-2. Since one of the immunopathological consequences of active visceral leishmaniasis in humans is suppression of T-cell responses, many studies have been conducted using experimental models. Immunosuppression is mainly Leishmania antigen specific, and T cells, Th2 cells and adherent antigen-presenting cells have been shown to be involved. Interactions of the co-stimulatory molecule family B7-CTLA-4 leading to increased level of TGF-ß as well as apoptosis of CD4+ T cells and inhibition of macrophage apoptosis by Leishmania infection are other components participating in immunosuppression. A better understanding of this complex immune response and the mechanisms of immunosuppression in experimental visceral leishmaniasis will contribute to the study of human disease and to vaccine development.

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

Science.gov (United States)

English, Clayton; Aloi, Joseph J

2015-04-01

Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of disease-modifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000-December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a 2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients

Symptom Experience Associated With Immunosuppressive Medications in Chinese Kidney Transplant Recipients.

Science.gov (United States)

Teng, Sha; Zhang, Shuping; Zhang, Wenxin; Lin, Xiaohong; Shang, Yabin; Peng, Xiao; Liu, Hongxia

2015-09-01

Kidney transplant recipients require lifelong treatment with immunosuppressive medications to avoid graft rejection and graft loss. Symptoms experienced may influence recipients' perceived quality of life and medication adherence. The purpose of this study was to evaluate the symptom experience associated with immunosuppressive medications in adult kidney transplant recipients and to explore the association between the symptom experience and adherence to immunosuppressive medications. A cross-sectional design was used. The study was conducted in a general hospital in China from October 2013 to September 2014. A total of 231 recipients with a follow-up of at least 1 year after kidney transplantation were included. Symptom experience associated with immunosuppressive medications was measured by the 13-item Symptom Experience of Immunosuppressive-related Side Effects Scale. Self-reported adherence to immunosuppressive medications was assessed using the Adherence with Immunosuppressive Medication Scale. Ridit analysis was used to rank symptom distress items. A proportion of 60.6% of recipients were male; the time after kidney transplantation was arbitrarily divided into a short-term cohort (1-4 years) and a long-term cohort (4-16 years) according to the median duration of follow-up (4 years). High blood pressure, hair loss, and tiredness were the three most distressing symptoms over all items of the whole sample. High blood pressure was the most distressing symptom for the 1- to 4-year cohort and the 4- to 16-year cohort. For men high blood pressure was the most distressing symptom, whereas for women hair loss was the most distressing symptom. Recipients in the 4- to 16-year cohort perceived a higher level of symptom distress compared with those in the 1- to 4-year cohort, especially in excess hair growth and difficulty sleeping. A negative relationship was found between symptom distress and adherence to immunosuppressive medications (r = -.541, p = .000). Recipients

Fibroblast Growth Factor-2 Enhances Expansion of Human Bone Marrow-Derived Mesenchymal Stromal Cells without Diminishing Their Immunosuppressive Potential

OpenAIRE

Auletta, Jeffery J.; Zale, Elizabeth A.; Welter, Jean F.; Solchaga, Luis A.

2011-01-01

Allogeneic hematopoietic stem cell transplantation is the main curative therapy for many hematologic malignancies. Its potential relies on graft-versus-tumor effects which associate with graft-versus-host disease. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties that make them attractive therapeutic alternatives. We evaluated the in vitro immunosuppressive activity of medium conditioned by human MSCs from 5 donors expanded 13 passages with or without FGF-2. FGF-2 supplemen...

Radiation therapy

International Nuclear Information System (INIS)

Bader, J.L.; Glatstein, E.

1987-01-01

The radiation oncologist encounters the critically ill immunosuppressed patient in four settings. First, the newly diagnosed cancer patient presents for initial evaluation and treatment, with immunosuppression from the cancer itself, malnutrition, concomitant infectious disease, prior drug or alcohol abuse or other medical problems. Second, the previously treated cancer patient presents with metastatic or recurrent primary cancer causing local symptoms. Immune dysfunction in this setting may be due to prior chemotherapy and/or radiation as well as any of the original factors. Third, the patient previously treated with radiation presents with a life-threatening problem possibly due to complications of prior therapy. In this setting, the radiation oncologist is asked to evaluate the clinical problem and to suggest whether radiation might be causing part or all of the problem and what can be done to treat these sequelae of radiation. Fourth, the patient with a benign diagnosis (not cancer) is seen with a problem potentially emeliorated by radiation (e.g., kidney transplant rejection, preparation for transplant, or intractable rheumatoid arthritis). This chapter reviews these four issues and presents clinical and radiobiologic principles on which recommendations for therapy are based

The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression

DEFF Research Database (Denmark)

Mocroft, Amanda; Bannister, Wendy P; Kirk, Ole

2012-01-01

The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression.......The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression....

Cell source-dependent in vivo immunosuppressive properties of mesenchymal stem cells derived from the bone marrow and synovial fluid of minipigs

Energy Technology Data Exchange (ETDEWEB)

Lee, Won-Jae [College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of); Hah, Young-Sool [Biomedical Research Institute, Gyeongsang National University Hospital, Jinju (Korea, Republic of); Ock, Sun-A. [Animal Biotechnology Division, National Institute of Animal Science, RDA, Suwon 441-706, Gyeonggi (Korea, Republic of); Lee, Jae-Hoon; Jeon, Ryong-Hoon; Park, Ji-Sung [College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of); Lee, Sang-Il [Department of Internal Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju (Korea, Republic of); Rho, Na-Young [Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada N1G 4S7 (Canada); Rho, Gyu-Jin [College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of); Research Institute of Life Sciences, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of); Lee, Sung-Lim, E-mail: sllee@gnu.ac.kr [College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of); Research Institute of Life Sciences, Gyeongsang National University, Jinju 660-701, Gyeongnam (Korea, Republic of)

2015-05-01

The in vitro differentiation and immunosuppressive capacity of mesenchymal stem cells (MSCs) derived from synovial fluid (SF-MSCs) and bone marrow extract (BM-MSCs) in an isogenic background of minipigs were comparatively analyzed in a collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis (RA). The proliferation capacity and expression of pluripotent transcription factors (Oct3/4 and Sox2) were significantly (P<0.05) higher in SF-MSCs than in BM-MSCs. The differentiation capacity of SF-MSCs into adipocytes, osteocytes and neurocytes was significantly (P<0.05) lower than that of BM-MSCs, and the differentiation capacity of SF-MSCs into chondrocytes was significantly (P<0.05) higher than that of BM-MSCs. Systemic injection of BM- and SF-MSCs significantly (P<0.05) ameliorated the clinical symptoms of CIA mice, with SF-MSCs having significantly (P<0.05) higher clinical and histopathological recovery scores than BM-MSCs. Furthermore, the immunosuppressive properties of SF-MSCs in CIA mice were associated with increased levels of the anti-inflammatory cytokine interleukin (IL)-10, and decreased levels of the pro-inflammatory cytokine IL-1β and osteoclast-related sRANKL. In conclusion, SF-MSCs exhibited eminent pluripotency and differentiation capacity into chondrocytes, addition to substantial in vivo immunosuppressive capacity by elevating IL-10 and reducing IL-1β levels in CIA mice. - Highlights: • Immunosuppressive capacity of BM-, SM-, and SF-MSCs was evaluated in an RA model. • Proliferation, pluripotency and chondrogenic differentiation capacity were higher in SF-MSCs. • SF-MSCs exhibited improved therapeutic effects than BM-MSCs. • SF-MSCs may have applications as immunosuppressive therapy in autoimmune diseases.

Comparison of the immunosuppressive effect of fractionated total lymphoid irradiation (TLI) vs conventional immunosuppression (CI) in renal cadaveric allotransplantation

International Nuclear Information System (INIS)

Waer, M.; Vanrenterghem, Y.; Ang, K.K.; van der Schueren, E.; Michielsen, P.; Vandeputte, M.

1984-01-01

Beginning in November 1981, eight patients with end stage diabetic nephropathy underwent renal cadaveric transplantation after TLI. Transplantation was done between 2 to 11 days after the end of a fractionated TLI to a total dose of 20 to 30 Gy. During the same observation period, 60 nondiabetic patients with end stage renal disease of different origin also received a cadaveric kidney graft, with a conventional regimen of immunosuppression that consists of anti-lymphocyte-globulin, tapering high doses of prednisone, and azathioprine. Phytohemagglutinin (PHA)-, concanavalin A (con A)-, and pokeweed mitogen (PWM)-induced blastogenesis, as well as the mixed lymphocyte reaction (MLR) and the cell-mediated lympholysis (CML) decreased progressively during the first months after conventional immunosuppression to 50% of the pretransplantation level, and remained there for the first year after transplantation. These tests were much more impaired after TLI and again no recovery occurred during the first year. In the clinic, the more profound immunosuppression in TLI patients was more frequently associated with viral infections (cytomegalovirus and herpes zoster). The incidence of rejections, however, was somewhat less frequent in the TLI-treated group and occurred significantly later. After TLI, the mean cumulative dose of steroids needed for kidney transplantation during the first year after transplantation could be substantially reduced

Association of elevated pretransplant sCD30 levels with graft loss in 206 patients treated with modern immunosuppressive therapies after renal transplantation.

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Heinemann, Falko M; Rebmann, Vera; Witzke, Oliver; Philipp, Thomas; Broelsch, Christoph E; Grosse-Wilde, Hans

2007-03-27

Recent reports suggest that high pretransplant serum levels of soluble CD30 (sCD30) are a risk factor for rejections after kidney transplantation. The aim of our study was to elucidate the predictive value of pretransplant sCD30 levels for kidney transplantation outcome in a single-center patient cohort that has been treated with modern immunosuppressive therapies after transplantation. We retrospectively analyzed sCD30 in multiple pretransplant sera from 206 patients, of whom 174 were transplanted with a cadaveric kidney and 32 patients received an allograft from a living donor. Renal function after transplantation was estimated by measuring serum creatinine and by rejection diagnosis. We could demonstrate a statistically significant association between increased pretransplant sCD30 values and graft failures (P=0.005). Receiver operating curve analysis revealed a cutoff value of 124 U/mL pretransplant sCD30. A multivariate analysis confirmed pretransplant sCD30 values >124 U/mL (P=0.011) and rejection episodes (PsCD30 levels and the incidence of graft failure, but we could not confirm that the development of rejection episodes is correlated with pretransplant sCD30 values.

INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

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AnnaMaria Nosari

2012-11-01

Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

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Castro-Manrreza, Marta E.; Mayani, Hector; Monroy-García, Alberto; Flores-Figueroa, Eugenia; Chávez-Rueda, Karina; Legorreta-Haquet, Victoria; Santiago-Osorio, Edelmiro

2014-01-01

Bone marrow-mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used in cell therapies as immune regulators for the treatment of graft-versus-host disease. We have previously characterized several biological properties of MSCs from placenta (PL) and umbilical cord blood (UCB), and compared them to those of BM—the gold standard. In the present study, we have compared MSCs from BM, UCB, and PL in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells. Our results confirm the immunosuppressive potential of BM-MSCs, and demonstrate that MSCs from UCB and, to a lesser extent PL, also have immunosuppressive potential. In contrast to PL-MSCs, BM-MSCs and UCB-MSCs significantly inhibited the proliferation of both CD4+ and CD8+ activated T cells in a cell–cell contact-dependent manner. Such a reduced proliferation in cell cocultures correlated with upregulation of programmed death ligand 1 on MSCs and cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) on T cells, and increased production of interferon-γ, interleukin-10, and prostaglandin E2. Importantly, and in contrast to PL-MSCs, both BM-MSCs and UCB-MSCs favored the generation of T-cell subsets displaying a regulatory phenotype CD4+CD25+CTLA-4+. Our results indicate that, besides BM-MSCs, UCB-MSCs might be a potent and reliable candidate for future therapeutic applications. PMID:24428376

Immunosuppression in the elderly renal allograft recipient

DEFF Research Database (Denmark)

Montero, Nuria; Pérez-Sáez, María José; Pascual, Julio

2016-01-01

BACKGROUND: The Elderly are the fastest growing part of kidney transplant recipients. The best immunosuppressive strategy is unknown. METHODS: We performed a systematic search of randomized controlled trials and observational studies focused on safety and efficacy of different immunosuppression...... strategies in elderly kidney recipients. Data extraction and risk of bias evaluation were systematically performed. RESULTS: Ten studies were included: 2 randomized clinical trials and 8 observational. A marginal benefit was found for early renal function with delayed tacrolimus or complete tacrolimus...... receptor antibody induction, calcineurin-inhibitor minimization with MMF and steroid minimization is advisable in the low immunologic risk elderly recipient, considering the increased risk of toxicities, infection and malignancies. In the high immunologic risk elderly recipient, taking into account...

CCL2 is critical for immunosuppression to promote cancer metastasis.

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Kudo-Saito, Chie; Shirako, Hiromi; Ohike, Misa; Tsukamoto, Nobuo; Kawakami, Yutaka

2013-04-01

We previously found that cancer metastasis is accelerated by immunosuppression during Snail-induced epithelial-to-mesenchymal transition (EMT). However, the molecular mechanism still remained unclear. Here, we demonstrate that CCL2 is a critical determinant for both tumor metastasis and immunosuppression induced by Snail(+) tumor cells. CCL2 is significantly upregulated in various human tumor cells accompanied by Snail expression induced by snail transduction or TGFβ treatment. The Snail(+) tumor-derived CCL2 amplifies EMT events in other cells including Snail(-) tumor cells and epithelial cells within tumor microenvironment. CCL2 secondarily induces Lipocalin 2 (LCN2) in the Snail(+) tumor cells in an autocrine manner. CCL2 and LCN2 cooperatively generate immunoregulatory dendritic cells (DCreg) having suppressive activity accompanied by lowered expression of costimulatory molecules such as HLA-DR but increased expression of immunosuppressive molecules such as PD-L1 in human PBMCs. The CCL2/LCN2-induced DCreg cells subsequently induce immunosuppressive CD4(+)FOXP3(+) Treg cells, and finally impair tumor-specific CTL induction. In murine established tumor model, however, CCL2 blockade utilizing the specific siRNA or neutralizing mAb significantly inhibits Snail(+) tumor growth and metastasis following systemic induction of anti-tumor immune responses in host. These results suggest that CCL2 is more than a chemoattractant factor that is the significant effector molecule responsible for immune evasion of Snail(+) tumor cells. CCL2 would be an attractive target for treatment to eliminate cancer cells via amelioration of tumor metastasis and immunosuppression.

Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches

Institute of Scientific and Technical Information of China (English)

Rita Diehl; Fabienne Ferrara; Claudia Müller; Antje Y Dreyer; Damian D McLeod; Stephan Fricke; Johannes Boltze

2017-01-01

Almost every experimental treatment strategy using non-autologous cell,tissue or organ transplantation is tested in small and large animal models before clinical translation.Because these strategies require immunosuppression in most cases,immunosuppressive protocols are a key element in transplantation experiments.However,standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species.Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation.This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects.It also summarizes contemporary knowledge of novel immunomodulatory strategies,such as the use of mesenchymal stem cells or antibodies.Thus,this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.

UVB-induced systemic immunosuppression: role of mast cells and histamine

International Nuclear Information System (INIS)

Hart, P.H.; Grimbaldeston, M.A.; Finlay-Jones, J.J.

1999-01-01

Full text: UVB radiation (290-320 nm) is immunosuppressive by multiple mechanisms allowing the outgrowth of UV-induced tumours in both mouse and man. Furthermore, patients with non-melanoma skin cancers have a higher risk of death from other cancers which could be explained by UV-induced immunomodulation. The mechanism(s) of suppression by UVB depend on whether the sensitising antigen is applied to the irradiated site ('local') or to non-irradiated sites ('systemic'). In the former, the activity of UV-induced TNFα is important as it affects the migration of Langerhans cells to draining lymph nodes. In contrast, histamine from dermal mast cells is critical to the early events by which UVB can suppress systemic immune responses. The prevalence of dermal mast cells in 7 strains and substrains of mice correlates directly with their susceptibility to UVB-induced systemic immunosuppression. Furthermore, mast cell depleted mice (Wf/Wf) are resistant to UVB-induced systemic immunomodulation. However, they become susceptible after reconstitution of the site to be irradiated with bone marrow derived mast cell precursors. The mice also gain susceptibility to cis-urocanic acid-induced systemic immunomodulation. There is considerable evidence that histamine is the mast cell product critical to downstream immunosuppressive events. Firstly, physiological concentrations of histamine suppress contact hypersensitivity responses. Secondly, histamine receptor antagonists halve UVB-induced systemic immunosuppression. Thirdly, mice with different UVB-susceptibilities are equally susceptible to histamine-induced immunosuppression, and finally, histamine can suppress contact hypersensitivity responses in Wf/Wf mice. We suggest that histamine may be immunomodulatory by multiple pathways. Histamine can induce the production of immunosuppressive prostanoids from keratinocytes. A lymphocyte-derived, histamine-induced suppressor factor was reported in the 1970's. More recently histamine has

Prevention and treatment of Encephalitozoon cuniculi infection in immunosuppressed rabbits with fenbendazole.

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Abu-Akkada, S S; Oda, S S

2016-01-01

This study was conducted to evaluate the efficacy of oral administration of fenbendazole (20 mg/kg body weight) prior to and after experimental infection of immunosuppressed rabbits with Encephalitozoon cuniculi . A total of thirty rabbits were divided into five groups: NN (non-immunosuppressed; non-infected), IN (immunosuppressed; non-infected), IPI (immunosuppressed; protected-infected), ITI (immunosuppressed; treated-infected), and II (immunosuppressed; infected) groups. Fenbendazole was administered as a prophylactic for seven successive days before infection with E. cuniculi and as a treatment for four weeks initiated on the 28th day post-challenge (PC). Experimental rabbits were infected with intraperitoneal injection of 2 × 10 5 E. cuniculi spores. Parameters evaluated were body weight, detection of spores in urine, serum antibody assay, hematological, biochemical and histopathological changes. The IPI and ITI groups showed a significant better final bwt than the II group. Spores were detected in urine of all infected rabbits from the 28th day PC until the end of the study. The IPI group showed the least values of antibodies (IgG) compared to the ITI and II groups. Concerning histopathological changes, the intensity of the lesions was marked particularly in the II rabbits and to a lesser extent in the ITI rabbits. Noticeable improvement was found in the IPI rabbits. It could be concluded that fenbendazole was effective to some extent in protection of rabbits against E. cuniculi infection, while when administered as a therapeutic no significant effects were observed.

[The variation and clinical significance of paroxysmal nocturnal hemoglobinuria clone in patients with aplastic anemia before and after immunosuppressive therapy].

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Sun, Ying-xin; Zhu, Ming-qing; He, Guang-sheng; Wang, Xiu-li; Fang, Bao-zhi; Lu, Cong; Liu, Zhen-zhen; Wu, Qian; Yang, Yong; Wu, De-pei; Sun, Ai-ning

2013-07-01

To evaluate the evolution of paroxysmal nocturnal hemoglobinuria (PNH) clone and its clinical significance before and after immunosuppressive therapy (IST) in patients with aplastic anemia (AA). A total of 186 patients diagnosed as AA were enrolled in this study. Among them, 55 patients were diagnosed as severe AA (SAA) and treated with cyclosporine (CsA) plus anti-thymocyte globulin (ATG), 131 were diagnosed as non SAA (NSAA) and treated with CsA alone. All patients were screened for PNH clone by flow cytometry before treatment and followed up for 18-76 months, with a median time of 22 months. Positive PNH clones were detected in 10 SAA (18.9%) patients, significantly more than that of NSAA group [9 patients (7.4%), t = 5.041, P = 0.025]. The proportions of PNH clones in SAA group at 6, 12, 24 and > 24 months were 13.38%, 14.88%, 20.00% and 18.85%, respectively, also significantly higher than those of NSAA patients (5.67%, 5.31%, 5.47% and 9.08%, all P values clone was positive or negative. PNH clone are detectable in AA patients either treated with ATG plus CsA or CsA alone, and more significant by ATG plus CsA. Whether PNH clone occurred before or after IST does not affect the therapeutic efficacy.

Use of High-Flow Nasal Cannula Oxygen Therapy in a Pregnant Woman with Dermatomyositis-Related Interstitial Pneumonia

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Tomohiro Shoji

2017-01-01

Full Text Available A 33-year-old pregnant woman was referred to our hospital with respiratory distress at 30 weeks of gestation. Chest computed tomography (CT scans revealed pulmonary infiltrates along the bronchovascular bundles and ground-glass opacities in both lungs. Despite immediate treatment with steroid pulse therapy for suspected interstitial pneumonia, the patient’s condition worsened. Respiratory distress was slightly alleviated after the initiation of high-flow nasal cannula (HFNC oxygen therapy (40 L/min, FiO2 40%. We suspected clinically amyopathic dermatomyositis (CADM complicating rapidly progressive refractory interstitial pneumonia. In order to save the life of the patient, the use of combination therapy with immunosuppressants was necessary. The patient underwent emergency cesarean section and was immediately treated with immunosuppressants while continuing HFNC oxygen therapy. The neonate was treated in the neonatal intensive care unit. The patient’s condition improved after 7 days of hospitalization; by this time, she was positive for myositis-specific autoantibodies and was diagnosed with interstitial pneumonia preceding dermatomyositis. This condition can be potentially fatal within a few months of onset and therefore requires early combination immunosuppressive therapy. This case demonstrates the usefulness of HFNC oxygen therapy for respiratory management as it negates the need for intubation and allows for various treatments to be quickly performed.

Travel and biologic therapy: travel-related infection risk, vaccine response and recommendations.

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Hall, Victoria; Johnson, Douglas; Torresi, Joseph

2018-01-01

Biologic therapy has revolutionized the management of refractory chronic autoimmune and auto-inflammatory disease, as well as several malignancies, providing rapid symptomatic relief and/or disease remission. Patients receiving biologic therapies have an improved quality of life, facilitating travel to exotic destinations and potentially placing them at risk of a range of infections. For each biologic agent, we review associated travel-related infection risk and expected travel vaccine response and effectiveness. A PUBMED search [vaccination OR vaccine] AND/OR ['specific vaccine'] AND/OR [immunology OR immune response OR response] AND [biologic OR biological OR biologic agent] was performed. A review of the literature was performed in order to develop recommendations on vaccination for patients in receipt of biologic therapy travelling to high-risk travel destinations. There is a paucity of literature in this area, however, it is apparent that travel-related infection risk is increased in patients on biologic therapy and when illness occurs they are at a higher risk of complication and hospitalization. Patients in receipt of biologic agents are deemed as having a high level of immunosuppression-live vaccines, including the yellow fever vaccine, are contraindicated. Inactivated vaccines are considered safe; however, vaccine response can be attenuated by the patient's biologic therapy, thereby resulting in reduced vaccine effectiveness and protection. Best practice requires a collaborative approach between the patient's primary healthcare physician, relevant specialist and travel medicine expert, who should all be familiar with the immunosuppressive and immunomodulatory effects resulting from the biologic therapies. Timing of vaccines should be carefully planned, and if possible, vaccination provided well before established immunosuppression.

Endogenous Nocardial Endophthalmitis in an Immunosuppressed Patient: A Serious Warning of an Underlying Life Threatening and Blinding Disorder.

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Trehan, Hemant; Kaushik, Jaya; Jain, Vaibhav Kumar; Parihar, Jitendra Kumar Singh; Avasthi, Abhijit

2017-01-01

To report a case of bilateral endogenous nocardial endophthalmitis with central nervous system involvement in an immunocompromised individual with an extremely poor outcome. A 35-year-old man with a history of long-term, prescribed oral steroid use for membranoproliferative glomerulonephritis presented with profound bilateral vision loss. Patient's diagnosis of bilateral endogenous nocardial endophthalmitis was delayed. Nocardia was finally isolated from a brain biopsy after a repeat magnetic resonance imaging revealed a brain abscess. With anti-nocardia therapy, patient improved systemically, but the visual outcome was poor, with no light perception in both eyes. Ocular nocardiosis is a serious vision and life threatening disorder, particularly in patients on immunosuppressive therapy. A high index of suspicion is required for successful treatment.

Rethinking the role of myeloid-derived suppressor cells in adoptive T-cell therapy for cancer

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Arina, Ainhoa

2014-01-01

The expansion of cancer-induced myeloid cells is thought to be one of the main obstacles to successful immunotherapy. Nevertheless, in murine tumors undergoing immune-mediated destruction by adoptively transferred T cells, we have recently shown that such cells maintain their immunosuppressive properties. Therefore, adoptive T-cell therapy can, under certain conditions, overcome myeloid cell immunosuppression. PMID:25050213

Immunosuppression and tolerance after total lymphoid irradiation (TLI)

International Nuclear Information System (INIS)

Strober, S.; Gottlieb, M.; Slavin, S.; King, D.P.; Hoppe, R.T.; Fuks, Z.; Bieber, C.P.; Kaplan, H.S.

1980-01-01

The immunosuppressive effects of total lymphoid irradiation (TLI) in humans and in several species of inbred and outbred laboratory animals have been investigated. A unique property of TLI, the prevention of the graft vs. host disease, was used to induce transplantation tolerance in order to study the mechanism of altered immunity when the celluar basis of the TLI-induced immunosuppression was examined by means of the mixed lymphocyte response (MLR), no suppression of the MLR was observed when spleen cells from unirradiated or whole body-irradiated donors were used instead of donors given TLI. These results indicated that TLI induces a population of cells in the spleen that can nonspecifically suppress the MLR

Immunosuppressive Treatment of Non-infectious Uveitis: History and Current Choices.

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Zhao, Chan; Zhang, Meifen

2017-04-10

Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosup- pressive treatment for uveitis since first introduced in 1950s, its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs, classified into alkylating agent, antimetabolites and T cell inhibitors, have been widely used as corticosteroid-sparing agents, each with characteristic safety/tolerance profiles on different uveitis entities. Recently, biologic agents, which target specific molecules in immunopathogenesis of uveitis, have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However, lack of large randomized controlled clinical trials, concerns about efficacy and safety of long-term usage, and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs (from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation, but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities (conventional immunosuppressive agents, biologics and local drug delivery systems) on hand, the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity, treatment availability, safety/tolerability, effectiveness, patient compliance, cost concerns and

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats.

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Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

2016-01-01

In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner.

Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels

DEFF Research Database (Denmark)

Kamara, David A; Smith, Colette; Ryom, Lene

2016-01-01

BACKGROUND: Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear......%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated...... with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas...

The use of immunosuppressive agents in the management of recalcitrant lower limb ulcers.

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Millen, A; Coulston, J; Brennan, J; Kennedy, T

2014-08-01

Lower limb ulcers that are resistant to standard forms of treatment place a significant burden on both patients and health services. There is no widely agreed definition of a recalcitrant ulcer but failure to heal following 6-12 months of focused treatment would identify a small group of patients with highly resistant ulceration. We describe a series of patients with recalcitrant ulceration for which immunosuppressive agents have been used. This is a case series of 13 patients who underwent immunomodulation therapy for lower limb ulcers at a tertiary referral university hospital. Regimens of immunomodulation used mainly ciclosporin and/or cyclophosphamide, with concurrent antibiotic therapy. Case notes and computer systems were analysed by two reviewers. A patient was deemed to have a success if their ulcer fully healed while on immunomodulation therapy. Over a period of eight years, from 2004-2012, 13 patients underwent immunomodulation therapy. Among these patients there were 18 ulcerated limbs. Ulcer healing occurred in 10 limbs out of 18 (55.6%) and full healing occurred in six patients (46.2%). Ulcers were present for a median of five years (range 2-40 years), with a median diameter of 7.5 cm (range 4-18 cm) before treatment. Treatment of truly recalcitrant ulceration can be very frustrating for both the patient and physician, with poor success from more standard forms of treatment. We report experience with immunomodulation therapy that suggests there may be benefit from using this treatment in a subset of patients with this debilitating disease.

The targeting of immunosuppressive mechanisms in hematological malignancies

DEFF Research Database (Denmark)

Andersen, M H

2014-01-01

enzymes such as indoeamine-2,3-dioxygenase (IDO). The possible therapeutic targeting of these pathways is also discussed. Exciting new strategies that might affect future antileukemia immunotherapy include monoclonal antibodies that block inhibitory T-cell pathways (PD-1/PD-L1) and the prevention...... of tryptophan depletion by IDO inhibitors. Furthermore, the clinical effect of several chemotherapeutic drugs may arise from the targeting of immunosuppressive cells. Evidence for a new feedback mechanism to suppress the function of regulatory immune cells was recently provided by the identification...... and characterization of spontaneous cytotoxic T lymphocyte (CTL) responses against regulatory immune cells. Such specific CTLs may be immensely useful in anticancer immunotherapy (for example, by anticancer vaccination). The targeting of one or more immunosuppressive pathways may be especially interesting...

Soluble CD30 does not predict late acute rejection or safe tapering of immunosuppression in renal transplantation.

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Valke, Lars L F G; van Cranenbroek, Bram; Hilbrands, Luuk B; Joosten, Irma

2015-01-01

Previous reports revealed the potential value of the soluble CD30 level (sCD30) as biomarker for the risk of acute rejection and graft failure after renal transplantation, here we examined its use for the prediction of safe tapering of calcineurin inhibitors as well as late acute rejection. In a cohort of renal transplant patients receiving triple immunosuppressive therapy we examined whether sCD30 can be used as a marker for safe (rejection-free) discontinuation of tacrolimus at six months after transplantation (TDS cohort: 24 rejectors and 44 non-rejecting controls). Also, in a second cohort of patients (n=22, rejectors n=11 and non-rejectors n=11), participating in a clinical trial of rituximab as induction therapy after renal transplantation (RITS cohort), we examined whether sCD30 could predict the occurrence of late (>3months post-transplant) acute rejection episodes. sCD30 was measured by ELISA in serum taken before and at several time points after transplantation. Overall, in the TDS cohort sCD30 decreased after transplantation. No difference in sCD30 was observed between rejectors and non-rejecting controls at any of the time points measured. In addition, in the RITS cohort, sCD30 measured at three months after transplantation were not indicative for the occurrence of late acute rejection. In two prospectively followed cohorts of renal transplant patients we found no association between sCD30 and the occurrence of either late acute rejection or acute rejection after reduction of immunosuppression. Copyright © 2014 Elsevier B.V. All rights reserved.

Neurologic emergencies in HIV-negative immunosuppressed patients.

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Guzmán-De-Villoria, J A; Fernández-García, P; Borrego-Ruiz, P J

HIV-negative immunosuppressed patients comprise a heterogeneous group including transplant patients, patients undergoing treatment with immunosuppressors, uremic patients, alcoholics, undernourished patients, diabetics, patients on dialysis, elderly patients, and those diagnosed with severe or neoplastic processes. Epileptic seizures, focal neurologic signs, and meningoencephalitis are neurologic syndromes that require urgent action. In most of these situations, neuroimaging tests are necessary, but the findings can be different from those observed in immunocompetent patients in function of the inflammatory response. Infectious disease is the first diagnostic suspicion, and the identification of an opportunistic pathogen should be oriented in function of the type and degree of immunosuppression. Other neurologic emergencies include ischemic stroke, cerebral hemorrhage, neoplastic processes, and pharmacological neurotoxicity. This article reviews the role of neuroimaging in HIV-negative immunodepressed patients with a neurologic complication that requires urgent management. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

DSP30 enhances the immunosuppressive properties of mesenchymal stromal cells and protects their suppressive potential from lipopolysaccharide effects: A potential role of adenosine.

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Sangiorgi, Bruno; De Freitas, Helder Teixeira; Schiavinato, Josiane Lilian Dos Santos; Leão, Vitor; Haddad, Rodrigo; Orellana, Maristela Delgado; Faça, Vitor Marcel; Ferreira, Germano Aguiar; Covas, Dimas Tadeu; Zago, Marco Antônio; Panepucci, Rodrigo Alexandre

2016-07-01

Multipotent mesenchymal stromal cells (MSC) are imbued with an immunosuppressive phenotype that extends to several immune system cells. In this study, we evaluated how distinct Toll-like receptor (TLR) agonists impact immunosuppressive properties of bone marrow (BM)-MSC and explored the potential mechanisms involved. We show that TLR4 stimulation by lipopolysaccharide (LPS) restricted the ability of MSC to suppress the proliferation of T lymphocytes, increasing the gene expression of interleukin (IL)-1β and IL-6. In contrast, stimulation of TLR9 by DSP30 induced proliferation and the suppressive potential of BM-MSC, coinciding with reducing tumor necrosis factor (TNF)-α expression, increased expression of transforming growth factor (TGF)-β1, increased percentages of BM-MSC double positive for the ectonucleotidases CD39+CD73+ and adenosine levels. Importantly, following simultaneous stimulation with LPS and DSP30, BM-MSC's ability to suppress T lymphocyte proliferation was comparable with that of non-stimulated BM-MSC levels. Moreover, stimulation of BM-MSC with LPS reduced significantly the gene expression levels, on co-cultured T lymphocyte, of IL-10 and interferon (IFN)γ, a cytokine with potential to enhance the immunosuppression mediated by MSC and ameliorate the clinical outcome of patients with graft-versus-host disease (GVHD). Altogether, our findings reiterate the harmful effects of LPS on MSC immunosuppression, besides indicating that DSP30 could provide a protective effect against LPS circulating in the blood of GVHD patients who receive BM-MSC infusions, ensuring a more predictable immunosuppressive effect. The novel effects and potential mechanisms following the stimulation of BM-MSC by DSP30 might impact their clinical use, by allowing the derivation of optimal "licensing" protocols for obtaining therapeutically efficient MSC. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Immunosuppressive potential of bardoxolone methyl using a modified murine local lymph node assay (LLNA).

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Kitsukawa, Mika; Tsuchiyama, Hiromi; Maeda, Akihisa; Oshida, Keiyu; Miyamoto, Yohei

2014-08-01

2-Cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me; bardoxolone methyl) is one of the synthetic oleanane triterpenoids (SOs). It is known that it is the strongest Nrf2/ARE signaling inducer of SOs and slightly inhibits immune response. Little was known about the immunomodulatory action of CDDO-Me in vivo. We assessed its immunosuppressive potential by using the modified mouse lymph node assay (LLNA) including immunosuppression-related gene expression analysis. In the modified LLNA, CDDO-Me showed a significant decrease in lymph node weight and changes in expressions of the immunosuppression-related genes, Zfp459 and Fmo2. It has been already reported that a decrease in lymph node weight was induced by several types of immunosuppressive chemicals such as calcineurin inhibitors, antimetabolites, steroids, and alkylators. In addition, changes in Zfp459 and Fmo2 expression was reported in response after only treatment of antimetabolites. From these results, CDDO-Me is considered to have an immunosuppressive action and similar mechanism to antimetabolites.

Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

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Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

2018-04-07

Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol

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2013-01-01

Background Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. Methods/Design The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. Discussion Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. Trial

Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis.

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Kumari, P; Nigam, R; Singh, A; Nakade, U P; Sharma, A; Garg, S K; Singh, S K

2017-09-01

Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis.

Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro.

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Martina, M N; Ramirez Bajo, M J; Bañon-Maneus, E; Moya Rull, D; Hierro-Garcia, N; Revuelta, I; Campistol, J M; Rovira, J; Diekmann, F

2016-11-01

Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro. Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells. Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B-cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27 + CD24 + phenotype was not modified by any immunosuppressive treatment. Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation. Copyright © 2016. Published by Elsevier Inc.

Anti-thymocyte serum as part of an immunosuppressive regimen in treating haematological immune-mediated diseases in dogs.

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Cuq, B; Blois, S L; Mathews, K A

2017-06-01

To report the outcomes associated with the use of rabbit anti-dog thymocyte serum in dogs with haematological immune-mediated diseases. Medical records from 2000 to 2016 of patients diagnosed with immune-mediated haemolytic anaemia, immune-mediated thrombocytopenia, pancytopenia and myelofibrosis were reviewed. All dogs had a severe or refractory disease and received rabbit anti-dog thymocyte serum. Lymphocyte counts were used to monitor the immediate anti-thymocyte effect of therapy; long-term patient outcome was recorded. A total of 10 dogs were included. All dogs except one had a notable decrease in their lymphocyte count after rabbit anti-dog thymocyte serum; four of nine had a decrease to less than 10% of the initial lymphocyte count and one dog reached 10·8%. All dogs were discharged from the hospital following their treatment. The dog with no alteration of lymphocyte count following therapy with rabbit anti-dog thymocyte serum had refractory immune mediated haemolytic anemia and was euthanised within two weeks. All other cases achieved clinical remission with immunosuppressive therapy eventually being tapered (3 of 10) or discontinued (6 of 10). Rabbit anti-dog thymocyte serum therapy might be of interest as an adjunctive therapy in refractory immune-mediated diseases and suppressed lymphocyte counts in most dogs. © 2017 British Small Animal Veterinary Association.

African American kidney transplantation survival: the ability of immunosuppression to balance the inherent pre- and post-transplant risk factors.

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Malat, Gregory E; Culkin, Christine; Palya, Aniruddha; Ranganna, Karthik; Kumar, Mysore S Anil

2009-10-22

Among organ transplant recipients, the African American population historically has received special attention. This is because secondary to their disposition to certain disease states, for example hypertension, an African American patient has a propensity to reach end-stage renal disease and require renal replacement earlier than a Caucasian patient. Regardless of the initiative to replace dialysis therapy with organ transplantation, the African American patient has many barriers to kidney transplantation, thus extending their time on dialysis and waiting time on the organ transplant list. These factors are among the many negative causes of decreased kidney graft survival, realized before kidney transplantation. Unfortunately, once the African American recipient receives a kidney graft, the literature documents that many post-transplant barriers exist which limit successful outcomes. The primary post-transplant barrier relates to designing proper immunosuppression protocols. The difficulty in designing protocols revolves around (i) altered genetic metabolism/lower absorption, (ii) increased immuno-active cytokines and (iii) detrimental effects of noncompliance. Based on the literature, dosing of immunosuppression must be aggressive and requires a diligent practitioner. Research has indicated that, despite some success with proven levels of immunosuppression, the African American recipient usually requires a higher 'dose per weight' regimen. However, even with aggressive immunosuppressant dosing, African Americans still have worse outcomes than Caucasian recipients. Additionally, many of the targeted sites of action that immunosuppression exerts its effects on have been found to be amplified in the African American population. Finally, noncompliance is the most discouraging inhibitor of long-term success in organ transplantation. The consequences of noncompliance are biased by ethnicity and affect the African American population more severely. All of these factors

IMMUNOSUPPRESSIVE EFFECTS OF ARGININE DEIMINASE FROM STREPTOCOCCUS PYOGENES

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E. A. Starikova

2015-01-01

Full Text Available Many pathogens use metabolic pathway of arginine for successful dissemination. Bacterial arginine deiminase hydrolyzes arginine to form one molecule of ammonia and two molecules of ATP. The activity of the enzyme contributes to the improvement of survival of pathogenic bacteria in conditions of low pH at the site of infection or in phagolysosome, as well as in anaerobic conditions, and also leads to deficiency of arginine. Metabolism of arginine plays an important role in regulating the functions of immune system cells in mammals. Arginine is a substrate of enzymes NOS and arginase. Arginine depletion, potentially contributs to immunosuppression. The review analyzed the literature data on the effect of streptococcal arginine deiminase on the metabolism of arginine eukaryotic cells, and discusses immunosuppressive action of the enzyme.

Recent advances in cell-based therapy for Parkinson disease

DEFF Research Database (Denmark)

Astradsson, Arnar; Cooper, Oliver; Vinuela, Angel

2008-01-01

In this review, the authors discuss recent advances in the field of cell therapy for Parkinson disease (PD). They compare and contrast recent clinical trials using fetal dopaminergic neurons. They attribute differences in cell preparation techniques, cell type specification, and immunosuppression...

Pulmonary tuberculosis in a patient with rheumatoid arthritis undergoig immunosuppressive treatment: case report

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Sandro Ceratti

2014-02-01

Full Text Available Rheumatoid arthritis is a disease which characteristically affects the joints. Because it is an autoimmune disease, immunosuppressive drugs are widely used in its treatment. The present case report illustrates the association of immunosuppressive treatment with the development of opportunistic infections in a 64-year-old patient.

A systematic checklist approach to immunosuppression risk management: An audit of practice at two clinical neuroimmunology centers.

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Mori, Amelia M; Agarwal, Smriti; Lee, Monique W M; Rafferty, Martina; Hardy, Todd A; Coles, Alasdair; Reddel, Stephen W; Riminton, D Sean

2017-11-15

There is no consensus approach to safety screening for immune intervention in clinical neuroimmunology. An immunosuppression risk evaluation checklist was used as an audit tool to assess real-world immunosuppression risk management and formulate recommendations for quality improvements in patient safety. Ninety-nine patients from two centres with 27 non-MS diagnoses were included. An average of 1.9 comorbidities with the potential to adversely impact morbidity and mortality associated with immunosuppression were identified. Diabetes and smoking were the most common, however a range of rarer but potentially life-threatening co-morbid disorders in the context of immunosuppression were identified. Inadequate documentation of risk mitigation tasks was common at 40.1% of total tasks across both cohorts. A routine, systematic immunosuppression checklist approach should be considered to improve immunosuppression risk management in clinical neuroimmunology practice. Copyright © 2017 Elsevier B.V. All rights reserved.

The Immunosuppressant Effect Comparation Between Ethyl Acetate and n-Butanol Fractions of Kalanchoe Pinnata (Lmk Pers In 2,6,10,14 Tetramethylpentadecane-Treated Mice

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Niken Indriyanti

2017-07-01

Full Text Available Immunosuppressant drugs are the main treatment of lupus patient. The ACR and SLICC treatment guidelines are able to increase the quality of life, but the outcome is not satisfying since the off-label therapy of corticosteroids and cytotoxic drugs give a lot of side effects. Many breakthrough efforts still develop in order to find the safe and effective drugs for lupus, such as finding immunosuppressant drugs from natural resources. One of the potential resources is Kalanchoe pinnata (Lmk Pers, which have immunosuppressant, anti-inflammatory, antinociceptive, and antioxidant effects. Thus, in the previous study, we found the effect of the aqueous extract of Kalanchoe pinnata (Lmk Pers is active to repair the lupus manifestation in 2,6,10,14 tetramethylpentadecane (TMPD-treated mice. Then, this research was focused on the in vivo immunosuppressant effect of a flavonoid-rich fraction of the extract which was consisted of the ethyl acetate (FE and n-butanol (FB fractions. The induction method and the extraction procedure were the same as the previous study and then the fractionation was performed by using liquid-liquid extraction. After 2-week treatment of both fractions, we obtained the differences in the total leukocytes, organ indexes, and also the spleen, kidney, and joint structure parameters. The total leukocyte of the FE group was 3,600±264 cells/mm3, which was lower than that in the FB group. The spleen and kidney indexes increased after the administration of FB fraction, while the FE fraction was not. At last, despite the histology observation of spleen resembled mild structural changes differences, the clear differences between both treatment groups occurred in the kidney and joint histology. The differences led to a conclusion that the FE fraction has the better immunosuppressant effect in TMPD-treated mice.

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation.

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Guba, Markus; Pratschke, Johann; Hugo, Christian; Krämer, Bernhard K; Pascher, Andreas; Pressmar, Katharina; Hakenberg, Oliver; Fischereder, Michael; Brockmann, Jens; Andrassy, Joachim; Banas, Bernhard; Jauch, Karl-Walter

2012-04-01

Early conversion to a calcineurin-inhibitor (CNI)-free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1-year renal function as compared with a cyclosporine (CsA)-based regimen (SMART core-study). This observational follow-up describes 132 patients followed up within the SMART study framework for 36months. At 36months, renal function continued to be superior in SRL-treated patients [ITT-eGFR(@36m) : 60.88 vs. 53.72 (CsA) ml/min/1.73m(2) , P=0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA-treated patients. In a multivariate analysis, donor age >60years, S-creatinine at conversion >2mg/dl, CMV naïve(-) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36months. Early conversion to a CNI-free SRL-based immunosuppression is associated with a sustained improvement of renal function up to 36months after transplantation. Patient selection will be key to derive long-term benefit and avoid treatment failure using this mTOR-inhibitor-based immunosuppressive regimen. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

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Geisler, Christian H; van T' Veer, Mars B; Jurlander, Jesper

2014-01-01

.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529....

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation.

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Witkowska, Agnieszka; Strzalka-Mrozik, Barbara; Owczarek, Aleksander; Gola, Joanna; Mazurek, Urszula; Grzeszczak, Wladyslaw; Gumprecht, Janusz

2015-12-01

Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only the ACD (adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression of ACD was downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis of ACD , DKC1 and hTERT mRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has

Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

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Xiaojie Wang

2015-01-01

Full Text Available Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1 or fibroblasts (FB, group 2 under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P<0.001 without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

Abatacept as a successful therapy for myositis—a case-based review.

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Kerola, Anne M; Kauppi, Markku J

2015-03-01

Only limited evidence exists on the therapeutic potential of biologic agents in the treatment of myositis. We present a brief review of the literature on off-label experiences of biologic agents in myositis, with a special interest in abatacept. Rituximab has been indicated to be beneficial and well tolerated in one large randomized controlled trial and many smaller studies. Initial data on tumour necrosis factor (TNF) inhibitors are conflicting. There are only a few case reports and mechanistic studies on the treatment of myositis with other biologics, including alemtuzumab, anakinra, tocilizumab and abatacept. We report a patient with severe myositis overlap syndrome, manifesting also as rheumatoid arthritis, peripheral vasculitis and interstitial lung disease. Her myositis was refractory to many conventional and biologic therapies but was well controlled with abatacept. This suggests that abatacept might be a beneficial option for the treatment of refractory myositis and that clinical trials are needed to further investigate its efficacy.

High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions be restored?

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Lugade, Amit A; Kalathil, Suresh; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-07-01

The accumulation of immunosuppressive cells and exhausted effector T cells highlight an important immune dysfunction in advanced stage hepatocellular carcinoma (HCC) patients. These cells significantly hamper the efficacy immunotherapies and facilitate HCC progression. We have recently demonstrated that the multipronged depletion of immunosuppressive cells potentially restores effector T-cell function in HCC.

Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy.

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Tsujimura, Shizuyo; Adachi, Tomoko; Saito, Kazuyoshi; Tanaka, Yoshiya

2017-01-01

P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp + CD4 + cells in organ manifestations in refractory SLE. The proportion of P-gp + CD4 + cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4 + cells and CD69-expressing CD4 + cells in peripheral blood was higher in SLE than control. The proportion of P-gp + CD69 + CD4 + cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp + CD69 + CD4 + cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp + CD69 + CD4 + cells. Marked accumulation of P-gp + CD4 + cells in renal interstitial tissue and high proportion of peripheral P-gp + CD69 + CD4 + cells were noted in patients with proliferative LN. The results showed high proportion of P-gp + CD69 + CD4 + cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4 + T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.

[Evaluation of immunosuppressive treatment on homocystein levels in patients after kidney transplantation during a 2 year observation period].

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Aksamit, Dariusz; Janda, Katarzyna; Kuźniewski, Marek; Krzanowski, Marcin; Ignacak, Ewa; Betkowska-Prokop, Alina; Chowaniec, Eve; Sułowicz, Wladysław

2012-01-01

months after) did not differ significantly when compared to pts receiving immunosuppressive therapy CsA vs. Tac (p=0.18). Even though notable differences were observed in the drop in Hcy level (immunosuppressive treatment scheme CsA vs. Tac) in measurements before Ktx and 24 months post (respectively: 27% and 57.6%), no statistical significance was noted (p=0.13). Using the Mann-Whitneys' Test, no statistical significance was noted (p=0.13) when comparing differences in creatinine clearance between the group of pts receiving CsA and Tac 24 months after Ktx. Patients treated with Tac achieved a higher creatinine clearance by 16.5% when compared with those receiving CsA. No significant differences were observed between these two groups (p=0.65) when serum creatinine levels were evaluated. Incidence of DGF, as well as prescribed immunosuppressive therapy does not have an influence on remote Hey levels in pts after Ktx. Graft function seems to be the main predictor that influences Hcy levels after Ktx in this group of pts.

Efficacy and safety of immunosuppressive therapy in the treatment of seronegative hepatitis associated aplastic anemia

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Chen HF

2014-09-01

Full Text Available Hai-Fei Chen,* Bin-Xian Xu, Hong-Shi Shen,* Zheng-Yang Li, Ling-Juan Jin, Jie-Qing Tang, Jing Wang, Jing-Jing Zhu, Long-Mei Qin, Qing-Ya Cui, Yong-Ya Ren, Tian-Qin Wu Department of hematology, 100th hospital of People’s Liberation Army, Suzhou, Jiangsu province, The People’s Republic of China *These authors have contributed equally to this paper Objective: To investigate the clinical characteristics of seronegative hepatitis-associated aplastic anemia (AA (SNHAA and hepatitis B virus (HBV infection complicating AA (HBVAA, and thereby compare the efficacy of immunosuppressive therapy (IST.Methods: An analysis was conducted on the clinical data of ten patients with SNHAA out of 332 cases of AA from our center at AA diagnosis, and on the efficacy of IST. This was compared to 22 cases of HBVAA at AA onset as well as the associated IST outcomes.Results: Nine patients with SNHAA developed severe aplastic anemia, with a median age of 18 years. After IST, six (60% of the SNHAA patients achieved complete remission and two achieved partial remission. The patients with HBVAA had a total response rate of 82.3%. The disease recurred in two HBVAA patients. No statistically significant differences were observed in response rate, mortality, and recurrence rate between both groups. As compared with HBVAA, patients with SNHAA had a shorter interval from the acute episode of hepatitis to AA onset (4 months versus 92 months, P=0.00, a quicker response to IST (2.5 months versus 4.5 months, P=0.018, a lower proportion of bone marrow hematopoietic tissues (20.6% versus 23.6%, P=0.03, and lower white blood cell and absolute neutrophil count (0.8×109/L versus 1.23×109/L and 0.26×109/L versus 0.58×109/L, P=0.026 and P=0.0009, respectively. No significant liver damage or hepatitis B fulminant infection was observed in either group during the follow-up. Conclusion: The prevalence of SNHAA is 3.01%. SNHAA often presents as severe AA and responds to IST quickly

Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis.

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Peng, Xia; Luo, Xin; Hou, Jing-Ying; Wu, Shu-Yun; Li, Liang-Zong; Zheng, Ming-Hua; Wang, Ling-Yun

2017-01-01

Currently, there are no effective therapeutic agents for patients with primary sclerosing cholangitis (PSC). This study aimed to evaluate the safety and efficiency of immunosuppressive agents (IAs) for the treatment of PSC. The literatures were searched using the following keywords singly or in combination: PSC, treatments, IAs. The primary outcome was defined as the need for liver transplantation or mortality. Two hundred sixty six patients from 7 eligible studies were analyzed. IAs had no remarkable effects on the rate of mortality or liver transplantation (relative risk, RR 1.02, 95% CI 0.58-1.62, p = 0.92). Subgroup analyses showed no significant effect of IAs co-administration therapy (IAs co-administered with ursodeoxycholic acid, IA co-administered with IA; RR 1.41, 95% CI 0.40-4.95, p = 0.60). IAs caused adverse events (AEs) such as diarrhea, abdominal pain, and pruritus (RR 1.81, 95% CI 1.07-3.07, p = 0.03). IAs therapy did not significantly improve markers of liver function except for aspartate transaminase (weighted mean difference -9.76, 95% CI -12.92 to -6.6, p IAs administrated as either monotherapy or combination therapy do not reduce the risk of mortality or liver transplantation. IAs monotherapy is associated with AEs. © 2017 S. Karger AG, Basel.

Psychosocial Variables Associated with Immunosuppressive Medication Non-Adherence after Renal Transplantation

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Jennifer Felicia Scheel

2018-02-01

Full Text Available IntroductionNon-adherence to immunosuppressive medication is regarded as an important factor for graft rejection and loss after successful renal transplantation. Yet, results on prevalence and relationship with psychosocial parameters are heterogeneous. The main aim of this study was to investigate the association of immunosuppressive medication non-adherence and psychosocial factors.MethodsIn 330 adult renal transplant recipients (≥12 months posttransplantation, health-related quality of life, depression, anxiety, social support, and subjective medication experiences were assessed, and their associations with patient-reported non-adherence was evaluated.Results33.6% of the patients admitted to be partially non-adherent. Non-adherence was associated with younger age, poorer social support, lower mental, but higher physical health-related quality of life. There was no association with depression and anxiety. However, high proportions of clinically relevant depression and anxiety symptoms were apparent in both adherent and non-adherent patients.ConclusionIn the posttransplant follow-up, kidney recipients with lower perceived social support, lower mental and higher physical health-related quality of life, and younger age can be regarded as a risk group for immunosuppressive medication non-adherence. In follow-up contacts with kidney transplant patients, physicians may pay attention to these factors. Furthermore, psychosocial interventions to optimize immunosuppressive medication adherence can be designed on the basis of this information, especially including subjectively perceived physical health-related quality of life and fostering social support seems to be of importance.

Risk of fracture in adults on renal replacement therapy

DEFF Research Database (Denmark)

Hansen, Ditte; Olesen, Jonas B; Gislason, Gunnar H

2016-01-01

BACKGROUND: Patients on dialysis treatment or living with a transplanted kidney have several risk factors for bone fracture, especially disturbances in mineral metabolism and immunosuppressive therapy. We describe the incidence of fracture in this retrospective national Danish cohort study and ex....... Differences in age, gender, drug use and comorbidity only partly explain this increased risk. Further studies are warranted to explore the reason for this increased fracture risk in patients on renal replacement therapy....

Dutch guidelines for diagnosis and therapy of proliferative lupus nephritis

NARCIS (Netherlands)

van Tellingen, A.; Voskuyl, A. E.; Vervloet, M. G.; Bijl, M.; de Sevaux, R. G. L.; Berger, S. P.; Derksen, R. H. W. M.; Berden, J. H. M.

Proliferative lupus nephritis is a strong predictor of morbidity and mortality in patients with systemic lupus erythematosus. Despite improvements in the management of lupus nephritis, a significant number of the patients do not respond to immunosuppressive therapy and progress to end-stage renal

Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein [version 1; referees: 2 approved

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Bryony Jenkins

2016-12-01

Full Text Available To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II, and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein [version 2; referees: 2 approved

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Bryony Jenkins

2017-02-01

Full Text Available To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II, and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

Genital Tuberculosis as the Cause of Tuboovarian Abscess in an Immunosuppressed Patient

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M. Ilmer

2009-01-01

Full Text Available Background. Although tuberculosis (TB is a major health problem worldwide, primary extrapulmonary tuberculosis (EPTB, and in particular female genital tract infection, remains a rare event. Case Report. A 35-year-old human immunodeficiency virus (HIV seropositive woman of African descent with lower abdominal pain and fever of two days duration underwent surgery due to left adnexal mass suggesting pelvic inflammatory disease. The surgical situs showed a four quadrant peritonitis, consistent with the clinical symptoms of the patient, provoked by a tuboovarian abscess (TOA on the left side. All routine diagnostic procedures failed to determine the causative organism/pathogen of the infection. Histopathological evaluation identified a necrotic granulomatous salpingitis and specific PCR analysis corroborated Mycobacterium tuberculosis (M. Tb. Consequently, antituberculotic therapy was provided. Conclusion. In the differential diagnosis of pelvic inflammatory disease, internal genital tuberculosis should be considered. Moreover, physicians should consider tuberculous infections early in the work-up of patients when immunosuppressive conditions are present.

Clinical Implications for the Timely Diagnosis of Mycobacterium marinum in the Age of Biologic Therapy: A Case Report and Review of the Literature

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Chris J. Lata

2017-01-01

Full Text Available Mycobacterium marinum infections typically present as cutaneous nodular lesions with a sporotrichoid lymphatic spread on extensor surfaces of extremities. The natural history of this infection can be altered if the host is immunosuppressed, leading to disseminated presentations. A detailed exposure history and high degree of suspicion for this indolent pathogen are often required for the correct diagnosis of this disease. We present a case of a 67-year-old male misdiagnosed with seronegative rheumatoid arthritis presenting with rheumatic nodules. Initiation of chronic immunosuppressant therapy including biologic monoclonal antibodies resulted in the exacerbation of initially localized disease to broadly disseminated lymphatic, joint, and myotendinous granulomatous disease and led to delay in the correct diagnosis. Cessation of immunosuppressants, with a prolonged course of antimicrobial therapy and multiple surgical debridements were required for cure.

Horse versus rabbit antithymocyte globulin in immunosuppressive therapy of treatment-naïve aplastic anemia: a systematic review and meta-analysis.

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Yang, Nan; Chen, Jinqiu; Zhang, Hui; Dai, Zhiming; Yao, Huan; Ma, Xiaorong; Bai, Ju; Zhang, Yilin; Zhang, Wanggang

2017-12-01

The first-line formulation of antithymocyte globulin (ATG) remains unknown. We aimed to systematically review evidence to compare the efficacy and safety profiles of different ATGs. We did a systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort controlled studies comparing horse and rabbit ATG in immunosuppressive therapy of treatment-naïve aplastic anemia. We searched The Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov , and conference proceedings of American Society of Hematology and European Society for Blood and Marrow Transplantation annual meetings. The outcomes were 3-, 6-, and 12-month response; early mortality; relapse; and evolution. We pooled hazard ratios for relapse and odds ratios (ORs) for other outcomes using fixed-effect or random-effect models based on the heterogeneity. This study was registered with PROSPERO, number CRD42016036945. We included 1636 participants from three RCTs and 11 cohort controlled studies. Allocation to horse ATG increased 6-month response events by 86% compared with rabbit ATG. The benefit of horse ATG was mainly driven by increase in studies with non-Asian (OR 95% CI = 2.39 (1.54-3.69), p < 0.0001) and good partial response criterion (OR 95% CI = 2.73 (1.53-4.89), p = 0.0007). The early mortality and evolution were similar between groups. Compared with rabbit ATG, horse ATG had superior remission by 6 months and equivalent safety profiles in patients with treatment-naïve AA. Evidence for further responses beyond 6 to 12 months was limited.

Risk of high-grade cervical dysplasia and cervical cancer in women with systemic lupus erythematosus receiving immunosuppressive drugs.

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Feldman, C H; Liu, J; Feldman, S; Solomon, D H; Kim, S C

2017-06-01

Objective Prior studies suggest an increased risk of cervical cancer among women with systemic lupus erythematosus. However, the relationship with immunosuppressive drugs is not well studied in US nationwide cohorts. We compared the risk of high-grade cervical dysplasia and cervical cancer among women with systemic lupus erythematosus who started immunosuppressive drugs versus hydroxychloroquine. Methods We identified systemic lupus erythematosus patients initiating immunosuppressive drugs or hydroxychloroquine using claims data from two US commercial health plans and Medicaid (2000-2012). We used a validated claims-based algorithm to identify high-grade cervical dysplasia or cervical cancer. To account for potential confounders, including demographic factors, comorbidities, medication use, HPV vaccination status, and health care utilization, immunosuppressive drugs and hydroxychloroquine initiators were 1:1 matched on the propensity score. We used inverse variance-weighted, fixed effect models to pool hazard ratios from the propensity score-matched Medicaid and commercial cohorts. Results We included 2451 matched pairs of immunosuppressive drugs and hydroxychloroquine new users in the commercial cohort and 7690 matched pairs in Medicaid. In the commercial cohort, there were 14 cases of cervical dysplasia or cervical cancer among immunosuppressive drugs users and five cases among hydroxychloroquine users (hazard ratio 2.47, 95% CI 0.89-6.85, hydroxychloroquine = ref). In Medicaid, there were 46 cases among immunosuppressive drugs users and 29 cases in hydroxychloroquine users (hazard ratio 1.24, 95% CI 0.78-1.98, hydroxychloroquine = ref). The pooled hazard ratio of immunosuppressive drugs was 1.40 (95% CI 0.92-2.12). Conclusion Among women with systemic lupus erythematosus, immunosuppressive drugs may be associated with a greater, albeit not statistically significant, risk of high-grade cervical dysplasia and cervical cancer compared to patients receiving

Nonadherence to immunosuppression: challenges and solutions

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Moreso F

2015-06-01

Full Text Available Francesc Moreso,1 Irina B Torres,1 Gemma Costa-Requena,2 Daniel Serón1 1Nephrology Department, 2Psychiatry Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, Barcelona, Spain Abstract: Nonadherence to immunosuppressant treatment is common after renal transplantation involving >20% of patients. It is associated with cellular rejection, appearance of donor-specific antibodies, and chronic rejection. It has been estimated that nonadherence can be detected in approximately 50% of failing grafts. Since the evaluation of sociodemographic factors do not allow characterizing the target population, it is necessary to combine different measures of adherence (self-reporting and collateral reporting, pill counts, biological monitoring of blood samples, or others to increase its diagnostic accuracy. During the last decade, it has been shown that the implementation of a multidimensional intervention including information, motivation, and behavioral interventions may lead to an improvement of adherence to treatment. On the other hand, it has been shown that one-off feedback from a nurse, simplification of treatment, or financial assistance programs offered little improvement. Thus, increasing the effectiveness of adherence interventions might have a far greater impact on the long-term outcome of renal transplants than any improvement in specific medical treatments. This will require coordinated action from health professionals, researchers, health planners, and policy makers. Keywords: renal transplantation, nonadherence, immunosuppressive treatment

Lethal subarachnoid bleeding under immunosuppressive therapy due to mycotic arteritis

International Nuclear Information System (INIS)

Weigel, S.; Kloska, S.; Freund, M.; Kehl, H.G.

2003-01-01

A subarachnoid haemorrhage (SAH) occurred 67 days after cardiac transplantation in 10-year-old girl with consecutive immunocompromising therapy. Neither digital subtraction angiography (DSA) nor computed tomographic angiography showed signs of intracranial vascular malformations. One month before the lethal SAH occurred, she had developed arterial hypertension and attacks of severe headache with cerebrospinal fluid (CSF) pleocytosis while CT scans showed an infarct of the left thalamus. Pathologic findings established the rare diagnosis of SAH due to aspergillosis-related mycotic arteritis. Imaging characteristics are presented. (orig.)

Predictors of Immunosuppressive Regulatory T Lymphocytes in Healthy Women

International Nuclear Information System (INIS)

Hampras, S. S.; Nesline, M.; Davis, W.; Moysich, K. B.; Wallace, P. K.; Odunsi, K.; Furlani, N.

2012-01-01

Immunosuppressive regulatory T (Treg) cells play an important role in antitumor immunity, self-tolerance, transplantation tolerance, and attenuation of allergic response. Higher proportion of Treg cells has been observed in peripheral blood of cancer cases compared to controls. Little is known about potential epidemiological predictors of Treg cell levels in healthy individuals. We conducted a cross-sectional study including 75 healthy women, between 20 and 80 years of age, who participated in the Data Bank and Bio Repository (DBBR) program at Roswell Park Cancer Institute (RPCI), Buffalo, NY, USA. Peripheral blood levels of CD4 + CD25 + FOXP3 + Treg cells were measured using flow cytometric analysis. A range of risk factors was evaluated using Wilcoxon Rank-Sum test, Kruskal-Wallis test, and linear regression. Age, smoking, medications for treatment of osteoporosis, postmenopausal status, body mass index (BMI), and hormone replacement therapy (HRT) were found to be significant positive predictors of Treg cell levels in peripheral blood (π≤0.05 ). Higher education, exercise, age at first birth, oral contraceptives, and use of Ibuprofen were found be significant (π<0.05) negative predictors of Treg levels. Thus, various epidemiological risk factors might explain interindividual variation in immune response to pathological conditions, including cancer.

Immunosuppressive compounds from a deep water marine sponge, Agelas flabelliformis.

Science.gov (United States)

Gunasekera, S P; Cranick, S; Longley, R E

1989-01-01

Two immunosuppressive compounds, 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol and 4,5-dibromo-2-pyrrolic acid were isolated from a deep water marine sponge, Agelas flabelliformis. Their structures were determined by comparison of their spectral data with those of samples isolated from other organisms. Both compounds were highly active in suppression of the response of murine splenocytes in the two-way mixed lymphocyte reaction (MLR) with little to no demonstrable cytotoxicity at lower doses. In addition, 4,5-dibromo-2-pyrrolic acid suppressed the proliferative response of splenocytes to suboptimal concentrations of the mitogen, concanavalin A (Con A). These results describe for the first time compounds isolated from the marine sponge A. flabelliformis that possess potent in vitro immunosuppressive activity.

EFFICACY OF DIFFERENT IMMUNOSUPPRESSIVE PROTOCOLS WITH CYCLOSPORINE AND METHOTREXATE FOR PATIENTS WITH SYSTEMIC VARIANT OF JUVENILE RHEUMATOID ARTHRITIS

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E.I. Alexeeva

2007-01-01

Full Text Available The article provides information on efficiency of different protocols of therapy with cyclosporine and methotrexate for patients suffering from severe systemic juvenile rheumatoid arthritis (JRA. it shows that a therapy combining cyclosporine with dosage of 4,4 ± 0,58 mg/kg of body per day and methotrexate with dosage of 8,1 ± 1,07 mg/m2 a week is more efficient than monotherapy with each of the same medications of same dosage. Combined use of immunosuppressants induces remission of articular syndrome and constitutional manifestations, as well as provides normalization of laboratory disease activity indications in more than 50% of cases of long clasting systemic variant of JRA on the average a year after the initiation of treatment. Combining cyclosporine with methotrexat improves the curative action of each of the medications without aggravation of their toxic influence. High efficiency of combining cyclosporine with methotrexate makes enables lowering the dosage of glucocorticoids to be taken orally, as well as not prescribing prednisolone to the severe cases of systemic variant of JRA.Key words: juvenile rheumatoid arthritis, treatment, cyclosporine, methotrexate, combined therapy, children.

Photobiomodulation with Pulsed and Continuous Wave Near-Infrared Laser (810 nm, Al-Ga-As Augments Dermal Wound Healing in Immunosuppressed Rats.

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Gaurav K Keshri

Full Text Available Chronic non-healing cutaneous wounds are often vulnerable in one or more repair phases that prevent normal healing and pose challenges to the use of conventional wound care modalities. In immunosuppressed subject, the sequential stages of healing get hampered, which may be the consequences of dysregulated or stagnant wound inflammation. Photobiomodulation (PBM or low-level laser (light therapy (LLLT emerges as a promising drug-free, non-invasive biophysical approach for promoting wound healing, reduction of inflammation, pain and restoration of functions. The present study was therefore undertaken to evaluate the photobiomodulatory effects of 810 nm diode laser (40 mW/cm2; 22.6 J/cm2 with pulsed (10 and 100 Hz, 50% duty cycle and continuous wave on full-thickness excision-type dermal wound healing in hydrocortisone-induced immunosuppressed rats. Results clearly delineated that 810 nm PBM at 10 Hz was more effective over continuous and 100 Hz frequency in accelerating wound healing by attenuating the pro-inflammatory markers (NF-kB, TNF-α, augmenting wound contraction (α-SM actin, enhancing cellular proliferation, ECM deposition, neovascularization (HIF-1α, VEGF, re-epithelialization along with up-regulated protein expression of FGFR-1, Fibronectin, HSP-90 and TGF-β2 as compared to the non-irradiated controls. Additionally, 810 nm laser irradiation significantly increased CCO activity and cellular ATP contents. Overall, the findings from this study might broaden the current biological mechanism that could be responsible for photobiomodulatory effect mediated through pulsed NIR 810 nm laser (10 Hz for promoting dermal wound healing in immunosuppressed subjects.

Immunomodulatory Role of Mesenchymal Stem Cell Therapy in Vascularized Composite Allotransplantation

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Richard Heyes

2016-01-01

Full Text Available This review aims to summarize contemporary evidence of the in vitro and in vivo immunomodulatory effects of mesenchymal stem cells (MSCs in promoting vascularized composite allotransplant (VCA tolerance. An extensive literature review was performed to identify pertinent articles of merit. Prospective preclinical trials in mammal subjects receiving VCA (or skin allograft with administration of MSCs were reviewed. Prospective clinical trials with intravascular delivery of MSCs in human populations undergoing solid organ transplant were also identified and reviewed. Sixteen preclinical studies are included. Eleven studies compared MSC monotherapy to no therapy; of these, ten reported improved graft survival, which was statistically significantly prolonged in eight. Eight studies analyzed allograft survival with MSC therapy as an adjunct to proven immunosuppressive regimens. In these studies, daily immunosuppression was transiently delivered and then stopped. In all studies, treatment-free graft survival was statistically significantly prolonged in animals that received MSC therapy. MSCs have been safely administered clinically and their use in renal transplant clinical trials provides evidence that they improve allograft transplant tolerance in clinical practice. There is potential for MSC induction therapy to overcome many of the obstacles to widespread VCA in clinical practice. Preclinical studies are needed before MSC-induced VCA tolerance becomes a clinical reality.

Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

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Unzu, C; Melero, I; Hervás-Stubbs, S; Sampedro, A; Mancheño, U; Morales-Kastresana, A; Serrano-Mendioroz, I; de Salamanca, R E; Benito, A; Fontanellas, A

2015-11-01

Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.

Immunosuppression and risk of cervical cancer

DEFF Research Database (Denmark)

Dugué, Pierre-Antoine; Rebolj, Matejka; Garred, Peter

2013-01-01

-stage renal disease seem to be at an increased risk of cervical cancer. A higher risk of cervical precancerous lesions was found in patients with some autoimmune diseases; particularly if treated with immunosuppressants. Among behavioral factors weakening the immune system, smoking appeared to strongly...... increase the risk of cervical cancer, while poor diet only moderately increased the risk. It is difficult to determine whether sexually transmitted infections other than human papillomavirus infection are independent risk factors. Identifying those groups of women likely to fail in clearing persistent...

Merkel cell carcinoma in an immunosuppressed patient.

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Góes, Heliana Freitas de Oliveira; Lima, Caren Dos Santos; Issa, Maria Cláudia de Almeida; Luz, Flávio Barbosa; Pantaleão, Luciana; Paixão, José Gabriel Miranda da

2017-01-01

Merkel cell carcinoma is an uncommon neuroendocrine carcinoma with a rising incidence and an aggressive behavior. It predominantly occurs in older patients, with onset occurring at a mean age of 75-80 years. Recognized risk factors are ultraviolet sunlight exposure, immunosuppression, and, more recently, Merkel cell polyomavirus. We report a case of Merkel cell carcinoma in a young HIV positive patient with Merkel Cell polyomavirus detected in the tumor.

Fatal infections in older patients with inflammatory bowel disease on anti-tumor necrosis factor therapy

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Way-Seah Lee

2017-10-01

Full Text Available Anti-tumor necrosis factor (anti-TNF is highly effective in inflammatory bowel disease (IBD; however, it is associated with an increased risk of infections, particularly in older adults. We reviewed 349 patients with IBD, who were observed over a 12-month period, 74 of whom had received anti-TNF therapy (71 patients were aged <60 years and 3 were aged ≥60 years. All the 3 older patients developed serious infectious complications after receiving anti-TNFs, although all of them were also on concomitant immunosuppressive therapy. One patient developed disseminated tuberculosis, another patient developed cholera diarrhea followed by nosocomial pneumonia, while the third patient developed multiple opportunistic infections (Pneumocystis pneumonia, cryptococcal septicemia and meningitis, Klebsiella septicemia. All 3 patients died within 1 year from the onset of the infection(s. We recommend that anti-TNF, especially when combined with other immunosuppressive therapy, should be used with extreme caution in older adult patients with IBD.

Chimeric antigen receptor T cell therapy in pancreatic cancer: from research to practice.

Science.gov (United States)

Jindal, Vishal; Arora, Ena; Masab, Muhammad; Gupta, Sorab

2018-05-04

Chimeric antigen receptor (CAR) T cell therapy is genetically engineered tumor antigen-specific anticancer immunotherapy, which after showing great success in hematological malignancies is currently being tried in advanced solid tumors like pancreatic cancer. Immunosuppressive tumor microenvironment and dense fibrous stroma are some of the limitation in the success of this novel therapy. However, genetic modifications and combination therapy is the topic of the research to improve its efficacy. In this article, we summarize the current state of knowledge, limitations, and future prospects for CAR T cell therapy in pancreatic cancer.

Biological Therapy in Systemic Lupus Erythematosus

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Mariana Postal

2012-01-01

Full Text Available Systemic lupus erythematosus (SLE is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations. Despite new and improved therapy having positively impacted the prognosis of SLE, a subgroup of patients do not respond to conventional therapy. Moreover, the risk of fatal outcomes and the damaging side effects of immunosuppressive therapies in SLE call for an improvement in the current therapeutic management. New therapeutic approaches are focused on B-cell targets, T-cell downregulation and costimulatory blockade, cytokine inhibition, and the modulation of complement. Several biological agents have been developed, but this encouraging news is associated with several disappointments in trials and provide a timely moment to reflect on biologic therapy in SLE.

Future immunosuppressive agents in solid-organ transplantation.

Science.gov (United States)

Gabardi, Steven; Cerio, Jeffrey

2004-06-01

To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium, everolimus, and FTY720. Clinical trials and abstracts evaluating mycophenolate sodium, everolimus, and FTY720 in solid-organ transplantation were considered for evaluation. English-language studies and published abstracts were selected for inclusion. Mycophenolate sodium has recently been approved by the Food and Drug Adminstration for marketing in the United States; everolimus and FTY720 are immunosuppressive agents that may soon be available in the United States. These agents have proven efficacy in reducing the incidence of acute rejection in solid-organ transplantation. Clinical trials have shown that these newer agents are relatively well tolerated. The most common adverse events associated with these agents were gastrointestinal and hematologic effects (mycophenolate sodium); hyperlipidemia, increased serum creatinine, and hematologic effects (everolimus): and gastrointestinal effects, headache, and bradycardia (FTY720). Mycophenolate sodium has been approved in some European countries and the United States. Everolimus has been approved in some European countries and a new drug application has been submitted to the Food and Drug Administration. FTY720 is currently in phase III clinical trials and submission to the Food and Drug Administration for approval is a few years away. The approval of these agents will furnish the transplant practitioner with even more options for immunosuppression.

Ganoderma atrum polysaccharide ameliorates ROS generation and apoptosis in spleen and thymus of immunosuppressed mice.

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Li, Wen-Juan; Li, Lu; Zhen, Weng-Ya; Wang, Le-Feng; Pan, Meng; Lv, Jia-Qian; Wang, Fan; Yao, Yu-Fei; Nie, Shao-Ping; Xie, Ming-Yong

2017-01-01

Ganoderma atrum polysaccharide (PSG-1) is a bioactive compound with antioxidant and immunomodulatory activities. The aim of this study was to determine the effect of PSG-1 on reactive oxygen species (ROS) generation and apoptosis in spleen and thymus of cyclophosphamide (CTX)-induced immunosuppressed mice. The results showed that PSG-1 protected mice against CTX-mediated immunosuppression, as evidenced by enhancing the ratios of thymus and spleen weights to body weight, promoting T cell and B cell survival, and increasing levels of TNF-α and IL-2. Apoptosis, ROS generation and lipid peroxidation in the immune organs of the immunosuppressed animals were ameliorated by PSG-1. The immune benefits of PSG-1 were associated with the enhancement of the activities of glutathione peroxidase, superoxide dismutase and catalase in the immune organs, implying that antioxidant activities of PSG-1 may play an important role in PSG-1-evoked immune protection. Taken together, these findings have demonstrated that PSG-1 may ameliorate CTX-induced immunosuppression through reducing apoptosis and oxidative damage in immunological system. Copyright © 2016. Published by Elsevier Ltd.

Effects of immunosuppressive treatment on protein expression in rat kidney

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Kędzierska K

2014-09-01

Full Text Available Karolina Kędzierska,1 Katarzyna Sporniak-Tutak,2 Krzysztof Sindrewicz,2 Joanna Bober,3 Leszek Domański,1 Mirosław Parafiniuk,4 Elżbieta Urasińska,5 Andrzej Ciechanowicz,6 Maciej Domański,1 Tomasz Smektała,2 Marek Masiuk,5 Wiesław Skrzypczak,6 Małgorzata Ożgo,6 Joanna Kabat-Koperska,1 Kazimierz Ciechanowski1 1Department of Nephrology, Transplantology, and Internal Medicine, 2Department of Dental Surgery, 3Department of Medical Chemistry, 4Department of Forensic Medicine, 5Department of Pathomorphology, Pomeranian Medical University, 6Department of Physiology, Cytobiology, and Proteomics, West Pomeranian University of Technology, Szczecin, Poland Abstract: The structural proteins of renal tubular epithelial cells may become a target for the toxic metabolites of immunosuppressants. These metabolites can modify the properties of the proteins, thereby affecting cell function, which is a possible explanation for the mechanism of immunosuppressive agents' toxicity. In our study, we evaluated the effect of two immunosuppressive strategies on protein expression in the kidneys of Wistar rats. Fragments of the rat kidneys were homogenized after cooling in liquid nitrogen and then dissolved in lysis buffer. The protein concentration in the samples was determined using a protein assay kit, and the proteins were separated by two-dimensional electrophoresis. The obtained gels were then stained with Coomassie Brilliant Blue, and their images were analyzed to evaluate differences in protein expression. Identification of selected proteins was then performed using mass spectrometry. We found that the immunosuppressive drugs used in popular regimens induce a series of changes in protein expression in target organs. The expression of proteins involved in drug, glucose, amino acid, and lipid metabolism was pronounced. However, to a lesser extent, we also observed changes in nuclear, structural, and transport proteins' synthesis. Very slight differences

Cerebral involvement in a patient with Goodpasture's disease due to shortened induction therapy: a case report

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Preul Christoph

2009-11-01

Full Text Available Abstract Introduction Goodpasture's disease is a rare immunological disease with formation of pathognomonic antibodies against renal and pulmonary basement membranes. Cerebral involvement has been reported in several cases in the literature, yet the pathogenetic mechanism is not entirely clear. Case presentation A 21-year-old Caucasian man with Goodpasture's disease and end-stage renal disease presented with two generalized seizures after a period of mild cognitive disturbance. Blood pressure and routine laboratory tests did not exceed the patient's usual values, and examination of cerebrospinal fluid was unremarkable. Cerebral magnetic resonance imaging (MRI revealed multiple cortical and subcortical lesions on fluid-attenuated inversion recovery sequences. Since antiglomerular basement membrane antibodies were found to be positive with high titers, plasmapheresis was started. In addition, cyclophosphamide pulse therapy was given on day 13. Encephalopathy and MRI lesions disappeared during this therapy, and antiglomerular basement membrane antibodies were significantly reduced. Previous immunosuppressive therapy was performed without corticosteroids and terminated early after 3 months. The differential diagnostic considerations were cerebral vasculitis and posterior reversible encephalopathy syndrome. Vasculitis could be seen as an extrarenal manifestation of the underlying disease. Posterior reversible encephalopathy syndrome, on the other hand, can be triggered by immunosuppressive therapy and may appear without a hypertensive crisis. Conclusion A combination of central nervous system symptoms with a positive antiglomerular basement membrane test in a patient with Goodpasture's disease should immediately be treated as an acute exacerbation of the disease with likely cross-reactivity of antibodies with the choroid plexus. In our patient, a discontinuous strategy of immunosuppressive therapy may have favored recurrence of Goodpasture's disease.

Myeloid derived suppressor cells (MDSCs are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs in chronic myeloid leukemia patients.

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Cesarina Giallongo

Full Text Available Tumor immune tolerance can derive from the recruitment of suppressor cell population, including myeloid derived suppressor cells (MDSCs, able to inhibit T cells activity. We identified a significantly expanded MDSCs population in chronic myeloid leukemia (CML patients at diagnosis that decreased to normal levels after imatinib therapy. In addition, expression of arginase 1 (Arg1 that depletes microenvironment of arginine, an essential aminoacid for T cell function, resulted in an increase in patients at diagnosis. Purified CML CD11b+CD33+CD14-HLADR- cells markedly suppressed normal donor T cell proliferation in vitro. Comparing CML Gr-MDSCs to autologous polymorphonuclear leukocytes (PMNs we observed a higher Arg1 expression and activity in PMNs, together with an inhibitory effect on T cells in vitro. Our data indicate that CML cells create an immuno-tolerant environment associated to MDSCs expansion with immunosuppressive capacity mediated by Arg1. In addition, we demonstrated for the first time also an immunosuppressive activity of CML PMNs, suggesting a strong potential immune escape mechanism created by CML cells, which control the anti-tumor reactive T cells. MDSCs should be monitored in imatinib discontinuation trials to understand their importance in relapsing patients.

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

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Preeti Chhabra

2011-01-01

Full Text Available Clinical islet transplantation is a -cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the -cells regenerative capacity of stem cells.

Current and emerging therapies for the treatment of myasthenia gravis

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Renato Mantegazza

2011-03-01

Full Text Available Renato Mantegazza, Silvia Bonanno, Giorgia Camera, Carlo AntozziDepartment of Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta, Milan, ItalyAbstract: Myasthenia gravis (MG is an autoimmmune disease in which autoantibodies to different antigens of the neuromuscular junction cause the typical weakness and fatigability. Treatment includes anticholinesterase drugs, immunosuppression, immunomodulation, and thymectomy. The autoimmune response is maintained under control by corticosteroids frequently associated with immunosuppressive drugs, with improvement in the majority of patients. In case of acute exacerbations with bulbar symptoms or repeated relapses, modulation of autoantibody activity by plasmapheresis or intravenous immunoglobulins provides rapid improvement. Recently, techniques removing only circulating immunoglobulins have been developed for the chronic management of treatment-resistant patients. The rationale for thymectomy relies on the central role of the thymus. Despite the lack of controlled studies, thymectomy is recommended as an option to improve the clinical outcome or promote complete remission. New videothoracoscopic techniques have been developed to offer the maximal surgical approach with the minimal invasiveness and hence patient tolerability. The use of biological drugs such as anti-CD20 antibodies is still limited but promising. Studies performed in the animal model of MG demonstrated that several more selective or antigen-specific approaches, ranging from mucosal tolerization to inhibition of complement activity or cellular therapy, might be feasible. Investigation of the transfer of these therapeutic approaches to the human disease will be the challenge for the future.Keywords: myasthenia gravis, therapy, immunosuppression, thymectomy, plasmapheresis

Survival predictors in paraquat intoxification and role of immunosuppression

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Keng-Hee Koh

2014-01-01

In contrast, there was no difference in survival with immunosuppression regime (38 out of 64 patients (59.4% compared to historical control (30 out of 52 patients (57.7% (p = 0.885 in those with eGFR > 50 ml/min/1.73 m2 or WBC 11,000/μL.

Alemtuzumab – nowy lek w terapii postaci rzutowej stwardnienia rozsianego. Pierwsza czy druga linia leczenia?

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Jacek Zaborski

2015-11-01

Full Text Available Alemtuzumab jest humanizowanym przeciwciałem monoklonalnym skierowanym przeciwko glikoproteinie CD52, powodującym deplecję (eliminację krążących limfocytów T i B. Proces odtwarzania obu populacji limfocytów przebiega odmiennie, co prowadzi do zaburzeń w układzie odpornościowym. Zmiany te skutkują zmniejszeniem aktywności procesu chorobowego. Skuteczność alemtuzumabu została potwierdzona w trzech badaniach klinicznych: jednym fazy drugiej – CAMMS223 oraz dwóch fazy trzeciej – CARE-MS I i CARE-MS II. W badaniach tych wykazano skuteczność kliniczną podawanego dożylnie alemtuzumabu u chorych z postacią rzutową stwardnienia rozsianego. Komparatorem był podawany podskórnie interferon beta-1a. W CAMMS223 i CARE-MS I wykazano istotny wpływ alemtuzumabu na spadek wskaźnika rzutów w porównaniu z interferonem, a w CAMMS223 i CARE-MS II – wpływ na zwolnienie narastania niesprawności. Terapia z zastosowaniem alemtuzumabu nie była wolna od istotnych działań niepożądanych, które należały do trzech zasadniczych grup: działania niepożądane bezpośrednio związane z podawaniem leku, ciężkie infekcje oraz zaburzenia autoimmunologiczne (samoistna plamica małopłytkowa, zaburzenia funkcji tarczycy i nefropatia. Terapia alemtuzumabem może być zarówno skuteczna, jak i bezpieczna, jednakże pod warunkiem zachowania właściwego programu monitorowania działań niepożądanych.

[Uveitis associated with juvenile idiopathic arthritis : Optimization of immunomodulatory therapy].

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Heiligenhaus, A; Tappeiner, C; Walscheid, K; Heinz, C

2016-05-01

Uveitis associated with juvenile idiopathic arthritis (JIA-associated uveitis) is a vision-threatening disorder with a high complication rate. Besides early diagnosis within screening programs an adequate therapy is essential for improvement of the long-term prognosis. Corticosteroid therapy is often insufficient. In addition to conventional immunosuppression, immunomodulatory drugs, so-called biologicals, are novel highly effective treatment modalities. A systematic search of the literature was carried out for biologicals currently used in the treatment of JIA-associated uveitis. Review of current publications, summary of treatment guidelines and discussion of treatment options for therapy refractive patients. In accordance with the current recommendations tumor necrosis factor (TNF) inhibitors are administered if uveitis inactivity cannot be achieved with topical corticosteroids and in the next stage with immunosuppressants (methotrexate preferred). According to the currently available data adalimumab is then preferred. When the effectiveness of TNF inhibitors ceases during long-term administration and/or recurrences, other biological response modifiers are attractive treatment options (e. g. lymphocyte inhibitors or specific receptor antagonists). The TNF inhibitors are of major importance for the treatment of JIA-associated uveitis. Prospective studies and registries would be desirable in order to be able to compare the value of TNF inhibitors and other biologicals and for optimization of treatment recommendations.

Immunosuppressive Drug Discontinuation in Noninfectious Uveitis From Real-Life Clinical Practice: A Survival Analysis.

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Abásolo, Lydia; Rosales, Zulema; Díaz-Valle, David; Gómez-Gómez, Alejandro; Peña-Blanco, Rayma C; Prieto-García, Ángela; Benítez-Del-Castillo, José Manuel; Pato, Esperanza; García-Feijoo, Julián; Fernández-Gutiérrez, Benjamín; Rodriguez-Rodriguez, Luis

2016-09-01

To assess in uveitis patients the rate of immunosuppressive drug (ISD) discontinuation in real-life clinical practice, comparing this rate among ISDs. Longitudinal retrospective cohort study. We included uveitis patients attending a tertiary eye referral center from Madrid (Spain) between 1989 and 2015, prescribed any ISDs (cyclosporine, methotrexate, azathioprine, anti-TNF drugs, or others). Our main outcome was discontinuation of all ISDs owing to clinical efficacy, inefficacy, adverse drug reaction (ADR), and other medical causes. Discontinuation rates (DRs) per 100 patient-years were estimated. Variables associated with specific-cause discontinuations were analyzed using Cox bivariate and multivariate models. We analyzed 110 patients with 263 treatment courses and 665.2 patient-years of observation. Cyclosporine (66.4%), methotrexate (47.3%), azathioprine (30.9%), and anti-TNFs (30.9%) were the most frequently used ISDs. Treatment was suspended in 136 cases (mostly owing to clinical efficacy [38.2%], inefficacy [26.5%], and ADRs [22.8%]). All-cause DR with 95% confidence interval was 20.4 [17.3-24.2]. Retention rates at 1 and 10 years were 74% and 16%, respectively. In the multivariate analysis, combined treatment exhibited higher DRs owing to clinical efficacy than other ISDs in monotherapy. Conversely, nonbiologic combination therapy with azathioprine exhibited the highest DR owing to ADRs. Clinical efficacy was the most frequent cause for ISD discontinuation, followed by inefficacy and ADRs. DR owing to efficacy was higher for combination therapy. Furthermore, nonbiologic combination therapy with azathioprine was associated with a higher DR owing to ADRs. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of basiliximab in the evolving renal transplantation immunosuppression protocol

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Paola Salis

2008-06-01

Full Text Available Paola Salis, Chiara Caccamo, Roberto Verzaro, Salvatore Gruttadauria, Mary ArteroDivision of Nephrology and Division of Abdominal Transplantation, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, ItalyAbstract: Basiliximab is a chimeric mouse-human monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2 receptor on activated T lymphocytes. It was shown in phase III trials to reduce the number and severity of acute rejection episodes in the first year following renal transplantation in adults and children, with a reasonable cost-benefit ratio. The drug does not increase the incidence of opportunistic infections or malignancies above baseline in patients treated with conventional calcineurin inhibitor-based immunosuppression. In the field of renal transplantation, basiliximab does not increase kidney or patient survival, despite the reduction in the number of rejection episodes. Basiliximab may reduce the incidence of delayed graft function. In comparison with lymphocyte-depleting antibodies basiliximab appears to have equal efficacy in standard immunological risk patients. Recently, IL-2 receptor monoclonal antibodies have been used with the objective of reducing or eliminating the more toxic elements of the standard immunosuppression protocol. Several trials have incorporated basiliximab in protocols designed to avoid or withdraw rapidly corticosteroids, as well as protocols which substitute target-of-rapamycin (TOR inhibitors for calcineurin inhibitors.Keywords: basiliximab, renal transplantation, IL-2 receptor antagonists, induction, immunosuppression, corticosteroids, calcineurin inhibitors

Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly.

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Gabardi, Steven; Tullius, Stefan G; Krenzien, Felix

2015-08-01

This review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. Over the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. Despite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully.

Prolonged extracorporeal membrane oxygenation therapy for severe acute respiratory distress syndrome in a child affected by rituximab-resistant autoimmune hemolytic anemia: a case report

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Beretta Chiara

2009-04-01

Full Text Available Abstract Introduction Autoimmune hemolytic anemia in children younger than 2 years of age is usually characterized by a severe course, with a mortality rate of approximately 10%. The prolonged immunosuppression following specific treatment may be associated with a high risk of developing severe infections. Recently, the use of monoclonal antibodies (rituximab has allowed sustained remissions to be obtained in the majority of pediatric patients with refractory autoimmune hemolytic anemia. Case presentation We describe the case of an 8-month-old Caucasian girl affected by a severe form of autoimmune hemolytic anemia, which required continuous steroid treatment for 16 months. Thereafter, she received 4 weekly doses of rituximab (375 mg/m2/dose associated with steroid therapy, which was then tapered over the subsequent 2 weeks. One month after the last dose of rrituximab, she presented with recurrence of severe hemolysis and received two more doses of rrituximab. The patient remained in clinical remission for 7 months, before presenting with a further relapse. An alternative heavy immunosuppressive therapy was administered combining cyclophosphamide 10 mg/kg/day for 10 days with methylprednisolone 40 mg/kg/day for 5 days, which was then tapered down over 3 weeks. While still on steroid therapy, the patient developed an interstitial pneumonia with Acute Respiratory Distress Syndrome, which required immediate admission to the intensive care unit where extracorporeal membrane oxygenation therapy was administered continuously for 37 days. At 16-month follow-up, the patient is alive and in good clinical condition, with no organ dysfunction, free from any immunosuppressive treatment and with a normal Hb level. Conclusions This case shows that aggressive combined immunosuppressive therapy may lead to a sustained complete remission in children with refractory autoimmune hemolytic anemia. However, the severe life-threatening complication presented by our

The use of irradiated food for immuno-suppressed hospital patients

International Nuclear Information System (INIS)

Pryke, D.C.

1994-01-01

The treatment of leukaemia and other forms of haematological malignancies involves destruction of the bone marrow followed by bone-marrow transplant. This results in patients becoming severely immuno-suppressed. Other diseases result in a similar condition, most notably Acquired Immuno-Deficiency Syndrome (AIDS). Irradiation using radioactive sources or machines has been proposed as a method for preparing foods for immuno-suppressed patients and other high risk groups. Doses of around 30 kGy ensure a total sterility whilst a dose of 10 kGy (the recommended maximum for food available to the general public) results in a significant reduction in the number of pathogenic microorganisms. Irradiation has a number of advantages over other processing methods, in particular that flavour, texture and nutritional changes are limited. This is important as patients are often in a compromised state and need clinical assistance in returning to normal eating habits. In recognition of the potential of irradiated foods for hospital patients this use has been specifically exempted from regulatory control in the UK. This paper reviews the experience in the UK of irradiation-sterilized foods in hospitals. It was found that for practical reasons use is currently restricted. The future prospects for food irradiated at non-sterilized doses are also considered. It is concluded that as well as providing greater choice for consumers (high risk and the general public as a whole) irradiated foods could extend and improved the diets of immuno-suppressed hospital patients; this could be an important factor in recovery. (author)

Severe neuro-Behcet's disease treated with a combination of immunosuppressives and a TNF-inhibitor.

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Korkmaz, Fatma Nur; Ozen, Gulsen; Ünal, Ali Uğur; Kahraman Koytak, Pınar; Tuncer, Nese; Direskeneli, Haner

2016-01-01

Abstract/ Resumo Behcet's disease (BD) is a multisystem inflammatory disorder characterized by recurrent oral and genital ulcers, skin lesions and uveitis. The nervous system involvement of BD, neuro-Behcet's disease (NBD), is one of the important causes of mortality of the disease. Herein, we present a 29-year-old male with parenchymal NBD who has progressed rapidly and was managed with an uncommon aggressive immunosuppresive combination therapy. The patient first presented six years ago with vertigo and difficulty in talking and walking. On examination, he had oral ulcers, acneiform lesions on the torso, genital ulcer scar, dysartria, and ataxia. Along with the magnetic resonance imaging (MRI) findings, the patient was diagnosed as NBD. After pulse methylprednisolone (1g/day, 3 days) and 8 courses of 1g/month iv cylophosphamide therapy, he was put on azathioprine and oral methlyprednisolone. On the 4th year of the maintenance therapy, he was admitted with NBD relapse which was treated with 3 days of iv 1g pulse methlyprednisolone. One year after the last relapse, the patient voluntarily stopped medications and presented with global aphasia, right hemihypoesthesia and quadriparesis. MRI findings were suggestive of NBD relapse. After exclusion of infection, pulse methylprednisolone was started but no improvement was observed. Considering the severity of the NBD, the patient was put on methylprednisolone (1mg/kg/day), iv cylophosphamide (1g) and adalimumab 40 mg/14 days subcutaneously with appropriate tuberculosis prophylaxis. Neurological examination and MRI findings after 4 weeks showed dramatic improvement however patient developed pulmonary tuberculosis. Methylprednisolone dose was decreased (0.5mg/kg/day) and quadruple antituberculosis therapy was started. Patient was discharged with 5/5 muscle strength in extremities without any respiratory symptoms 2 months after first presentation. Prompt introduction of immunosuppressive therapy is crucial in NBD. Although

De novo Renal Transplantation after Kaposi Sarcoma: Favorable Outcome in a Patient Receiving Sirolimus and Mycophenolate-Based Immunosuppression

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F. Friedersdorff

2010-04-01

Full Text Available Immunosuppressive treatment increases the risk of infection and malignancy in organ transplant recipients. We report on a 42-year-old male renal transplant recipient who lost his first graft after reduction of immunosuppressive treatment due to Kaposi sarcoma and who successfully underwent a second renal transplant 10 years later. The patient’s current treatment consists of low-dose prednisone, and the two antiproliferative immunosuppressants mycophenolate mofetil and rapamycin. 4.5 years after his second transplant, the serum creatinine is 1 mg/dl and the patient has no signs of recurrent disease.

Cell-mediated immune response to Leishmania chagasi experimental infection of BALB/c immunosuppressed mice

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JG Machado

2010-01-01

Full Text Available Leishmaniasis, a zoonosis of worldwide distribution, presents a significant impact on immunosupressed patients. This study aimed to evaluate Leishmania chagasi infection in BALB/c mice immunosuppressed with dexamethasone. Spleen cells stimulated or not with L. chagasi were cultured for cytokine quantification (IFN-γ, IL-2, IL-4 and IL-10 by sandwich ELISA. Parasite loads in the spleen and liver were determined by means of culture microtitration. Immunosuppressed groups showed statistically lower spleen weight and CD4-cell percentage in blood on the day of infection and produced Th1 and Th2 cytokines on other days of the study. The other infected groups, weather immunosupressed or not, also produced Th1 and Th2 cytokines. Parasite loads in the spleen and liver were not statistically different among the groups. It was concluded that L. chagasi infection was not affected by dexamethasone-induced immunosuppression, probably due the reversible effect of the treatment.

Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

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Penninga, Luit; Penninga, Ida Elisabeth Irene; Møller, Christian H

2013-01-01

Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without...

Pathway-based analysis of a melanoma genome-wide association study: analysis of genes related to tumour-immunosuppression.

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Nils Schoof

Full Text Available Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs in 43 genes (39 genomic regions related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp=0.002, as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp=0.006 and secretion of suppressive factors (p(emp=0.0004, thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

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Chhabra, Preeti; Brayman, Kenneth L.

2011-01-01

Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells. PMID:22046502

Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols.

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Hire, Kelly; Hering, Bernhard; Bansal-Pakala, Pratima

2010-08-01

Despite advances in islet transplantation, challenges remain in monitoring for anti-islet immune responses. Soluble CD30 (sCD30) has been investigated as a predictor of acute rejection in kidney, lung, and heart transplantation as well as in a single study in human islet cell recipients. In this study, sCD30 levels were retrospectively assessed in 19 allograft recipients treated with three different immunosuppression induction therapies. Soluble CD30 levels were assessed at pre-transplant; early post-transplant (day 4-day 7); one-month post-transplant; and late post-transplant (day 90-day 120) and then correlated with eventual graft outcomes at 1-year follow-up. Results showed no correlation between mean serum sCD30 levels at any point in time pre- or post-transplant and graft function at 1-year follow-up. However, analysis demonstrated that mean sCD30 levels at day 28 or day 90-day 120 decreased from pre-transplant levels in recipients with long-term islet allograft function compared to recipients with partial or non-graft function (a decrease of 43.6+/-25.6% compared to 16.7+/-35.2%, psCD30 levels post-transplant overall. A larger reduction post-transplant correlated with full graft function. The results demonstrate that a relative reduction in sCD30 levels post-transplant may be applicable as a biomarker to monitor graft function in islet allograft recipients. Additionally, knowledge of the impact of various immunosuppression protocols on the timing and extent of changes in post-transplant sCD30 levels could aid in patient-specific tailoring of immunosuppression. Copyright © 2010 Elsevier B.V. All rights reserved.

Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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Sergey V. Tokalov

2010-01-01

Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Polysaccharide from Lentinus edodes inhibits the immunosuppressive function of myeloid-derived suppressor cells.

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Hao Wu

Full Text Available Reversing the function of immune suppressor cells may improve the efficacy of cancer therapy. Here, we have isolated a novel polysaccharide MPSSS (577.2 Kd from Lentinus edodes and examined its effects on differentiation and function of myeloid-derived suppressor cells (MDSCs. MPSSS is composed of glucose (75.0%, galactose (11.7%, mannose (7.8%, and xylose (0.4%. In vivo, it inhibits the growth of McgR32 tumor cells, which is correlated with a reduced percentage of MDSCs in peripheral blood. In vitro, it induces both morphological and biophysical changes in MDSCs. Importantly, MPSSS up-regulates MHC II and F4/80 expression on MDSCs, and reverses their inhibition effect on CD4(+ T cells in a dose-dependent manner. The mechanism study shows that MPSSS may stimulate MDSCs through a MyD88 dependent NF-κB signaling pathway. Together, we demonstrated for the first time that MPSSS stimulates the differentiation of MDSCs and reverses its immunosuppressive functions, shedding new light on developing novel anti-cancer strategies by targeting MDSCs.

Neuroblastoma arginase activity creates an immunosuppressive microenvironment that impairs autologous and engineered immunity

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Mussai, Francis; Egan, Sharon; Hunter, Stuart; Webber, Hannah; Fisher, Jonathan; Wheat, Rachel; McConville, Carmel; Sbirkov, Yordan; Wheeler, Kate; Bendle, Gavin; Petrie, Kevin; Anderson, John; Chesler, Louis; De Santo, Carmela

2015-01-01

Neuroblastoma is the most common extra cranial solid tumour of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumour cells suppress T cell proliferation, through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34+ progenitor proliferation. Finally we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1 specific TCR and GD2-specific CAR engineered T cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for neuroblastoma patients. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumour and blood that leads to impaired immune surveillance and sub-optimal efficacy of immunotherapeutic approaches. PMID:26054597

Cervical HPV prevalence and genotype distribution in immunosuppressed Danish women

DEFF Research Database (Denmark)

Roensbo, Mette T; Blaakær, Jan; Skov, Karin

2018-01-01

INTRODUCTION: Women receiving immunosuppressive treatment due to organ transplantation are at increased risk of Human papilloma virus (HPV)-related diseases, including cervical neoplasia. This pilot study aimed to describe the cervical HPV prevalence and genotype distribution in immunosuppressed...... in 2014 had three cervical cytologies performed; one before and two after transplantation. The samples were examined for cytological abnormalities and tested for HPV using Cobas(®) HPV Test and CLART(®) HPV2 Test. RESULTS: Of 94 eligible cases we included 60 RTR and BMTR. The overall prevalence of high......-risk HPV was 15.0 (95% CI; 7.1-26.6) and the prevalence was higher among BMTR (29.4, CI; 10.3-56.0) than in RTR (9.3%, CI; 2.6-22.1) although this was not statistically significant (p=0.10). The distribution of high-risk HPV was broad with HPV 45 as the most common genotype (3.3%). The prevalences of high...

Immunosuppression in irradiated breast cancer patients: In vitro effect of cyclooxygenase inhibitors

International Nuclear Information System (INIS)

Wasserman, J.; Blomgren, H.; Rotstein, S.; Petrini, B.; Hammarstroem, S.

1989-01-01

We have documented in previous studies that local irradiation therapy for breast cancer caused severe lymphopenia with reduction of both T and non-T lymphocytes. Non-T cells were relatively more depressed but recovered within six months. The recovery of T cells, on the other hand, remained incomplete 10-11 years after irradiation. Several lymphocyte functions were also severely impaired. An association was found between prognosis and postirradiation mitogen reactivity of lymphocytes from these patients. Mortality up to eight years after irradiation was significantly higher in patients with low postirradiation phytohemagglutinin and PPD reactivity. The radiation induced decrease in mitogenic response seemed mainly to be caused by immunosuppressive monocytes, which suggests that the underlying mechanism might be mediated by increased production of prostaglandins by monocytes. For this reason we examined the effect of some cyclooxygenase products on different lymphocyte functions and found that prostaglandins A2, D2, and E2 inhibited phytohemagglutinin response in vitro. Natural killer cell activity was also reduced by prostaglandins D2 and E2. The next step was to examine various inhibitors of cyclooxygenase in respect to their capacity to revert irradiation-induced suppression of in vitro mitogen response in lymphocytes from breast cancer patients. It was demonstrated that Diclofenac Na (Voltaren), Meclofenamic acid, Indomethacin, and lysin-mono-acetylsalicylate (Aspisol) could enhance mitogen responses both before and after radiation therapy. This effect was most pronounced at completion of irradiation. On a molar basis, Diclofenac Na was most effective followed by Indomethacin, Meclofenamic acid, and lysin-monoacetylsalicylate

Immunosuppression in irradiated breast cancer patients: In vitro effect of cyclooxygenase inhibitors

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Wasserman, J.; Blomgren, H.; Rotstein, S.; Petrini, B.; Hammarstroem, S.

1989-01-01

We have documented in previous studies that local irradiation therapy for breast cancer caused severe lymphopenia with reduction of both T and non-T lymphocytes. Non-T cells were relatively more depressed but recovered within six months. The recovery of T cells, on the other hand, remained incomplete 10-11 years after irradiation. Several lymphocyte functions were also severely impaired. An association was found between prognosis and postirradiation mitogen reactivity of lymphocytes from these patients. Mortality up to eight years after irradiation was significantly higher in patients with low postirradiation phytohemagglutinin and PPD reactivity. The radiation induced decrease in mitogenic response seemed mainly to be caused by immunosuppressive monocytes, which suggests that the underlying mechanism might be mediated by increased production of prostaglandins by monocytes. For this reason we examined the effect of some cyclooxygenase products on different lymphocyte functions and found that prostaglandins A2, D2, and E2 inhibited phytohemagglutinin response in vitro. Natural killer cell activity was also reduced by prostaglandins D2 and E2. The next step was to examine various inhibitors of cyclooxygenase in respect to their capacity to revert irradiation-induced suppression of in vitro mitogen response in lymphocytes from breast cancer patients. It was demonstrated that Diclofenac Na (Voltaren), Meclofenamic acid, Indomethacin, and lysin-mono-acetylsalicylate (Aspisol) could enhance mitogen responses both before and after radiation therapy. This effect was most pronounced at completion of irradiation. On a molar basis, Diclofenac Na was most effective followed by Indomethacin, Meclofenamic acid, and lysin-monoacetylsalicylate.

Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer.

Science.gov (United States)

Scott, Frank I; Mamtani, Ronac; Brensinger, Colleen M; Haynes, Kevin; Chiesa-Fuxench, Zelma C; Zhang, Jie; Chen, Lang; Xie, Fenglong; Yun, Huifeng; Osterman, Mark T; Beukelman, Timothy; Margolis, David J; Curtis, Jeffrey R; Lewis, James D

2016-02-01

Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs. To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC. In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012. Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery. A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models. Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study

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Marsicano, Elisa Oliveira; Fernandes, Neimar Silva; Colugnati, Fernando Ant?nio Basile; Fernandes, Natalia Maria Silva; De Geest, Sabina; Sanders-Pinheiro, Helady

2015-01-01

Background Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system. Methods Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adher...

The peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs

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Christine eNeudoerfl

2013-02-01

Full Text Available In the context of kidney transplantation, little is known about the involvement of NK cells in the immune reaction leading to either rejection or immunological tolerance under immunosuppression. Therefore, the peripheral NK cell repertoire of patients after kidney transplantation was investigated in order to identify NK cell subsets that may be associated with the individual immune status at the time of their protocol biopsies for histopathological evaluation of the graft. Alterations in the peripheral NK cell repertoire could be correlated to the type of immunosuppression, i.e. calcineurin-inhibitors like CyclosporinA vs. Tacrolimus with or without addition of mTOR inhibitors. Here, we could demonstrate that the NK cell repertoire in peripheral blood of kidney transplant patients differs significantly from healthy individuals. The presence of donor-specific antibodies was associated with reduced numbers of CD56dim NK cells. Moreover, in patients, down-modulation of CD16 and CD6 on CD56dim NK cells was observed with significant differences between CyclosporinA- and Tac-treated patients. Tac-treatment was associated with decreased CD69, HLA-DR and increased CD94/NKG2A expression in CD56dim NK cells indicating that the quality of the immunosuppressive treatment impinges on the peripheral NK cell repertoire. In vitro studies with PBMC of healthy donors showed that this modulation of CD16, CD6, CD69, and HLA-DR could also be induced experimentally. The presence of calcineurin or mTOR inhibitors had also functional consequences regarding degranulation and IFN--production against K562 target cells, respectively. In summary, we postulate that the NK cell composition in peripheral blood of kidney transplanted patients represents an important hallmark of the efficacy of immunosuppression and may be even informative for the immune status after transplantation in terms of rejection vs. drug-induced allograft tolerance. Thus,NK cells can serve as sensors

The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation.

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Brifkani, Zaid; Brennan, Daniel C; Lentine, Krista L; Horwedel, Timothy A; Malone, Andrew F; Delos Santos, Rowena; Maw, Thin Thin; Alhamad, Tarek

2017-03-01

White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Análise da eficácia do laser de baixa potência no tratamento da dor tendínea em ratos imunossuprimidos Analysis of low-level laser therapy efficacy on tendon pain treatment in immunosuppressed rats

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Fernanda de Oliveira Busarello

2011-12-01

Full Text Available O comprometimento do sistema imune, que pode ser apresentado por indivíduos com doenças crônicas, leva à baixa resposta imunológica. Um dos tratamentos utilizados para lesões agudas em tendões é o laser de baixa potência, contudo há uma lacuna em relação ao seu uso em imunodepressão. O objetivo do presente estudo foi analisar se o laser de baixa potência é eficaz para o tratamento da dor em ratos imunodeprimidos submetidos a trauma tendíneo. Foram utilizados 23 ratos, machos, da linhagem Wistar, divididos aleatoriamente em três grupos: grupo controle, placebo e laser. Os animais foram imunodeprimidos (por administração de Ciclosporina A e submetidos à lesão no tendão calcâneo direito, com impacto de cerca de 0,40 J. Para o tratamento, utilizou-se laser de baixa potência, 670 nm, 30 mW e dose de 2 J/cm², durante 3 dias. A avaliação da dor foi realizada pelo teste de incapacidade funcional e por filamento de Von Frey digital. Os resultados apresentaram valores significativos para o grupo laser, com diminuição de dor funcional e da dor à pressão na superfície plantar e no local lesionado (tendão calcâneo direito. Portanto, concluiu-se que o laser de baixa potência é eficaz para reduzir a dor em ratos imunodeprimidos submetidos a trauma tendíneo.The commitment of immune system, which may be presented by individuals with chronic diseases, leading to a low immune response. One of the treatments used for acute injuries in tendons is the low-power laser, however there is a gap in relation to its use in immunosuppression. The objective of this study was to analyze if low-level laser therapy is effective for the treatment of pain in immunosuppressed rats subjected to trauma tendon. We used 23 male rats of Wistar strain, divided randomly in three groups: control group, placebo and laser. The animals were immunosuppressed (by administration of Cyclosporin A and underwent right Achilles tendon injury, with impact of about

Occurrence of immunosuppressive drugs and their metabolites in the sewage-impacted Vistula and Utrata Rivers and in tap water from the Warsaw region (Poland).

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Giebułtowicz, Joanna; Nałęcz-Jawecki, Grzegorz

2016-04-01

Immunosuppresive therapy following organ transplant frequently includes treatment with tacrolimus and mycophenolic acid derivatives. These pharmaceuticals may enter the environment through wastewater treatment plant (WWTP) effluents and may have a potentially harmful effect on aquatic biota. Tacrolimus, mycophenolic acid and their metabolites were measured at specific points of a large Polish river (Vistula), a smaller river (Utrata) and in tap water samples from the Warsaw region. Analysis was performed using liquid chromatography tandem mass spectrometry, after solid phase extraction for water samples, or QuEChERS extraction for sediments. Residues of tacrolimus were below quantitation limits in both water and sediment samples. However, in water samples mycophenolic acid concentrations were measured at up to 180 ng L(-1) downstream of WWTP outfalls. No immunosuppressive drugs were detected in tap water. Concentrations of mycophenolic acid exceeded the predicted no effect concentration (PNEC) value in some Polish surface water, and risk calculations predicted at least twice higher concentrations in some other countries of the European Union. To the best of the authors' knowledge, this is the first report of these immunosuppressive drug concentrations in the environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Severe neuro-Behcet’s disease treated with a combination of immunosuppressives and a TNF-inhibitor.

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Fatma Nur Korkmaz

2016-10-01

Full Text Available Abstract/ Resumo Behcet's disease (BD is a multisystem inflammatory disorder characterized by recurrent oral and genital ulcers, skin lesions and uveitis. The nervous system involvement of BD, neuro-Behcet's disease (NBD, is one of the important causes of mortality of the disease. Herein, we present a 29-year-old male with parenchymal NBD who has progressed rapidly and was managed with an uncommon aggressive immunosuppresive combination therapy. The patient first presented six years ago with vertigo and difficulty in talking and walking. On examination, he had oral ulcers, acneiform lesions on the torso, genital ulcer scar, dysartria, and ataxia. Along with the magnetic resonance imaging (MRI findings, the patient was diagnosed as NBD. After pulse methylprednisolone (1g/day, 3 days and 8 courses of 1g/month iv cylophosphamide therapy, he was put on azathioprine and oral methlyprednisolone. On the 4th year of the maintenance therapy, he was admitted with NBD relapse which was treated with 3 days of iv 1g pulse methlyprednisolone. One year after the last relapse, the patient voluntarily stopped medications and presented with global aphasia, right hemihypoesthesia and quadriparesis. MRI findings were suggestive of NBD relapse. After exclusion of infection, pulse methylprednisolone was started but no improvement was observed. Considering the severity of the NBD, the patient was put on methylprednisolone (1mg/kg/day, iv cylophosphamide (1g and adalimumab 40 mg/14 days subcutaneously with appropriate tuberculosis prophylaxis. Neurological examination and MRI findings after 4 weeks showed dramatic improvement however patient developed pulmonary tuberculosis. Methylprednisolone dose was decreased (0.5mg/kg/day and quadruple antituberculosis therapy was started. Patient was discharged with 5/5 muscle strength in extremities without any respiratory symptoms 2 months after first presentation. Prompt introduction of immunosuppressive therapy is crucial in

Primary Cutaneous Cryptococcosis Treated with Debridement and Fluconazole Monotherapy in an Immunosuppressed Patient: A Case Report and Review of the Literature

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Jennifer Wang

2015-01-01

Full Text Available Cryptococcus neoformans is an opportunistic yeast present in the environment. Practitioners are familiar with the presentation and management of the most common manifestation of cryptococcal infection, meningoencephalitis, in patients with AIDS or other conditions of immunocompromise. There is less awareness, however, of uncommon presentations where experience rather than evidence guides therapy. We report a case of primary cutaneous cryptococcosis (PCC in a patient who had been immunosuppressed by chronic high-dose corticosteroid for the treatment of severe asthma. This case highlights the importance of early recognition of aggressive cellulitis that fails standard empiric antibiotic treatment in an immunocompromised patient. It also demonstrates successful treatment of PCC with a multispecialty approach including local debridement and fluconazole monotherapy.

Effect of β-3-Thienylalanine on Antibody Synthesis V. Immunosuppression in Mice by Short Diet and Drug Treatments

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Misefari, Aldo; La Via, Mariano F.

1971-01-01

The analogue of phenylalanine, β-3-thienylalanine, depresses severely the primary and secondary immune response to sheep erythrocytes in mice when administered for a few days immediately before and after each injection of antigen. For this immunosuppression to occur, animals must be maintained on a phenylalanine-free diet during the times of drug injection since dietary phenylalanine will restore anamnestic response. With these experimental conditions, the number of direct and indirect plaque-forming cells is greatly reduced during immune responses. The finding that marked immunosuppression can be obtained with a very short drug and diet treatment points to a potential usefullness of the analogue as a powerful immunosuppressant. PMID:5154884

[Treatment with immunosuppressive and biologic drugs of pregnant women with systemic rheumatic or autoimmune disease].

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Alijotas-Reig, Jaume; Esteve-Valverde, Enrique; Ferrer-Oliveras, Raquel

2016-10-21

Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Fungemia Due to Fusarium sacchari in an Immunosuppressed Patient

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Guarro, Josep; Nucci, Marcio; Akiti, Tiyomi; Gené, Josepa; Barreiro, M. Da Gloria C.; Gonçalves, Renato T.

2000-01-01

The fungus Fusarium sacchari was isolated repeatedly from the blood of an immunosuppressed host. The infection was treated successfully with a small dose of amphotericin B. The strain was resistant to this antifungal in vitro. MICs and minimum fungicidal concentrations of six antifungals for the clinical isolate are provided. To our knowledge, this is the first report involving this fungus in a case of fungemia. PMID:10618130

IL-10 is an effector molecule mediating urocanic acid-induced immunosuppression

Czech Academy of Sciences Publication Activity Database

Krulová, Magdalena; Kuffová, Lucia; Zajícová, Alena; Filipec, M.; Holáň, Vladimír

1999-01-01

Roč. 31, - (1999), s. 1218-1219 ISSN 0041-1345 R&D Projects: GA MZd IZ3964; GA ČR GA310/97/1261; GA MŠk VS97099 Keywords : immunosuppression, urocanic acid Subject RIV: EC - Immunology Impact factor: 0.590, year: 1999

Immunosuppressive sesquiterpenes from Buddleja daviddi.

Science.gov (United States)

Zhang, Wen; Yao, Zhi; Zhang, Yan Wen; Zhang, Xing Xiang; Takaishi, Yoshihisa; Duan, Hong Quan

2010-11-01

Six new sesquiterpenes, 2,6(12),10-humulatrien-7β-ol-1-one (1), 2 α-acetoxy-5α-methoxy-enantio-caryophylla-8(15)-en-3-one (2), 2α-acetoxy-5α-hydroxy-enantio-caryophylla-8(15)-en-3-one (3), 2α-acetoxy-4β,5α-hydroxy-enantio-caryophylla-8(15)-en-3-one ( 4), 2α-acetoxy-4β,5β-hydroxy-enantio-caryophylla-8(15)-en-3-one (5), 2β-acetoxy-4-caryophyllen-8β-ol-3-one (6), and nineteen known compounds were isolated from the ethanol extract of Buddleja daviddi. The structures were elucidated by spectroscopic methods. Compounds 8-11, 14, 16, 17, and 20 showed significant immunosuppressive activities, and 8-11 and 14 were cytotoxic on HeLa and L929 cell lines. © Georg Thieme Verlag KG Stuttgart · New York.

Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant.

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Gorden Muduma

Full Text Available Several meta-analyses comparing ciclosporin with tacrolimus have been conducted since the 1994 publication of the tacrolimus registration trials, but most captured data from randomized controlled trials (RCTs predating recent improvements in waiting list prioritization, induction protocols and concomitant medications. The present study comprised a systematic review and meta-analysis of ciclosporin and tacrolimus in liver transplant recipients using studies published since January 2000.Searches of PubMed, the Cochrane Library and EMBASE identified RCTs of tacrolimus and ciclosporin as the immunosuppressant in adult primary liver transplant recipients, published between January 2000 and August 6, 2014. A random effects meta-analysis was conducted to evaluate the relative risk of death, graft loss, acute rejection (AR, new-onset diabetes after transplantation (NODAT and hypertension with tacrolimus relative to ciclosporin at 12 months.The literature search identified 11 RCTs comparing ciclosporin with tacrolimus. Relative to ciclosporin, tacrolimus was associated with significantly improved outcomes in terms of patient mortality (risk ratio [RR] with ciclosporin of 1.26; 95% confidence interval [95%CI] 1.01-1.58. Tacrolimus was superior to ciclosporin in terms of hypertension (RR with ciclosporin 1.26; 95%CI 1.07-1.47, but inferior in terms of NODAT (RR with ciclosporin 0.60; 95%CI 0.47-0.77. There were no significant differences between ciclosporin and tacrolimus in terms of graft loss or AR.Meta-analysis of RCTs published since 2000 showed tacrolimus to be superior to ciclosporin in terms of patient mortality and hypertension, while ciclosporin was superior in terms of NODAT. No significant differences were identified in terms of graft loss or AR. These findings provide further evidence supporting the use of tacrolimus as the cornerstone of immunosuppressive therapy in liver transplant recipients.

Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies.

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Ransohoff, Julia D; Kwong, Bernice Y

2017-12-01

The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug-targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care. Copyright © 2017 Elsevier Inc. All rights reserved.

Low-dose-rate total lymphoid irradiation: a new method of rapid immunosuppression

International Nuclear Information System (INIS)

Blum, J.E.; de Silva, S.M.; Rachman, D.B.; Order, S.E.

1988-01-01

Total Lymphoid Irradiation (TLI) has been successful in inducing immunosuppression in experimental and clinical applications. However, both the experimental and clinical utility of TLI are hampered by the prolonged treatment courses required (23 days in rats and 30-60 days in humans). Low-dose-rate TLI has the potential of reducing overall treatment time while achieving comparable immunosuppression. This study examines the immunosuppressive activity and treatment toxicity of conventional-dose-rate (23 days) vs low-dose-rate (2-7 days) TLI. Seven groups of Lewis rats were given TLI with 60Co. One group was treated at conventional-dose-rates (80-110 cGy/min) and received 3400 cGy in 17 fractions over 23 days. Six groups were treated at low-dose-rate (7 cGy/min) and received total doses of 800, 1200, 1800, 2400, 3000, and 3400 cGy over 2-7 days. Rats treated at conventional-dose-rates over 23 days and at low-dose-rate over 2-7 days tolerated radiation with minimal toxicity. The level of immunosuppression was tested using allogeneic (Brown-Norway) skin graft survival. Control animals retained allogeneic skin grafts for a mean of 14 days (range 8-21 days). Conventional-dose-rate treated animals (3400 cGy in 23 days) kept their grafts 60 days (range 50-66 days) (p less than .001). Low-dose-rate treated rats (800 to 3400 cGy total dose over 2-7 days) also had prolongation of allogeneic graft survival times following TLI with a dose-response curve established. The graft survival time for the 3400 cGy low-dose-rate group (66 days, range 52-78 days) was not significantly different from the 3400 cGy conventional-dose-rate group (p less than 0.10). When the total dose given was equivalent, low-dose-rate TLI demonstrated an advantage of reduced overall treatment time compared to conventional-dose-rate TLI (7 days vs. 23 days) with no increase in toxicity

Geranylated flavonoids from the roots of Campylotropis hirtella and their immunosuppressive activities.

Science.gov (United States)

Shou, Qing-Yao; Fu, Run-Zhong; Tan, Qing; Shen, Zheng-Wu

2009-08-12

In an effort to identify new immunosuppressive agents from natural sources, 12 new geranylated flavonoids, 5,7,4'-trihydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavone (1), a racemate of 5,7,2',4'-tetrahydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavanone (2), 2''(S)-5,7-dihydroxy-[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (3), (2''S,3''R,4''S)-5,7,3'',4''-tetrahydroxy[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (4), a racemate of 3'-geranyl-5,7,2',4'-tetrahydroxyisoflavanone (5), a racemate of 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavanone (6), 3'-geranyl-5,7,4',5'-tetrahydroxyisoflavone (8), 3'-geranyl-5,7,2',5'-tetrahydroxyisoflavone (9), 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavone (10), 2(R),3(R)-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (12), (2R,3R)-6-methyl-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (13), and 5,7-dihydroxy-4'-O-geranylisoflavone (14), were isolated from the roots of Campylotropis hirtella (Franch.) Schindl. together with three previously described flavonoids. Their structures were elucidated by spectroscopic measurements, including two-dimensional nuclear magnetic resonance (NMR) techniques. The immunosuppressive effects of these compounds were assessed using mitogen-induced splenocyte proliferation, and the cytotoxicity of the compounds was also examined. The IC50 values of the compounds were found to be in the range of 1.49-61.23 microM for T lymphocyte suppression and 1.16-73.07 microM for B lymphocyte suppression. An analysis of their structure-activity relationships revealed that an isoflavonoid carbon skeleton with a C10 substituent at the C3' position was necessary for the activity. As many of the compounds exhibited good immunosuppressive activities, they may be promising as novel immunosuppressive agents.

Vedolizumab: toward a personalized therapy paradigm for people with ulcerative colitis

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Dart RJ

2017-03-01

Full Text Available Robin J Dart,1–3,* Mark A Samaan,1,* Nick Powell,1,4 Peter M Irving1 1Department of Gastroenterology, IBD Centre, St. Thomas’ Hospital, 2Immunosurveillance Laboratory, The Francis Crick Institute, London, 3Division of Immunology, Infection, and Inflammatory Disease (DIIID, King’s College London, 4Department of Experimental Immunobiology, Division of Transplantation and Mucosal Biology, King’s College London, London, UK *These authors contributed equally to this work Abstract: Ulcerative colitis (UC is a chronic relapsing and remitting inflammatory bowel disease, with a characteristic leukocytic infiltration of the mucosa. Immunosuppression including anti-TNF-α therapy is a mainstay of treatment for many; however, systemic immunosuppression is not universally effective and is associated with potential side effects. The gut-tropic integrin α4β7, which is expressed on leukocytes, mediates migration from the circulation to the intestinal mucosa. Vedolizumab is a monoclonal antibody which blocks the egress of leukocytes via α4β7, preventing accumulation in the mucosa, and attenuating inflammation without systemic immunosuppression. Vedolizumab has been evaluated in UC in a phase III trial, demonstrating efficacy as both an induction and a maintenance agent. In this article, we review the clinical trial data and also explore the growing body of “real-world” effectiveness data, investigating response and remission rates of vedolizumab in clinical practice. In addition, we review the increasing volume of data supporting the reassuring safety profile associated with vedolizumab. Keywords: vedolizumab, ulcerative colitis, personalized therapy

Anti-B cell antibody therapies for inflammatory rheumatic diseases

DEFF Research Database (Denmark)

Faurschou, Mikkel; Jayne, David R W

2014-01-01

Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus...... and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies....

Postradiation therapy skin complications and aspects of their treatment

International Nuclear Information System (INIS)

Derveniece, A.; Hartmane, I.; Cema, I.; Strode, E.; Mikazans, I.

2001-01-01

X-ray is a common therapy for malignant skin cancers. 60-70 Gy is the necessary therapeutic dose for squamous cell carcinoma. Early and late postradiation complications are X-ray dermatitis, erosions, ulcers and atrophies. The therapy for complications includes topical antiseptics and antibacterial agents, debridement, dressing, and even plastic and reconstructive surgery. Capillary regrowth, immunosuppression, local ischemia and epithelialisation are to be considered. The aim of this study was to observe and compare the topical agents in treatment of postradiation skin compilations. Early compilations were treated effectively using Diaethonum ointment (prophylaxis and therapy), Fucicort cream, Linoladiol-HN cream. With late complications Chlorhexidine gluconate 0.05% solution, Iruxol and Desitin ointments showed good results, dealing with trophical ulcers. There is no universal drug for treating X-ray caused complications, in every case the therapy is to be considered individually. (authors)

Non-adherence to immunosuppressive medications in kidney transplantation: intent vs. forgetfulness and clinical markers of medication intake.

Science.gov (United States)

Griva, Konstadina; Davenport, Andrew; Harrison, Michael; Newman, Stanton P

2012-08-01

Although adherence to immunosupressive medication after transplantation is important to maximize good clinical outcomes it remains suboptimal and not well-understood. The purpose of this study was to examine intentional and unintentional non-adherence to immunosuppression medication in kidney transplant patients. A cross-sectional sample of N=218 patients [49.6 ± 12.3 years] recruited in London, UK (1999-2002) completed measures of medication beliefs, quality-of-life, depression, and transplantation-specific emotions. Adherence was measured with self-report and serial immunosuppressive assays. Intentional non-adherence was low (13.8 %) yet 62.4 % admitted unintentional non-adherence and 25.4 % had sub-target immunosuppressive levels. The risk of sub-target serum immunosuppressive levels was greater for patients admitting unintentional non-adherence (OR=8.4; p=0.004). Dialysis vintage, doubts about necessity, and lower worry about viability of graft explained R(2)=16.1 to 36 % of self-report non-adherence. Depression was related only to intentional non-adherence. Non-adherence is common in kidney transplantation. Efforts to increase adherence should be implemented by targeting necessity beliefs, monitoring depression, and promoting strategies to decrease forgetfulness.

A targeted mutation within the feline leukemia virus (FeLV) envelope protein immunosuppressive domain to improve a canarypox virus-vectored FeLV vaccine.

Science.gov (United States)

Schlecht-Louf, Géraldine; Mangeney, Marianne; El-Garch, Hanane; Lacombe, Valérie; Poulet, Hervé; Heidmann, Thierry

2014-01-01

We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins that is critical for virus propagation in vivo. The envelope-mediated immunosuppression was assessed by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection. Using this approach, we identified key residues whose mutation (i) specifically abolishes immunosuppressive activity without affecting the "mechanical" function of the envelope protein and (ii) significantly enhances humoral and cellular immune responses elicited against the virus. The objective of this work was to study the immunosuppressive activity of the envelope protein (p15E) of feline leukemia virus (FeLV) and evaluate the effect of its abolition on the efficacy of a vaccine against FeLV. Here we demonstrate that the FeLV envelope protein is immunosuppressive in vivo and that this immunosuppressive activity can be "switched off" by targeted mutation of a specific amino acid. As a result of the introduction of the mutated envelope sequence into a previously well characterized canarypox virus-vectored vaccine (ALVAC-FeLV), the frequency of vaccine-induced FeLV-specific gamma interferon (IFN-γ)-producing cells was increased, whereas conversely, the frequency of vaccine-induced FeLV-specific interleukin-10 (IL-10)-producing cells was reduced. This shift in the IFN-γ/IL-10 response was associated with a higher efficacy of ALVAC-FeLV against FeLV infection. This study demonstrates that FeLV p15E is immunosuppressive in vivo, that the immunosuppressive domain of p15E can modulate the FeLV-specific immune response, and that the efficacy of FeLV vaccines can be enhanced by inhibiting the immunosuppressive activity of the IS domain through an appropriate mutation.

aPKC-ι/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma.

Science.gov (United States)

Qian, Yawei; Yao, Wei; Yang, Tao; Yang, Yan; Liu, Yan; Shen, Qi; Zhang, Jian; Qi, Weipeng; Wang, Jianming

2017-10-01

Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial-mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C-iota (aPKC-ι) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC-ι, Snail, and infiltrated immunosuppressive cells were significantly up-regulated in CCA tumor tissues and linked to poor prognosis. aPKC-ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC-ι did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC-ι and Snail in relation to EMT, quantitative iTRAQ-based phosphoproteomic analysis and liquid chromatography-tandem mass spectrometry were conducted to identify the substrates of aPKC-ι-dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC-ι on Ser59 (P-Sp1). Both Sp1 and P-Sp1 were up-regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P-Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P-Sp1 also regulated aPKC-ι/Snail-induced EMT-like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4 + )CD25 - cells rather than to increase CD4 + CD25 + natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor β1 and interleukin 2. These results demonstrate that a

Assessment of readiness for clinical decision support to aid laboratory monitoring of immunosuppressive care at U.S. liver transplant centers.

Science.gov (United States)

Jacobs, J; Weir, C; Evans, R S; Staes, C

2014-01-01

Following liver transplantation, patients require lifelong immunosuppressive care and monitoring. Computerized clinical decision support (CDS) has been shown to improve post-transplant immunosuppressive care processes and outcomes. The readiness of transplant information systems to implement computerized CDS to support post-transplant care is unknown. a) Describe the current clinical information system functionality and manual and automated processes for laboratory monitoring of immunosuppressive care, b) describe the use of guidelines that may be used to produce computable logic and the use of computerized alerts to support guideline adherence, and c) explore barriers to implementation of CDS in U.S. liver transplant centers. We developed a web-based survey using cognitive interviewing techniques. We surveyed 119 U.S. transplant programs that performed at least five liver transplantations per year during 2010-2012. Responses were summarized using descriptive analyses; barriers were identified using qualitative methods. Respondents from 80 programs (67% response rate) completed the survey. While 98% of programs reported having an electronic health record (EHR), all programs used paper-based manual processes to receive or track immunosuppressive laboratory results. Most programs (85%) reported that 30% or more of their patients used external laboratories for routine testing. Few programs (19%) received most external laboratory results as discrete data via electronic interfaces while most (80%) manually entered laboratory results into the EHR; less than half (42%) could integrate internal and external laboratory results. Nearly all programs had guidelines regarding pre-specified target ranges (92%) or testing schedules (97%) for managing immunosuppressive care. Few programs used computerized alerting to notify transplant coordinators of out-of-range (27%) or overdue laboratory results (20%). Use of EHRs is common, yet all liver transplant programs were largely

Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK.

Science.gov (United States)

Hoyle, M; Crathorne, L; Garside, R; Hyde, C

2011-05-01

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic lymphocytic leukaemia (CLL), based upon the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer's estimates of effectiveness based on evidence from a single-arm, non-randomised study. An 'area-under-the-curve' or 'partitioned-survival' model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: 'alive pre-progression', 'alive post progression' and 'dead'. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were

Renal Transplant Recipients: The Factors Related to Immunosuppressive Medication Adherence Based on the Health Belief Model.

Science.gov (United States)

Kung, Pen-Chen; Yeh, Mei Chang; Lai, Ming-Kuen; Liu, Hsueh-Erh

2017-10-01

Kidney transplant failures are caused primarily by lack of adherence to immunosuppressive medication regimens by patients after transplantation. A number of studies have indicated that health-related beliefs are an effective predictor of health-related behavior. The aim of this study is to understand the influence of the personal characteristics and health-related beliefs of patients on adherence to treatment with immunosuppressive medication based on the Health Belief Model. This cross-sectional study distributed questionnaires to patients who had been recruited via purposive sampling at one medical center in Taipei. All of the potential participants had undergone kidney transplantation at least 6 months previously. The self-developed questionnaire collected data in three areas: personal characteristics, health-related beliefs regarding transplant rejection, and adherence to the immunosuppressive medication regimen. One hundred twenty-two valid questionnaires were received. The collected data were analyzed using descriptive statistics, independent t test, one-way analysis of variance, Pearson's correlation, and multiple regression. Participants who had received dialysis treatment or had experienced rejection perceived susceptibility to rejection more strongly than those who had not. Participants who had undergone transplantation in Taiwan, had experienced more drug-related symptoms, or had contracted severe to extremely severe infections in the past showed lower rates of adherence to treatment with immunosuppressive medication. Adherence to medication regimens correlated negatively with length of time since transplantation. Length of time since transplantation, drug-related symptoms, perceived susceptibility to rejection, and perceived benefits of treatment were identified as major predictors of adherence to immunosuppressive medication regimens. The results partially conformed to the concepts of the Health Belief Model. Perceived susceptibility to rejection and

Fatal tick-borne encephalitis in an immunosuppressed 12-year-old patient

Czech Academy of Sciences Publication Activity Database

Chmelík, V.; Chrdle, A.; Růžek, Daniel

2016-01-01

Roč. 74, 1 January (2016), s. 73-74 ISSN 1386-6532 R&D Projects: GA ČR GAP502/11/2116 Institutional support: RVO:60077344 Keywords : Tick-borne encephalitis * immunosuppressed patient * fatal case * haemophagocytic lymphohistiocytosis Subject RIV: EE - Microbiology, Virology Impact factor: 3.051, year: 2016

[Side effects of the HMG-CoA reductase inhibitors (statins). Lupus erythematosus induced by Atorvastatin therapy].

Science.gov (United States)

Hydzik, Piotr; Szpak, Dorota

2011-01-01

The paper describes the case of 56 years old woman admitted to the Toxicology Department because of skin lesions, joint and muscle pain and elevated activity of transaminases and creatine phosfokinase as well in biochemical analysis. The symptoms occurred after 6 days of the Atorvastatin therapy. The clinical picture indicated side effects of the hipolipemic therapy, but the presence of the skin lesions suggested drug induced collagenosis (lupus erythrematosus, dermatomyositis). Immunological studies confirmed association with antinuclear antibodies (ANA) and anti-Mi-2 autoantibodies in the serum. Immunosuppressive therapy was ordered with clinical and biochemical improvement.

Transplantation of co-aggregates of Sertoli cells and islet cells into liver without immunosuppression.

Science.gov (United States)

Takemoto, Naohiro; Liu, Xibao; Takii, Kento; Teramura, Yuji; Iwata, Hiroo

2014-02-15

Transplantation of islets of Langerhans (islets) was used to treat insulin-dependent diabetes mellitus. However, islet grafts must be maintained by administration of immunosuppressive drugs, which can lead to complications in the long term. An approach that avoids immunosuppressive drug use is desirable. Co-aggregates of Sertoli cells and islet cells from BALB/c mice that were prepared by the hanging drop method were transplanted into C57BL/6 mouse liver through the portal vein as in human clinical islet transplantation. The core part of the aggregates contained mainly Sertoli cells, and these cells were surrounded by islet cells. The co-aggregates retained the functions of both Sertoli and islet cells. When 800 co-aggregates were transplanted into seven C57BL/6 mice via the portal vein, six of seven recipient mice demonstrated quasi-normoglycemia for more than 100 days. The hanging drop method is suitable for preparing aggregates of Sertoli and islet cells for transplantation. Notably, transplantation of these allogeneic co-aggregates into mice with chemically induced diabetes via the portal vein resulted in long-term graft survival without systemic immunosuppression.

Long-term outcome of intensive initial immunosuppression protocol in pediatric deceased donor renal transplantation.

LENUS (Irish Health Repository)

Olaitan, Oyedolamu K

2010-02-01

To report the long-term outcome of deceased donor kidney transplantation in children with emphasis on the use of an intensive initial immunosuppression protocol using R-ATG as antibody induction. Between January 1991 and December 1997, 82 deceased donor kidney transplantations were performed in 75 pediatric recipients. Mean recipient age at transplantation was 12.9 yr and the mean follow-up period was 12.6 yr. All patients received quadruple immunosuppression with steroid, cyclosporine, azathioprine, and antibody induction using R-ATG-Fresenius. Actual one, five, and 10 yr patient survival rates were 99%, 97%, and 94%, respectively; only one patient (1.2%) developed PTLD. Actual one, five, and 10 yr overall graft survival rates were 84%, 71%, and 50%, respectively; there were five cases (6%) of graft thrombosis and the actual immunological graft survival rates were 91%, 78%, and 63% at one, five, and 10 yr, respectively. The use of an intensive initial immunosuppression protocol with R-ATG as antibody induction is safe and effective in pediatric recipients of deceased donor kidneys with excellent immunological graft survival without an increase in PTLD or other neoplasms over a minimum 10-yr follow up.

Why do Patients Forget to Take Immunosuppression Medications and Miss Appointments: Can a Mobile Phone App Help?

OpenAIRE

Israni, Ajay; Dean, Carl; Kasel, Brian; Berndt, Lisa; Wildebush, Winston; Wang, C Jason

2016-01-01

Background Kidney transplant recipients must adhere to their immunosuppressive medication regimen. However, non-adherence remains a major problem. Objective The aim of this paper is to determine how kidney transplant recipients remember to take their medications, and assess their perception and beliefs about adherence to immunosuppressive medications and barriers to medication adherence. In addition, we aim to assess perception and beliefs about willingness to use a hypothetical, mobile phone...

Pharmacotherapy for uveitis: current management and emerging therapy

Science.gov (United States)

Barry, Robert J; Nguyen, Quan Dong; Lee, Richard W; Murray, Philip I; Denniston, Alastair K

2014-01-01

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects. PMID:25284976

Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation

Science.gov (United States)

2012-02-01

10-1-0927 TITLE: Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation...immunosuppression. Bone Marrow Derived Mesenchymal stem cells (BM-MSCs) are pluripotent cells, capable of differentiation along multiple mesenchymal lineages into...As part of implemented transition from University of Pittsburgh to Johns Hopkins University, we optimized our mesenchymal stem cell (MSC) isolation

Self-efficacy beliefs, locus of control, religiosity and non-adherence to immunosuppressive medications in kidney transplant patients.

Science.gov (United States)

Silva, Andresa Nascimento; Moratelli, Lucas; Tavares, Paula Liziero; Marsicano, Elisa De Oliveira; Pinhati, Renata Romanholi; Colugnati, Fernando Antonio Basile; Lucchetti, Giancarlo; Sanders-Pinheiro, Helady

2016-11-01

Adherence to immunosuppressive medication is essential for favourable kidney transplant outcomes. The present study aims to investigate how self-efficacy beliefs, health locus of control and religiosity are associated with adherence to immunosuppressives in post kidney transplant recipients. This is a cross-sectional study with 88 recipients with more than 1 year after transplantation. Three methods were used to classify patients as adherent or non-adherent: Basel Assessment of Adherence Scale for Immunosuppressives - BAASIS, the collateral report and blood levels of immunosuppressive medications. Self-efficacy, health locus of control, and religiosity were evaluated applying General Perceived Self-Efficacy Scale, Multidimensional Health Locus of Control Scale and Duke University Religion Index, respectively. Non-adherence was modelled by uni- and multivariated analysis. Sixty-three percent of the patients were male, age 47.2 ± 12.9 years, and median post-transplant time 108.71 (49.0-266.0) months. We found 70.5% of patients were non-adherent through at least one method. Adherent patients presented higher self-efficacy scores (45.1 ± 4.9 vs 38.3 ± 8.6; P locus of control (OR 1.23, IC 1.04-1.45, P = 0.016) and lower intrinsic religiosity (OR 0.56, IC 0.38-0.84, P = 0.006). Our study showed that self-efficacy, chance locus of control, and intrinsic religiosity were associated with non-adherence to immunosuppressives. A broader perception of the kidney transplant patient´s integrality can help health professionals to design strategies to promote adherence in this population. © 2015 Asian Pacific Society of Nephrology.

Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

Science.gov (United States)

Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

2011-11-15

The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

Abnormal chest shadow on CT in immunosuppressed patients

International Nuclear Information System (INIS)

Tanaka, Nobuyuki; Matsumoto, Tsuneo; Nakamura, Hiroshi

1992-01-01

An abnormal chest shadow was observed on CT scans in 25 cases of 23 immunosuppressed patients. Pulmonary disease was pathologically confirmed to be pneumocystis carinii pneumonia (PC pneumonia) in four patients, cytomegalovirus pneumonia (CMV pneumonia) in one, bacterial pneumonia in seven, fungal infection in three, miliary tuberculosis in one, leukemic infiltration in two, lymphangitis carcinomatosa in three, drug-induced pneumonitis in three, and ARDS in one. In almost all patients, especially those with infectious diseases such as PC pneumonia, CMV pneumonia, and bacterial pneumonia, the abnormal shadow was wide and visible in the bilateral lung fields. We presumed that such findings as lobular shadow, centrilobular shadow, and mosaic pattern reflected the extension of disease via the respiratory tract, and that those findings are typical of infectious diseases. Because such findings as abnormal linear shadow and swelling of a broncho-vascular bundle were very frequently recognized in patients with lymphangitis carcinomatosa and frequently recognized in those with drug-induced pneumonitis, these diseases may be distinguished from other diseases. An area of slightly increased density was frequently recognized in patients with PC pneumonia, bacterial pneumonia, and drug-induced pneumonitis. Such lesions were pathologically confirmed to be located in the interstitium and/or alveolus. CT was extremely useful in comprehending the character and extension of particular diseases among various diseases. As the number of patients studied was small, the utility of CT in immunosuppressed patients requires further investigation in a larger number of patients. (author)

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Science.gov (United States)

Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G

2017-05-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4 + T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4 + T cells more effectively while inhibiting the proliferation of CD4 + T cells in old mice. Both TAC-treated murine and human CD4 + T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8 + T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4 + T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

[Mechanisms of retroviral immunosuppressive domain-induced immune modulation].

Science.gov (United States)

Blinov, V M; Krasnov, G S; Shargunov, A V; Shurdov, M A; Zverev, V V

2013-01-01

Immunosuppressive domains (ISD) of viral envelope glycoproteins provide highly pathogenic phenotypes of various retroviruses. ISD interaction with immune cells leads to an inhibition of a response. In the 1980s it was shown that the fragment of ISD comprising of 17 amino acids (named CKS-17) is carrying out such immune modulation. However the underlying mechanisms were not known. The years of thorough research allowed to identify the regulation of Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cellular pathways as a result of ISD interaction with immune cells. By the way, this leads to decrease of secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory, anti-inflammatory ones (e.g., IL-10). One of the receptor tyrosine kinases inducing signal in these pathways acts as the primary target of ISD while other key regulators--cAMP and diacylglycerol (DAG), act as secondary messengers of signal transduction. Immunosuppressive-like domains can be found not only in retroviruses; the presence of ISD within Ebola viral envelope glycoproteins caused extremely hard clinical course of virus-induced hemorrhagic fever. A number of retroviral-origin fragments encoding ISD can be found in the human genome. These regions are expressed in the placenta within genes of syncytins providing a tolerance of mother's immune system to an embryo. The present review is devoted to molecular aspects of retroviral ISD-induced modulation of host immune system.

Influence of Interferon-Alpha Combined with Chemo (Radio Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

Directory of Open Access Journals (Sweden)

Svetlana Karakhanova

2014-03-01

Full Text Available Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

Myasthenia gravis: recent advances in immunopathology and therapy.

Science.gov (United States)

Lee, John-Ih; Jander, Sebastian

2017-03-01

Myasthenia gravis is the most frequent acquired disorder of neuromuscular transmission. In the majority of cases, pathogenic antibodies against components of the postsynaptic muscle endplate membrane can be detected. In recent years there have been significant advances in the pathophysiological understanding and therapy of the disease. Areas covered: PubMed searches were conducted for the term 'myasthenia gravis' cross-referenced with the terms 'immunology', 'subgroups', 'antibody', 'ocular', 'thymoma', 'treatment' and 'thymectomy'. Additionally, we summarized the current state of immunopathology and therapy. Expert commentary: Immunological research defined new target antigens at the postsynaptic neuromuscular junction which along with clinical features allow a refined definition of disease subgroups. Overall the prognosis of myasthenia gravis with best possible symptomatic, immunosuppressive and supportive treatment is good but new immunomodulatory treatment options are developed for patients who do not respond well to the first line therapy. For most patients individually adapted long-term drug therapy is needed.

Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients.

Science.gov (United States)

Fairfield, Cameron; Penninga, Luit; Powell, James; Harrison, Ewen M; Wigmore, Stephen J

2018-04-09

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects. To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017. Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids. We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a

In Silico Characterization and Structural Modeling of Dermacentor andersoni p36 Immunosuppressive Protein

Directory of Open Access Journals (Sweden)

Martin Omulindi Oyugi

2018-01-01

Full Text Available Ticks cause approximately $17–19 billion economic losses to the livestock industry globally. Development of recombinant antitick vaccine is greatly hindered by insufficient knowledge and understanding of proteins expressed by ticks. Ticks secrete immunosuppressant proteins that modulate the host’s immune system during blood feeding; these molecules could be a target for antivector vaccine development. Recombinant p36, a 36 kDa immunosuppressor from the saliva of female Dermacentor andersoni, suppresses T-lymphocytes proliferation in vitro. To identify potential unique structural and dynamic properties responsible for the immunosuppressive function of p36 proteins, this study utilized bioinformatic tool to characterize and model structure of D. andersoni p36 protein. Evaluation of p36 protein family as suitable vaccine antigens predicted a p36 homolog in Rhipicephalus appendiculatus, the tick vector of East Coast fever, with an antigenicity score of 0.7701 that compares well with that of Bm86 (0.7681, the protein antigen that constitute commercial tick vaccine Tickgard™. Ab initio modeling of the D. andersoni p36 protein yielded a 3D structure that predicted conserved antigenic region, which has potential of binding immunomodulating ligands including glycerol and lactose, found located within exposed loop, suggesting a likely role in immunosuppressive function of tick p36 proteins. Laboratory confirmation of these preliminary results is necessary in future studies.

The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro

Energy Technology Data Exchange (ETDEWEB)

Skardelly, Marco, E-mail: Marco.Skardelly@med.uni-tuebingen.de [Department of Neurosurgery, University Hospital, Leipzig (Germany); Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany); Glien, Anja; Groba, Claudia; Schlichting, Nadine [Department of Neurosurgery, University Hospital, Leipzig (Germany); Kamprad, Manja [Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig (Germany); Meixensberger, Juergen [Department of Neurosurgery, University Hospital, Leipzig (Germany); Milosevic, Javorina [Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany)

2013-12-10

In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment. - Highlights: • Four immunosuppresants (ISs) were tested in human neural progenitor cells in vitro. • Cyclosporine A and mycophenolic acid showed a prominent anti-proliferative activity • Mycophenolic acid exhibited a significant pro-apoptotic effect. • NAD(P)H-dependent metabolic activity was occasionally induced by ISs. • Neuronal differentiation and migration potential remained unaffected by ISs treatment.

Pharmacodynamic Monitoring of Tacrolimus-based Immunosuppression in CD14+ Monocytes after Kidney Transplantation

NARCIS (Netherlands)

N.M. Kannegieter (Nynke); D.A. Hesselink (Dennis); M. Dieterich (Marjolein); G.N. de Graav (Gretchen); R. Kraaijeveld (Rens); A.T. Rowshani (Ajda); P.J. Leenen (Pieter); C.C. Baan (Carla)

2017-01-01

markdownabstractBackground: Monocytes significantly contribute to ischemia-reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Conventional pharmacokinetic methods for

Differential role of basal keratinocytes in UV-induced immunosuppression and skin cancer

NARCIS (Netherlands)

J. Jans (Judith); G.A. Garinis (George); W. Schul; A. van Oudenaren (Adri); M.J. Moorhouse (Michael); M. Smid (Marcel); Y.-G. Sert (Yurda-Gul); A. van der Velde (Albertina); Y.M. Rijksen (Yvonne); F.R. de Gruijl (Frank); P.J. van der Spek (Peter); A. Yasui (Akira); J.H.J. Hoeijmakers (Jan); P.J. Leenen (Pieter); G.T.J. van der Horst (Gijsbertus)

2006-01-01

textabstractCyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression

OpenAIRE

Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-01-01

Background To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Methods Retrospective multicenter study using the Swiss ...

Chondrocytic Potential of Allogenic Mesenchymal Stem Cells Transplanted without Immunosuppression to Regenerate Physeal Defect in Rabbits

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P. Gál

2007-01-01

Full Text Available Mesenchymal stem cells (MSCs from bone marrow are multipotent cells capable of forming cartilage, bone, and other connective tissues. The objective of this study was to determine whether the use of allogenic mesenchymal stem cells could functionally heal a defect in the distal femoral physis in rabbits without the use of immunosuppressive therapy. A iatrogenic defect was created in the lateral femoral condyle of thirty-two New Zealand white rabbits, 7 weeks old, weighing 2.25 ± 0.24 kg. Each defect, 3.5 mm in width and 12 mm in length, in the right distal femoral physis was treated with allogenic mesenchymal stem cells in new composite hyaluronate/collagen type I/fibrin scaffold. The healing response was evaluated radiographically, by MRI (three weeks and four months after implantation and also histologically, by Pearl’s reaction and with immunofluorescence (four months after implantation. The results were compared with the data for the control defects (without stem cell implantation in left distal femoral physes. On average, right femurs with a damaged distal physis and transplanted MSCs grew more in length (0.55 ± 0.21 cm compared with left femurs with a physeal defect without stem cell transplantation (0.46 ± 0.23 cm. Valgus deformity of right femurs with a physeal defect and transplanted MSCs was mild (0.2 ± 0.1 °. On the contrary, left femurs with a physeal defect without transplanted MSCs showed a significant valgus deformity (2.7 ± 1.6 °. For defects treated with allogenic mesenchymal stem cell implants, no adverse immune response and implant rejection were detected in this model. Histologically, no lymphocytic infiltration occurred. At four months after transplantation, hyaline cartilage had formed throughout the defects treated with allogenic MSCs. Labelled mesenchymal stem cells/differentiated chondrocytes were detected in the physeal defects based on magnetic resonance imaging and immunofluorescence. The results of this study

Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

International Nuclear Information System (INIS)

McCune, W.J.; Buckley, J.A.; Belli, J.A.; Trentham, D.E.

1982-01-01

Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type II collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLi and cyclophosphamide are immunosuppressive in an experimentally inducible autoimmune disease

Albendazole inhibits Pneumocystis carinii proliferation in inoculated immunosuppressed mice.

OpenAIRE

Bartlett, M S; Edlind, T D; Lee, C H; Dean, R; Queener, S F; Shaw, M M; Smith, J W

1994-01-01

Albendazole, a benzimidazole derivative widely used for treating helminth infections, was successfully used to treat and prevent development of Pneumocystis carinii pneumonia in transtracheally inoculated immunosuppressed mice. For treatment, 3 weeks postinoculation, albendazole at 300 and 600 mg/kg of body weight per day was administered in food for 3 weeks. For prophylaxis, albendazole was begun on the same day as inoculation at 300 mg/kg/day for 7 days, and then the dose was reduced to 150...

Forging a link between oncogenic signaling and immunosuppression in melanoma.

Science.gov (United States)

Khalili, Jahan S; Hwu, Patrick; Lizée, Gregory

2013-02-01

Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of BRAF V600E with vemurafenib relieves interleukin-1 (IL-1)-induced T-cell suppression as mediated by melanoma tumor associated fibroblasts (TAFs). These results suggest that inhibitors of the MAPK pathway in combination with T cell-based immunotherapies may induce long-lasting and durable responses.

Hidden sources of grapefruit in beverages: potential interactions with immunosuppressant medications.

Science.gov (United States)

Auten, Ashley A; Beauchamp, Lauren N; Joshua Taylor; Hardinger, Karen L

2013-06-01

The interaction between grapefruit-containing beverages and immunosuppressants is not well defined in the literature. This study was conducted to investigate possible sources of grapefruit juice or grapefruit extract in common US-manufactured beverages. The goal was to identify those products that might serve as hidden sources of dietary grapefruit intake, increasing a transplant patient's risk for drug interactions. A careful review of the ingredients of the 3 largest US beverage manufacturer's product lines was conducted through manufacturer correspondence, product labeling examination, and online nutrition database research. Focus was placed on citrus-flavored soft drinks, teas, and juice products and their impact on a patient's immunosuppressant regimens. Twenty-three beverages were identified that contained grapefruit. Five did not contain the word "grapefruit" in the product name. In addition to the confirmed grapefruit-containing products, 17 products were identified as possibly containing grapefruit juice or grapefruit extract. A greater emphasis should be placed upon properly educating patients regarding hidden sources of grapefruit in popular US beverages and the potential for food-drug interactions.

The release of immunosuppressive factor(s) in young males following exercise.

Science.gov (United States)

Tian, Ye; Nie, Jinlei; Tong, Tom K; Baker, Julien S

2012-01-01

It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years) were taken before and immediately after ten sets of exercise consisting of 15 free and 30 10-kg loaded squat jumps in each set. The suppression of lymphocyte proliferation was analysed with high pressure liquid chromatography. It was noted from the result of gel chromatography columns that the post-exercise values of the suppression of lymphocyte proliferation, in comparison to corresponding pre-exercise values, were generally greater with significant differences observed in 7.5th-9th min post-exercise eluates (P exercise may lead to generation of immunosuppressive factor(s) in young males.

The Release of Immunosuppressive Factor(s in Young Males Following Exercise

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Julien S. Baker

2012-05-01

Full Text Available It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years were taken before and immediately after ten sets of exercise consisting of 15 free and 30 10-kg loaded squat jumps in each set. The suppression of lymphocyte proliferation was analysed with high pressure liquid chromatography. It was noted from the result of gel chromatography columns that the post-exercise values of the suppression of lymphocyte proliferation, in comparison to corresponding pre-exercise values, were generally greater with significant differences observed in 7.5th–9th min post-exercise eluates (P < 0.05. Such findings suggest that intense eccentric type exercise may lead to generation of immunosuppressive factor(s in young males.

Sequential kidney/islet transplantation using prednisone-free immunosuppression.

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Kaufman, Dixon B; Baker, Marshall S; Chen, Xiaojuan; Leventhal, Joseph R; Stuart, Frank P

2002-08-01

Islet transplantation is becoming established as a treatment option for type I diabetes in select patients. Individuals with type I diabetes who have previously received a successful kidney allograft may be good candidates for islet transplantation. They have already assumed the risks of chronic immunosuppression, so the added procedural risk of a subsequent islet transplant would be minimal. Furthermore, because of the preimmunosuppressed state it is possible that islet-after-kidney transplantation may result in a more efficient early islet engraftment. Consequently, insulin independence might be achieved with significantly fewer islets than the approximately 8-10,000 islet equivalents/kg/b.w. currently required. A mass that usually demands two or more cadaveric donors. A case of successful islet-after-kidney transplantation is described using the steroid-free Edmonton immunosuppression protocol. Characteristics of the final islet product are: a) islet equivalents: 265,888 (4100 islet equivalents/kg/b.w.); b) islet purity: 75-80%; c) viability: >95% (trypan blue exclusion); and d) mean islet potency (static low-high glucose challenge): 4.16 +/- 1.91-fold increase. Post-transplant the patient's hypoglycemic episodes abated. Exogenous insulin requirements were eliminated at week 12 post-transplant as basal and Ensure (Abbott Laboratories, Abbott Park, IL, USA) oral glucose stimulated C-peptide levels peaked and stabilized. Twenty-four-hour continuous glucose monitoring confirmed moment-to-moment glycemic control, and periodic nonfasting finger stick glucose determinations over the next month confirmed glycemia was controlled. Hemoglobin A1c levels declined from a pretransplant level of 6.9% to 5.3%. Renal allograft function remained changed.

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

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Blaslov, Kristina; Katalinic, Lea; Kes, Petar; Spasovski, Goce; Smalcelj, Ruzica; Basic-Jukic, Nikolina

2014-05-01

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal

Pulmonary aspergillosis in immunosuppressed patients with haematological malignancies.

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Spearing, R L; Pamphilon, D H; Prentice, A G

1986-06-01

Invasive pulmonary aspergillosis as a cause of mortality and morbidity in patients with haematological malignancies is becoming more common. Predisposing factors are powerful immunosuppressive chemotherapy, neutropenia and synergistic combinations of antibiotics of great potency and wide spectrum of activity. Clinical and radiological signs are heterogeneous, sometimes misleading and often absent. Treatment is often empirical on suspicion alone. Amphotericin B is the only effective drug but it has marked toxicity, mainly renal. Infection is usually fatal without adequate treatment. This paper describes eight cases of invasive pulmonary aspergillosis seen in one centre in two years, reviews the literature and assesses associated problems.

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques.

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Meyer, C; Walker, J; Dewane, J; Engelmann, F; Laub, W; Pillai, S; Thomas, Charles R; Messaoudi, I

2015-09-01

In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease. © 2015 British Society for Immunology.

Immunosuppressive effects of sesquiterpene lactones from Laser trilobum (L.) Borkh

Czech Academy of Sciences Publication Activity Database

Zídek, Zdeněk; Harmatha, Juraj; Vokáč, Karel; Kmoníčková, Eva

2009-01-01

Roč. 75, č. 9 (2009), s. 905-905 ISSN 0032-0943. [International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research /57./. 16.08.2009-20.08.2009, Geneva] R&D Projects: GA ČR GA305/07/0061 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50390512 Keywords : immunosuppressive effects * Laser trilobum Subject RIV: CC - Organic Chemistry

Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice.

Science.gov (United States)

Rosas-Taraco, Adrian G; Perez-Liñan, Amira R; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I; Salinas-Carmona, Mario C

2012-07-01

Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.

Identification of poly(rC) binding protein 2 (PCBP2) as a target protein of immunosuppressive agent 15-deoxyspergualin

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Murahashi, Masataka; Simizu, Siro; Morioka, Masahiko [Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan); Umezawa, Kazuo, E-mail: umezawa@aichi-med-u.ac.jp [Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195 (Japan)

2016-08-05

15-Deoxyspergualin (DSG) is an immunosuppressive agent being clinically used. Unlike tacrolimus and cyclosporine A, it does not inhibit the calcineurin pathway, and its mechanism of action and target molecule have not been elucidated. Therefore, we previously prepared biotinylated derivative of DSG (BDSG) to fish up the target protein. In the present research, we identified poly(rC) binding protein 2 (PCBP2) as a DSG-binding protein using this probe. DSG was confirmed to bind to PCBP2 by pull-down assay. Intracellular localization of PCBP2 was changed from the nucleus to the cytoplasm by DSG treatment. DSG inhibited the cell growth, and over-expression of PCBP2 reduced the anti-proliferative activity of DSG. PCBP2 is known to regulate various proteins including STAT1/2. Thus, we found PCBP2 as the first target protein of DSG that can explain the immunosuppressive activity. -- Highlights: •Fifteen-deoxyspergualin (DSG) is an immunosuppressive agent clinically used. •We have identified PCBP2, an RNA-binding protein, as a molecular target of DSG. •Alteration of PCBP2 activity may explain the immunosuppressive activity of DSG.

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study.

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Elisa Oliveira Marsicano

Full Text Available Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system.Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adherence score consisting of three methods (self-report [i.e., The Basel Adherence Scale for Assessment of Immunossupressives-BAASIS], collateral report, and immunosuppressive blood levels. Multilevel correlations of non-adherence were assessed (macro, meso, micro and patient level. Univariate and multivariate logistic regression was applied to assess the correlates of non-adherence.Our sample consisted primarily of male (65%, Caucasians (72% with a mean age of 45.0 ± 13.5 years old, who received grafts from a living donor (89%, with a mean time after transplantation of 72.3 ± 44.4 months. Prevalence of non-adherence was 51%. Family income higher than five reference wages (21.6 vs. 4%; OR 6.46 [1.35-30.89], p = 0.009; patient level, and having access to private health insurance (35.3% vs. 18.4%; OR 2.42 [0.96-6.10], p = 0.04; meso level were associated with non-adherence in univariate analysis. Only the higher family income variable was retained in the multiple logistic regression model (OR 5.0; IC: 1.01-25.14; p = 0.04.Higher family income was the only factor that was associated with immunosuppressive non-adherence. In Brazil, lower income recipients benefit from better access to care and coverage of health care costs after transplantation. This is supposed to result in a better immunosuppressive adherence compared to high-income patients who have experienced these benefits continuously.

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study.

Science.gov (United States)

Marsicano, Elisa Oliveira; Fernandes, Neimar Silva; Colugnati, Fernando Antônio Basile; Fernandes, Natalia Maria Silva; De Geest, Sabina; Sanders-Pinheiro, Helady

2015-01-01

Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system. Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adherence score consisting of three methods (self-report [i.e., The Basel Adherence Scale for Assessment of Immunossupressives-BAASIS], collateral report, and immunosuppressive blood levels). Multilevel correlations of non-adherence were assessed (macro, meso, micro and patient level). Univariate and multivariate logistic regression was applied to assess the correlates of non-adherence. Our sample consisted primarily of male (65%), Caucasians (72%) with a mean age of 45.0 ± 13.5 years old, who received grafts from a living donor (89%), with a mean time after transplantation of 72.3 ± 44.4 months. Prevalence of non-adherence was 51%. Family income higher than five reference wages (21.6 vs. 4%; OR 6.46 [1.35-30.89], p = 0.009; patient level), and having access to private health insurance (35.3% vs. 18.4%; OR 2.42 [0.96-6.10], p = 0.04; meso level) were associated with non-adherence in univariate analysis. Only the higher family income variable was retained in the multiple logistic regression model (OR 5.0; IC: 1.01-25.14; p = 0.04). Higher family income was the only factor that was associated with immunosuppressive non-adherence. In Brazil, lower income recipients benefit from better access to care and coverage of health care costs after transplantation. This is supposed to result in a better immunosuppressive adherence compared to high-income patients who have experienced these benefits continuously.

Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination.

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Cheetham, T Craig; Marcy, S Michael; Tseng, Hung-Fu; Sy, Lina S; Liu, In-Lu Amy; Bixler, Felicia; Baxter, Roger; Donahue, James G; Naleway, Allison L; Jacobsen, Steven J

2015-07-01

To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines. Copyright © 2015 Mayo Foundation for Medical Education and Research. All rights reserved.

Similar effect of autologous and allogeneic cell therapy for ischemic heart disease : Systematic review and meta-analysis of large animal studies

NARCIS (Netherlands)

Jansen of Lorkeers, Sanne J.; Eding, Joep Egbert Coenraad; Vesterinen, Hanna Mikaela; van der Spoel, Tycho Ids Gijsbert; Sena, Emily Shamiso; Duckers, Henricus Johannes; Doevendans, Pieter Adrianus; Macleod, Malcolm Robert; Chamuleau, Steven Anton Jozef

2015-01-01

Rationale: In regenerative therapy for ischemic heart disease, use of both autologous and allogeneic stem cells has been investigated. Autologous cell can be applied without immunosuppression, but availability is restricted, and cells have been exposed to risk factors and aging. Allogeneic cell

Modified uterine allotransplantation and immunosuppression procedure in the sheep model.

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Li Wei

Full Text Available OBJECTIVE: To develop an orthotopic, allogeneic, uterine transplantation technique and an effective immunosuppressive protocol in the sheep model. METHODS: In this pilot study, 10 sexually mature ewes were subjected to laparotomy and total abdominal hysterectomy with oophorectomy to procure uterus allografts. The cold ischemic time was 60 min. End-to-end vascular anastomosis was performed using continuous, non-interlocking sutures. Complete tissue reperfusion was achieved in all animals within 30 s after the vascular re-anastomosis, without any evidence of arterial or venous thrombosis. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil and methylprednisolone tablets. Graft viability was assessed by transrectal ultrasonography and second-look laparotomy at 2 and 4 weeks, respectively. RESULTS: Viable uterine tissue and vascular patency were observed on transrectal ultrasonography and second-look laparotomy. Histological analysis of the graft tissue (performed in one ewe revealed normal tissue architecture with a very subtle inflammatory reaction but no edema or stasis. CONCLUSION: We have developed a modified procedure that allowed us to successfully perform orthotopic, allogeneic, uterine transplantation in sheep, whose uterine and vascular anatomy (apart from the bicornuate uterus is similar to the human anatomy, making the ovine model excellent for human uterine transplant research.

Electronically-measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation*

Science.gov (United States)

Israni, Ajay K.; Weng, Francis L.; Cen, Ye-Ying; Joffe, Marshall; Kamoun, Malek; Feldman, Harold I.

2013-01-01

Background Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss. Methods In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR. Results The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%) and 30 (12%) had >85–100%, 50–85% and adherence, respectively. 79 (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time. Conclusions Non-adherence with a single immunosuppressive medication, was not associated with kidney allograft outcomes. PMID:20977496

Electronically measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation.

Science.gov (United States)

Israni, Ajay K; Weng, Francis L; Cen, Ye-Ying; Joffe, Marshall; Kamoun, Malek; Feldman, Harold I

2011-01-01

Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss. In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR. The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%), and 30 (12%) had >85-100%, 50-85%, and adherence, respectively. Seventy-nine (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time. Non-adherence with a single immunosuppressive medication was not associated with kidney allograft outcomes. © 2010 John Wiley & Sons A/S.

Classifying PML risk with disease modifying therapies.

Science.gov (United States)

Berger, Joseph R

2017-02-01

To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS). All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk. A method of contextualizing PML risk for DMTs is warranted. Classification of PML risk was predicated on three criteria:: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed. Among the DMTs, natalizumab occupies a place of its own with respect to PML risk. Significantly lesser degrees of risk exist for fingolimod and dimethyl fumarate. Whether PML will be observed with other DMTs in use for MS, such as, rituximab, teriflunomide, and alemtuzumab, remains uncertain. A logical classification for stratifying DMT PML risk is important for both the physician and patient in contextualizing risk/benefit ratios. As additional experience accumulates regarding PML and the DMTs, this early effort will undoubtedly require revisiting. Copyright © 2016 Elsevier B.V. All rights reserved.

A Pilot Study of Mesenchymal Stem Cell Therapy for Acute Liver Allograft Rejection

OpenAIRE

Shi, Ming; Liu, Zhenwen; Wang, Ying; Xu, Rounan; Sun, Yanling; Zhang, Min; Yu, Xi; Wang, Hongbo; Meng, Lingzhan; Su, Haibin; Jin, Lei; Wang, Fu‐Sheng

2017-01-01

Abstract Acute allograft rejection remains common after liver transplantation despite modern immunosuppressive agents. In addition, the long‐term side effects of these regimens, including opportunistic infections, are challenging. This study evaluated the safety and clinical feasibility of umbilical cord‐derived mesenchymal stem cell (UC‐MSC) therapy in liver transplant patients with acute graft rejection. Twenty‐seven liver allograft recipients with acute rejection were randomly assigned int...

A 27-Year-Old Severely Immunosuppressed Female with Misleading Clinical Features of Disseminated Cutaneous Sporotrichosis

Directory of Open Access Journals (Sweden)

Atiyah Patel

2016-01-01

Full Text Available Sporotrichosis is a subacute or chronic granulomatous mycosis caused by fungus of the Sporothrix schenckii complex. It is considered to be a rare condition in most parts of the world. It mostly causes cutaneous infection but can also cause multisystemic disease. Unlike most deep cutaneous mycoses which have a primary pulmonary focus, it is usually caused by direct inoculation of the fungus into the skin causing a classical linear, lymphocutaneous nodular eruption. However, atypical presentations of the condition can occur especially in immunosuppressed individuals. We report the case of a severely immunosuppressed female who presented with disseminated cutaneous sporotrichosis which was initially diagnosed and treated as disseminated cutaneous Kaposi’s sarcoma.

A 27-Year-Old Severely Immunosuppressed Female with Misleading Clinical Features of Disseminated Cutaneous Sporotrichosis

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Patel, Atiyah; Mudenda, Victor; Lakhi, Shabir; Ngalamika, Owen

2016-01-01

Sporotrichosis is a subacute or chronic granulomatous mycosis caused by fungus of the Sporothrix schenckii complex. It is considered to be a rare condition in most parts of the world. It mostly causes cutaneous infection but can also cause multisystemic disease. Unlike most deep cutaneous mycoses which have a primary pulmonary focus, it is usually caused by direct inoculation of the fungus into the skin causing a classical linear, lymphocutaneous nodular eruption. However, atypical presentations of the condition can occur especially in immunosuppressed individuals. We report the case of a severely immunosuppressed female who presented with disseminated cutaneous sporotrichosis which was initially diagnosed and treated as disseminated cutaneous Kaposi's sarcoma. PMID:26881148

Combination antiretroviral therapy and cancer risk

DEFF Research Database (Denmark)

Borges, Álvaro H

2017-01-01

PURPOSE OF REVIEW: To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. RECENT FINDINGS: HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignanci......ART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.......PURPOSE OF REVIEW: To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. RECENT FINDINGS: HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies...... into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk...

Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

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Kopecka, Joanna; Gazzano, Elena; Sara, Orecchia; Ghigo, Dario; Riganti, Chiara

2015-01-01

The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

Association of Human Leukocyte Antigen DRB1*15 and DRB1*15:01 Polymorphisms with Response to Immunosuppressive Therapy in Patients with Aplastic Anemia: A Meta-Analysis

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Liu, Shan; Li, Qing; Zhang, Ying; Li, Qiushuang; Ye, Baodong; Wu, Dijiong; Wu, Li; Lu, Hanti; Ji, Conghua

2016-01-01

This study aimed to review and quantitatively analyze (1) the association of aplastic anemia (AA) with human leukocyte antigen (HLA)-DRB1*15 and HLA-DRB1*15:01 polymorphisms and (2) the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to immunosuppressive therapy (IST) in AA. Published studies have reported conflicting and heterogeneous results regarding the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to IST in AA. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese BioMedical Literature, Wangfang and Chinese Social Sciences Citation Index databases were searched. All relevant publications were searched through December 2015. Odds ratio (OR), risk ratio (RR), and 95% confidence intervals (CI) for the comparison between case–control or cohort studies were evaluated. Finally, 24 articles were identified. For HLA-DRB1*15 and HLA-DRB1*15:01, the OR (95% CI) was 2.24(1.33–3.77), P 0.05). Sensitivity analyses revealed that the results were statistically robust. The meta-analysis suggested that HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms might be associated with increased AA risk in Asians. IST might be more effective in HLA-DRB1*15+ and HLA-DRB1*15:01+ Asian patients with AA than in HLA-DRB1*15− and HLA-DRB1*15:01− Asian patients with AA. Future studies with adequate methodological quality on gene–gene and gene–environment interactions and gene treatment may yield valid results. PMID:27611583

Correlation of immunosuppression scheme with renal graft complications detected by dynamic renal scintigraphy

International Nuclear Information System (INIS)

Martins, Flavia Paiva Proenca; Gutfilen, Bianca

2001-01-01

Dynamic renal scintigraphy allows the diagnosis of complications in patients submitted to organ transplantation, such as perfusion abnormalities, acute tubular necrosis and rejection. In this study we employed 99m Tc-DTPA scintigraphy to study patients submitted to kidney transplantation. The results obtained and the clinical findings were conjunctively analyzed in order to detect graft rejection or other complications. The type of immunosuppressive scheme used was also correlated with the observed complications. Fifty-five patients submitted to kidney transplantation from 1989 to 1999 were evaluated. All patients with nephrotoxicity received a 3-drug immunosuppressive scheme. In this study, acute rejection was the most frequent complication (40.4%) observed following transplantation. Thirteen of 15 recipients of cadaveric kidney grafts presented acute tubular necrosis. Only one false-positive case was observed when scintigraphy and clinical findings were not concordant. We suggest carrying out renal scintigraphy to follow-up post-transplantation patients. (author)

Microwave – assisted reduction of racemic intermediates potential immunosuppressant

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Wender A. Silva

2012-06-01

Full Text Available Immunosuppressant are drugs that reduce the immune response, as important in the treatment of autoimmune diseases and rejection attenuators in organ transplants, the structural point of view generally have a high complexity. Within this context it is indispensable structural simplifications, new molecules are proposed with potential action on a stage is a necessary, reduction system α,β-unsaturated specifically, chalcone, to their respective alcohol saturated. Therefore, a new method was developed for microwave assisted subsequently coupling to other fragments to the total synthesis of the novel compounds.

Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation.

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Schweizer, Riccardo; Gorantla, Vijay S; Plock, Jan A

2015-12-01

Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor-specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA.

Ultraviolet spectral energy differences affect the ability of sunscreen lotions to prevent ultraviolet-radiation-induced immunosuppression

International Nuclear Information System (INIS)

Roberts, L.K.; Beasley, D.G.; Learn, D.B.; Giddens, L.D.; Beard, J.; Stanfield, J.W.

1996-01-01

Acute exposure to UV radiation causes immunosuppression of contact hypersensitivity (CH) responses. Past studies conducted with unfiltered sunlamps emitting non-solar spectrum UV power (wavelengths below 295 nm) or using excessive UV doses have suggested sunscreens may not prevent UV-induced immunosuppression in mice. This study was thus designed to evaluate critically the effects of different UV energy spectra on the immune protection capacity of sunscreen lotions. Minimum immune suppression doses (MISD), i.e. the lowest UV dose to cause ∼ 50% suppression of the CH response to dinitrofluorobenzene in C3H mice, were established for three artificial UV sources. The MISD for each UV source was 0.25 kJ/m 2 for unfiltered FS20 sunlamps (FS), 0.90 kJ/m 2 for Kodacel-filtered FS20 sunlamps (KFS), which do not emit UV power at wavelengths 2 for a 1000 W filtered xenon arc lamp solar simulator. Using MISD as baseline, sunscreens with labeled sun protection factors (SPF) of 2, 8, 15 and 30 were tested with each UV source to establish their relative immune protection factors. The immune protection factor of each sunscreen exceeded its labeled SPF in tests conducted with the solar simulator, which has a UV power spectrum (295-400 nm) similar to that of sunlight. Conversely, sunscreen immune protection factors were significantly less than the labeled SPF in tests conducted with FS and KFS. Comparison of the immunosuppression effectiveness spectra showed that relatively small amounts of nonsolar spectrum UV energy, i.e. UVC (200-290 nm) and/or shorter wavelength UVB (between 290 and 295 nm), produced by FS and KFS contributes significantly to the induction of immunosuppression. (Author)

Immunosuppressive effect of the anti-IL-2-receptor monoclonal antibody, AMT-13, on organ-cultured fetal pancreas allograft survival

International Nuclear Information System (INIS)

Burkhardt, K.; Loughnan, M.S.; Diamantstein, T.; Mandel, T.E.

1988-01-01

Recently, prolongation of cardiac allograft survival in mice was reported using a rat anti-IL-2R mAb (AMT-13). However, its immunosuppressive action in vivo, alone and in combination with other immunosuppressants, and its effect on other organ transplants has not been extensively studied. We grafted cultured fetal pancreas from CBA (H-2k) donors to Balb/c (H-2d) mice. Recipients were treated with 10 consecutive daily injections each of 20 micrograms AMT-13 only, or with an additional mild immunosuppression of 350 rads irradiation. Control groups received rat immunoglobulin or 350 rads irradiation. Graft survival and the phenotype of infiltrating cells were assessed histologically and immunocytochemically on days 12, 17, and 21, and soluble IL-2R levels were measured in the serum with a quantitative ELISA in all recipients. Two of five grafts in the AMT-13-treated group had islets on day 12 posttransplantation despite lymphocytic infiltration in all grafts, while at this time all grafts of rat Ig treated control mice were completely rejected with only scar tissue and a few lymphocytes remaining. Additional immunosuppression with 350 rads irradiation had a marked additive effect with AMT-13. Soluble IL-2R levels in the serum of untreated recipients were not elevated compared with normal serum levels, but recipients injected with AMT-13 had multifold increased soluble IL-2R levels. The percentage of IL-2R+ cells in the grafts of AMT-13-treated animals was either normal (less than 5%) or increased (20%) in the additionally irradiated mice, providing strong evidence that the immunosuppressive effect of AMT-13 is not due to a depletion of activated IL-2R+ lymphocytes

Use of polyclonal/monoclonal antibody therapies in transplantation.

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Yeung, Melissa Y; Gabardi, Steven; Sayegh, Mohamed H

2017-03-01

For over thirty years, antibody (mAb)-based therapies have been a standard component of transplant immunosuppression, and yet much remains to be learned in order for us to truly harness their therapeutic capabilities. Current mAbs used in transplant directly target and destroy graft-destructive immune cells, interrupt cytokine and costimulation-dependent T and B cell activation, and prevent down-stream complement activation. Areas covered: This review summarizes our current approaches to using antibody-based therapies to prevent and treat allograft rejection. It also provides examples of promising novel mAb therapies, and discusses the potential for future mAb development in transplantation. Expert opinion: The broad capability of antibodies, in parallel with our growing ability to synthetically modulate them, offers exciting opportunities to develop better biologic therapeutics. In order to do so, we must further our understanding about the basic biology underlying allograft rejection, and gain better appreciation of how characteristics of therapeutic antibodies affect their efficacy.

Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

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Angelica Loskog

2015-11-01

Full Text Available Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

Neuromuscular complications of immune checkpoint inhibitor therapy.

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Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

2018-01-17

Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

Immunosuppressive Therapy-Related Kaposi Sarcoma

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... Sarcoma Treatment Childhood Vascular Tumors Treatment Research Kaposi Sarcoma Treatment (PDQ®)–Patient Version General Information About Kaposi Sarcoma Go to Health Professional Version Key Points Kaposi ...

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients

Science.gov (United States)

Tedesco-Silva, Helio; Peddi, V. Ram; Sánchez-Fructuoso, Ana; Marder, Brad A.; Russ, Graeme R.; Diekmann, Fritz; Flynn, Alison; Hahn, Carolyn M.; Li, Huihua; Tortorici, Michael A.; Schulman, Seth L.

2016-01-01

Background Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. Methods This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m2 or greater improvement in estimated glomerular filtration rate from randomization to month 24. Results The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus. PMID:27500260

Effect of Low-Level Laser therapy on the fungal proliferation of Candida albicans

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Carneiro, Vanda S. M.; Araújo, Natália C.; Menezes, Rebeca F. d.; Moreno, Lara M.; Santos-Neto, Alexandrino d. P.; Gerbi, Marleny Elizabeth M.

2016-03-01

Candida albicans plays an important role in triggering infections in HIV+ patients. The indiscriminate use of antifungals has led to resistance to Candida albicans, which requires new treatment alternatives for oral candidiasis. Low-level laser therapy promotes a considerable improvement in the healing of wounds and in curing illnesses caused by microorganisms. The aim of the present study was to assess the effect of laser radiation on the cell proliferation of Candida albicans in immunosuppressed patients. Six Candida albicans strains that had been isolated from immunosuppressed patients were divided into a control group and experimental groups, which received eight sessions of laser therapy (InGaAlP, λ685nm, P = 30mW, CW, Φ~6 mm and GaAlAs, λ830nm, P = 40mW, CW, Φ~6 mm) using dosimetries of 6J/cm2, 8J/cm2, 10J/cm2 and 12J/cm2 for each wavelength and power. The results were not statistically significant (Kruskal Wallis, p > 0.05), although the proliferation of Candida albicans was lower in some of the experimental groups. The dosimetry of 6J/cm2 (GaAlAs, λ830nm, P = 40mW) provided lower mean scores than the other groups for the growth of Candida. Further studies are required to confirm whetehr laser therapy is a viable option in the treatment of fungal infections.

CD14+ monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells

International Nuclear Information System (INIS)

Wang, Ding; Chen, Ke; Du, Wei Ting; Han, Zhi-Bo; Ren, He; Chi, Ying

2010-01-01

Here, the effect of CD14 + monocytes on human umbilical cord matrix stem cell (hUC-MSC)-mediated immunosuppression was studied in vitro. hUC-MSCs exerted a potent inhibitory effect on the proliferation and interferon-γ (IFN-γ) secretion capacities of CD4 + and CD8 + T cells in response to anti-CD3/CD28 stimulation. Transwell co-culture system revealed that the suppressive effect was primarily mediated by soluble factors. Addition of prostaglandin synthesis inhibitors (indomethacin or NS-398) almost completely abrogated the immunosuppression activity of hUC-MSCs, identifying prostaglandin E 2 (PGE 2 ) as an important soluble mediator. CD14 + monocytes were found to be able to enhance significantly the immunosuppressive effect of hUC-MSCs in a dose-dependent fashion. Moreover, the inflammatory cytokine IL-1β, either exogenously added or produced by CD14 + monocytes in culture, could trigger expression of high levels of PGE 2 by hUC-MSCs, whereas inclusion of the IL-1 receptor antagonist (IL-1RA) in the culture down-regulated not only PGE 2 expression, but also reversed the promotional effect of CD14 + monocytes and partially restored CD4 + and CD8 + T cell proliferation and IFN-γ secretion. Our data demonstrate an important role of monocytes in the hUC-MSC-induced immunomodulation, which may have important implications in future efforts to explore the clinical potentials of hUC-MSCs.

Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs.

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van Gelder, Teun; Gabardi, Steven

2013-08-01

Within the field of solid organ transplantation, the patents for a number of immunosuppressive drugs have expired in the last few years. Tacrolimus, cyclosporine, and mycophenolate mofetil are now available as generic drugs. In some countries, the market penetration of these generic formulations is as high as 70%, whereas in some other countries, this figure is below 10%. Several professional societies have published position papers on the risks and benefits of generic substitution of immunosuppressive drugs. It often appears that transplant professionals are not fully aware of the requirements for registration of generic drugs. This article describes the registration requirements with a focus on bioequivalence testing, the strengths and weaknesses in this process, and the differences between Europe and the US. © 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.

Prevalence of premature ovarian failure in systemic lupus erythematosus patients treated with immunosuppressive agents in Thailand.

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Akawatcharangura, P; Taechakraichana, N; Osiri, M

2016-04-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects most women of reproductive age. The prevalence of premature ovarian failure (POF) in SLE patients is higher than that in the general population. However, the data on this condition are limited in Asian countries. To determine the prevalence and associated factors of POF in SLE patients who received immunosuppressive therapy. Women aged 18-40 years who were diagnosed with SLE according to the 1997 revised criteria for the classification of SLE or patients with biopsy-proven lupus nephritis were evaluated. All patients had received at least one of the following immunosuppressive agents: cyclophosphamide (CYC), azathioprine, mycophenolate mofetil, chlorambucil or cyclosporine for more than six months. POF was diagnosed in those who had sustained amenorrhea for more than six consecutive months, with a level of estradiol ≤ 110 pmol/L (30 pg/mL) and follicle stimulating hormone ≥40 IU/L. Ninety two SLE patients were included in this study. Mean age at enrollment was 30 ± 6.9 years and disease duration was 103 ± 67.5 months. The mean Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) damage index was 1.7 ± 1.7. Seventy five patients (82%) had lupus nephritis. Sixty four patients (70%) received CYC. Eleven patients (12%) with POF were observed. For the binary logistic regression model, CYC cumulative dosage of more than 10 g was the only independent risk factor of POF (hazard ratio 17.0, 95% CI 1.96-147.72, p = 0.01). From our data, 12% of SLE patients developed POF. A cumulative dose of CYC of more than 10 g was the only risk factor for POF. To prevent these events, systematic evaluation and early recognition of POF should be promoted in the care of SLE patients. © The Author(s) 2015.

Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial.

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Ondrej Viklicky

Full Text Available There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(reactivated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy.In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1 followed by 5 mg/kg Infliximab (d2. For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13 or sirolimus (SIR, n = 7 monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months.TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6-98.9 and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10 and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+ patients. However, recruitment into SIR-arm was stopped (after n = 7 because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up.In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full-scale study will be needed to confirm our findings.EudraCT Number: 2006-003110-18.

Clinical aspects of immunosuppression in poultry

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Rеsаnоvić Rаdmilа

2015-01-01

Full Text Available Immunity is ability to stop an infection. Immunosupression is a status where the immunity is reduced. Humoral (antibodies and/or cell immunity may be depressed. Immunosupression can be caused by infectious agents, improper feeding balance (deficiencies, lack of biosecurity, management failures, stress or by a combination of these factors. Each of these possible causes must be seriously worked out to prevent the consequences of immunosupression on profitability. Environmental factors and numerous infectious pathogens have been identified as a multi-factorial cause of various degrees of immunosupression. Mainly subclinical character and coinfections make the diagnosis of the primary immunosuppressive agents difficult. On the other hand, early diagnosis and identification of contributing factors are important to develop strategies to fight immunosupression in birds successfully. A combination of biosecurity measures, optimized housing condition and stress reduction together with appropriate vaccination strategies is necessary for the successful control of immunosupression in commercial poultry.

[Immunosuppresive agents, retinoids and new trends in the therapy of psoriasis].

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Svozil, M

2002-11-01

Some psoriasis forms can be successfully treated with topical medicaments; serious and extensive forms cannot be cured without systemic treatment with retinoids (etretinate, acitretin, tazarotene) or with immunosuppressives (methotrexate, cyclosporine A, tacrolimus, SDZ 281-240). Immunotherapy and nucleotide analogues are being newly introduced, a number of potentially effective substances interfering with pathogenetic mechanisms participating in the emergence and self-prolongation of psoriasis are in the stage of research and clinical trials, and gene therapy possibilities are being investigated. The development and testing of drugs serving therapy for psoriasis correlates with the development of knowledge about the origins of the disease and the mechanisms of how antipsoriatics in current use as well as the new potential ones work.

Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy

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Nadia E. Aikawa

Full Text Available ABSTRACT Objective: To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Methods: Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints; specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. Results: 194 patients [67 with rheumatoid arthritis (RA, 47 with ankylosing spondylitis (AS, 36 with juvenile idiopathic arthritis (JIA, 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42 ± 16 years, with 68 (35% male and mean disease duration of 15 ± 10 years. Sixty-four (33% patients were receiving adalimumab, 59 (30% etanercept and 71 (36% infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressant drugs. At the time of the study, only one (0.5% patient had localized fungal infection (vaginal candidiasis. None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. Conclusions: This was the first study to assess the prevalence of invasive and localized fungal disease by Candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use.

Progressive necrotic encephalopathy following tacrolimus therapy for liver transplantation.

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Aridon, Paolo; Ragonese, Paolo; Di Benedetto, Norma; Grasso, Giovanni; Conaldi, Pier Giulio; D'Amelio, Marco; Savettieri, Giovanni

2009-12-01

Previously described neurologic damage induced by immunosuppressive treatments includes transient or reversible central nervous system involvement. We describe a 57-year-old man who underwent liver transplantation and was started on immunosuppressive therapy with tacrolimus (FK506). Six months later, he started complaining of a progressive motor and sensory impairment of the left side, together with cognitive impairment. Brain MRI showed an enlarging lesion of the white matter with peripheral contrast enhancement. PET study indicated severe hypometabolism in the right hemisphere and spectroscopic MRI showed a peak of choline and relative reduction of other metabolites. Findings of CSF examinations and cultures, serology, and molecular techniques were normal. Tacrolimus treatment was stopped. A cerebral biopsy of the lesion showed a sub acute necrotizing process. In the following months, cognitive status of the patient tended to improve although he remained hemiplegic, while serial MRI confirmed the tendency to the recovery of the lesion that was still present 1 year after. The present observation describes a progressive encephalopathy associated with immune suppression with an unusual feature and permanent brain damage.

Systematic immunosuppression induced by photodynamic therapy (PDT) is adoptively transferred by macrophages

International Nuclear Information System (INIS)

Lynch, D.H.; Haddad, S; King, V.J.; Ott, M.J.; Jolles, C.J.; Straight, R. C.

1989-01-01

The purpose of this study was to determine whether photodynamic therapy induced suppression of contact hypersensitivity (CHS) responses was an active phenomenon that could be adoptively transferred by viable splenocytes from PDT-treated mice. Although induction of adoptively transferable suppressor cells in PDT-treated mice required exposure to antigen, the suppressor cells were found to be antigen nonspecific in their function. Furthermore, splenocytes from PDT-treated mice were capable of generating levels of allospecific cytotoxic T lymphocyte (CTL) activity which were comparable to those generated by normal control mice, but the ability of irradiated spleen cells from PDT-treated mice to stimulate a mixed lymphocyte response (MLR) was dramatically impaired. Finally, chromatographic separation of T cells, B cells and macrophages showed that the cell type which mediates adoptively transferable suppression of CHS responsiveness is in the macrophage lineage. (author)

Abbreviated AUC monitoring of cyclosporine more adequately identified patients at risk for acute rejection during induction of immunosuppressive therapy after kidney transplantation than recommended C2 concentration values.

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Troncoso, P; Ortiz, A M; Jara, A; Vilches, S

2009-01-01

Monitoring of cyclosporine (CsA) is critical during the induction of immunosuppressive therapy. Although most centers have incorporated C2 levels, our unit still uses an abbreviated AUC model which includes concentrations at C1, C2, and C6 post-dose (AUC(1-6)). The objective of this study was to compare both strategies of CsA monitoring during the first 30 days after kidney transplantation. The study included 89 recipients induced with CsA microemulsion and steroids. AUC(1-6) profiles were performed around days 3, 10, and 30 after transplantation with a target of 5500 to 6000 ng*h/mL considered therapeutic. For comparison purposes, a value of C2 >/= 1500 ng/mL was also considered therapeutic. Mean C2 and AUC(1-6) values were low dated with biopsy-proven acute rejection episodes (BPAR) during the study period. Twenty patients received living donor kidneys and overall there were 46 females. During this period, 253 AUC(1-6) were performed including 44 (17.4%) below the therapeutic range. When the analysis included only C2, 171 (67.6%) were below the therapeutic target (P AUC(1-6) at day 10 discriminated rejectors versus nonrejectors (5645 +/- 1390 and 8221 +/- 2502, respectively; P = .008). C2 was not significantly different at any time in either group. In this study, abbreviated AUC monitoring more adequately identified patients at risk for acute rejection than C2. Recommended C2 concentration levels need to be redefined in our patients.

Presentation of hemophagocytic lymphohistiocytosis due to a novel MUNC 13–4 mutation masked by partial therapeutic immunosuppression

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Garrett Jackie P-D

2012-05-01

Full Text Available Abstract Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. An associated gene mutation may be found which impairs cytolytic lymphocyte function. We describe a pediatric case of hemophagocytic lymphohistiocytosis with a novel mutation of MUNC 13–4 whose diagnosis was confounded by concurrent immunosuppression. Clinical reassessment for hemophagocytic lymphohistiocytosis is necessary in persistently febrile patients with laboratory derangements in the setting of immunosuppressive agent exposure.

Clinical Grade Regulatory CD4+ T Cells (Tregs: Moving Toward Cellular-Based Immunomodulatory Therapies

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Richard Duggleby

2018-02-01

Full Text Available Regulatory T cells (Tregs are CD4+ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a Novel Target to Treat Diseases With Macrophage Imbalances

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Anna Ohradanova-Repic

2018-04-01

Full Text Available If misregulated, macrophage (Mϕ–T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA. We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF- and Mϕ colony-stimulating factor (M-CSF-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ, adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX formulation to the immunosuppressive FRβ+CD39+CD73+ Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.

Why Targeted Therapies are Necessary for Systemic Lupus Erythematosus

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Durcan, Laura; Petri, Michelle

2016-01-01

Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side-effects. Current management strategies rely heavily on non-specific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic pre-clinical data and promising early phase studies have ultimately been disappointing in phase III randomized controlled studies. Recent efforts have focused on B cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated including interferon alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID:27497251

Homologous tracheal transplantation with grafts previously exposed to high doses of gamma radiation in dogs without immunosuppressive agents

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Yokomise, Hiroyasu; Inui, Kenji; Kure, Toshio; Wada, Hiromi; Itomi, Shigeki

1993-01-01

The study was designed to determine whether previous high doses irradiation of gamma radiation would contribute to tracheal transplantation with no use of immunosuppressive agents. Twenty mongrel dogs were used as experimental animals. Five rings of thoracic tracheas, which were extracted from recipients, were exposed to 20000, 50000, or 100000 cGy in each 5 dogs. Five other non-irradiated dogs served as controls. Irradiated tracheal grafts were transplanted and covered with pedicled omentum. After transplantation, no immunosuppressive agents were given to dogs. All dogs in the control group died of tracheal stenosis due to graft-host rejection within one month. All but one long-term survivor died of tracheal stenosis, as well, in both the 20000 cGy and 50000 cGy groups. In the 100000 cGy group, grafts became viable in 4 dogs, and three of these survived one year or more. In conclusion, previous irradiation with high doses of 100000 cGy allowed homologous tracheal transplantation even when no immunosuppressive agents are given. (N.K.)

Strategies to improve the immunosuppressive properties of human mesenchymal stem cells

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Lee, Myoung Woo; Ryu, Somi; Kim, Dae Seong; Sung, Ki Woong; Koo, Hong Hoe; Yoo, Keon Hee

2015-01-01

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases because of their immunosuppressive capacities. However, few clinical trials of MSCs have yielded satisfactory results. A number of clinical trials using MSCs are currently in progress worldwide. Unfortunately, protocols and methods, including optimized culture conditions for the harvest of MSCs, have not been standardized. In this regard, complications in the ex vivo expansion of MSCs and MSC...

Diminished physical function in older HIV-infected adults in the Southeastern U.S. despite successful antiretroviral therapy.

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Audrey L Khoury

Full Text Available As antiretroviral therapy efficacy improves, HIV is gradually being recognized more as a chronic disease within the aging HIV-infected population. While these individuals are surviving into old age, they may, however, be experiencing "accelerated aging" with greater declines in physical function than that observed among comparably matched individuals free of HIV. This decline is not well understood and it remains unclear if physical decline correlates with the degree of immunosuppression based on CD4 lymphocyte nadir.In a cross-sectional study of accelerated aging in the older HIV-infected population on antiretroviral therapy (ART, physical performance evaluations were completed on a cohort of 107 HIV-infected subjects, age 50 years or older (with no HIV-1 RNA >200 copies/mL in the prior 12 months, and compared to reference ranges for age- and gender-matched HIV-uninfected persons. Physical performance testing consisted of four validated assessments: the 2.4-meter walk, 30-second chair stand, grip strength and 6-minute walk test.When compared to age- and gender-matched HIV-uninfected reference controls, older HIV-infected persons had diminished physical function. No correlation was found between physical function and degree of immunosuppression as determined by pre-ART CD4 nadir.Despite improved survival, HIV-infected adults on suppressive ART have diminished physical function compared to HIV-uninfected persons. The degree of HIV-associated immunosuppression does not correlate with the observed degree of physical function decline in older HIV-infected persons, suggesting the decline is mediated by other mechanisms.

A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model.

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Abhiram R Bhashyam

Full Text Available Previously, we have demonstrated that mucociliary clearance (MCC is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation.Fifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls were intraperitoneally injected with three 100 µL doses of phosphate buffered saline and eight mice (immunosuppressed were injected with three 100 µL injections of tacrolimus (1 mg/kg, mycophenolate mofetil (30 mg/kg, and prednisone (2 mg/kg once daily. Then, mice inhaled the radioisotope (99mtechnetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1-1.5 hrs and at 6-6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance.Although there was a slowing of MCC at 1-1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1-1.5 hrs for the two groups of mice. At 6-6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78±5.9% cleared versus 23.01±11.7% cleared, respectively (p = 0.006.These preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a Hungarian nationwide observational study

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Simon László

2009-09-01

Full Text Available Abstract Background Infliximab (IFX has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD, with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. Methods During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6 at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. Results Three hundred and sixty three patients (183 women and 180 men were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4% with therapy-refractory CD, 195 patients (53.7% with fistulas, 16 patients (4.4% with both therapy-refractory CD and fistulas, and 26 patients (7.2% with steroid dependent CD. Overall response rate was 86.2% (313/363. A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99 and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596. Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%, 17 delayed type hypersensitivity (4.7%, 16 infections (4.4%, and 3 malignancies (0.8%. Conclusion IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy

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Helmschrott M

2017-06-01

Full Text Available Matthias Helmschrott,1 Rasmus Rivinius,1 Thomas Bruckner,2 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: A calcineurin inhibitor (CNI-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs seems to be attractive in patients after heart transplantation (HTX in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC-based vs cyclosporine-A (CSA-based immunosuppression (in combination with mycophenolate mofetil. However, data regarding renal function after HTX in mTOR/CNI patients remain limited. Aim: Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. Methods: Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR calculated from Modification of Diet in Renal Disease equation. Results: Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant. Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. Conclusion: The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen. Keywords: heart transplantation, cyclosporine A, tacrolimus, risk factors

Stored blood--an effective immunosuppressive method for transplantation of kidneys from unrelated donors. An 11-year follow-up.

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Galvão, M M; Peixinho, Z F; Mendes, N F; Sabbaga, E

1997-06-01

Thirty-seven patients were submitted to kidney transplantation after transfusion at 2-week intervals with 4-week stored blood from their potential donors. All patients and donors were typed for HLA-A-B and DR antigens. The patients were also tested for cytotoxic antibodies against donor antigens before each transfusion. The percentage of panel reactive antibodies (PRA) was determined against a selected panel of 30 cell donors before and after the transfusions. The patients were immunosuppressed with azathioprine and prednisone. Rejection crises were treated with methylprednisolone. The control group consisted of 23 patients who received grafts from an unrelated donor but who did not receive donor-specific pretransplant blood transfusion. The incidence and reversibility of rejection episodes, allograft loss caused by rejection, and patient and graft survival rates were determined for both groups. Non-parametric methods (chi-square and Fisher tests) were used for statistical analysis, with the level of significance set at P transplant days did not differ significantly between groups. The actuarial graft and patient survival rates at five years were 56% and 77%, respectively, for the treated group and 39.8% and 57.5% for the control group. Graft loss due to rejection was significantly higher in the untreated group (P = 0.0026) which also required more intense immunosuppression (P = 0.0001). We conclude that transfusions using stored blood have the immunosuppressive effect of fresh blood transfusions without the risk of provoking a widespread formation of antibodies. In addition, this method permits a reduction of the immunosuppressive drugs during the process without impairing the adequate functioning of the renal graft.

Radiostrontium-induced oncogenesis and the role of immunosuppression. Pt. 2

International Nuclear Information System (INIS)

Bierke, P.; Nilsson, A.

1990-01-01

The significance of depressed immune function for the development and progression of tumours induced by 90 Sr (mainly osteosarcomas and malignant lymphomas) was investigated in a series of experiments by comparing the tumour responses in normal mice with those in immunocompromised mice. The present paper (part II) reports on lympho-reticular (LR) and extraskeletal neoplastic lesions in male CBA/SU mice after exposure to different single doses of 90 Sr with or without additional immunosuppression by adult thymectomy (ATx) and/or prolonged antilymphocyteglobulin (ALG) treatment. Neoplastic lesions in bone were reported in part I. The status of the animal's immune system and responsive ability were examined in parallel experiments. The tumor yields were analysed in relation to the dosage of 90 Sr and the immunosuppressive treatments employed. Although the incidences and latency times of induced tumours were clearly dose-dependent, they were never significantly influenced by ATx/ALG treatments. Thus, no substantial support was gained for the theory that the immune system plays a controlling or modifying role in 90 Sr carcinogenesis. The results, which are in agreement with the bone tumour responses, suggest that 90 Sr induced tumours either do not express the antigens necessary for immune rejection or that the decline in immune responsiveness induced by ATx/ALG was of little consequence for tumour development and spread. The pathogenesis of 90 Sr induced malignant lymphomas (MLs) and their immunophenotypes are discussed. (orig.)

Palmoplantar peeling secondary to sirolimus therapy.

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Liu, L S; McNiff, J M; Colegio, O R

2014-01-01

Sirolimus (rapamycin) is an immunosuppressive agent commonly used in transplant recipients. Although sirolimus has less renal toxicity than calcineurin inhibitors, its use has been limited by its side effects. The most common cutaneous pathologies associated with sirolimus are inflammatory acneiform eruptions, lymphedema and aphthous ulcers. We present a novel cutaneous manifestation of sirolimus therapy that limited its use in at least one transplant recipient. Upon commencing sirolimus therapy, four solid organ transplant recipients developed tender, nonpruritic palmoplantar peeling within the first month of therapy. The peeling clinically resembled a mild form of hand-foot syndrome, yet none of the patients had been treated with chemotherapeutics. Desquamation presented on the palms and soles with dry vesicles and minor peeling extending to the dorsal aspects of the hands and feet. Histologically, the lesions were noninflammatory; the epidermis showed subtle separation between keratinocytes, suggesting either spongiosis or a defect in intercellular adhesion. One patient opted to discontinue treatment because of the tenderness associated with the palmoplantar peeling, which resulted in complete resolution within 2 weeks. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

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Miettinen, Johanna A.; Pietilae, Mika; Salonen, Riikka J.; Ohlmeier, Steffen; Ylitalo, Kari; Huikuri, Heikki V.; Lehenkari, Petri

2011-01-01

Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-α) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-α exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-α exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-α exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-α exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-α exposure, which might influence MSC differentiation stage and capacity.

Tumor necrosis factor alpha promotes the expression of immunosuppressive proteins and enhances the cell growth in a human bone marrow-derived stem cell culture

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Miettinen, Johanna A., E-mail: johanna.miettinen@oulu.fi [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Pietilae, Mika [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Salonen, Riikka J. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Ohlmeier, Steffen [Proteomics Core Facility, Biocenter Oulu, Department of Biochemistry, University of Oulu, P.O. Box 3000, FIN-90014 Oulu (Finland); Ylitalo, Kari; Huikuri, Heikki V. [Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland); Lehenkari, Petri [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu (Finland)

2011-04-01

Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-{alpha}) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-{alpha} exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-{alpha} exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-{alpha} exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-{alpha} exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-{alpha} exposure, which might influence MSC differentiation stage and capacity.

Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus

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Pradnya J Londhe

2014-01-01

Full Text Available Background: Rituximab, a monoclonal anti-CD20 antibody, has been used with encouraging results in pemphigus. We describe herein refractory cases of pemphigus vulgaris (n = 23 and pemphigus foliaceus (n = 1 treated with rituximab in addition to steroids and immunosuppressants. Aims: To assess the response to treatment, the duration of clinical remission, serology of the response and adverse effects of rituximab in pemphigus patients. Methods: We recorded observations of 24 patients with pemphigus having either refractory disease in spite of high dose of steroids and immunosuppressants, corticosteroid-dependent disease, strong contraindications to corticosteroids, or severe disease. The patients were treated with infusions of one injection per week for three consecutive weeks of 375 mg of rituximab per m 2 of body-surface area. One similar infusion was repeated after 3 months of 3 rd dose. We observed the clinical outcome after 6 months of 3 rd dose of rituximab and looked for complete healing of cutaneous and mucosal lesions (complete remission. Observations: After follow-up of 7-24 months, five patients showed only partial improvement while 19 of 24 patients had a complete remission 3 months after rituximab. Of these 19 patients, 12 patients achieved complete remission and are off all systemic therapy, and the rest are continuing with no or low dose of steroids with immunosuppressants. Two patients relapsed after initial improvement; one was given moderate dose of oral steroids and immunosuppressant and the other was given repeat single dose of rituximab to control relapse. Conclusion: Rituximab is able to induce a prolonged clinical remission in pemphigus after a single course of four infusions. The high cost and limited knowledge of long term adverse effects are limitations to the use of this biologic agent.

CD14{sup +} monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells

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Wang, Ding, E-mail: qqhewd@gmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Chen, Ke, E-mail: chenke_59@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Du, Wei Ting, E-mail: duwtpumc@yahoo.com.cn [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); Han, Zhi-Bo, E-mail: zhibohan@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); Ren, He, E-mail: knifesharp2000@hotmail.com [National Engineering Research Center of Cell Products, AmCellGene Co. Ltd, TEDA, Tianjin (China); Chi, Ying, E-mail: caizhuying@hotmail.com [The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020 (China); TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin (China); and others

2010-09-10

Here, the effect of CD14{sup +} monocytes on human umbilical cord matrix stem cell (hUC-MSC)-mediated immunosuppression was studied in vitro. hUC-MSCs exerted a potent inhibitory effect on the proliferation and interferon-{gamma} (IFN-{gamma}) secretion capacities of CD4{sup +} and CD8{sup +} T cells in response to anti-CD3/CD28 stimulation. Transwell co-culture system revealed that the suppressive effect was primarily mediated by soluble factors. Addition of prostaglandin synthesis inhibitors (indomethacin or NS-398) almost completely abrogated the immunosuppression activity of hUC-MSCs, identifying prostaglandin E{sub 2} (PGE{sub 2}) as an important soluble mediator. CD14{sup +} monocytes were found to be able to enhance significantly the immunosuppressive effect of hUC-MSCs in a dose-dependent fashion. Moreover, the inflammatory cytokine IL-1{beta}, either exogenously added or produced by CD14{sup +} monocytes in culture, could trigger expression of high levels of PGE{sub 2} by hUC-MSCs, whereas inclusion of the IL-1 receptor antagonist (IL-1RA) in the culture down-regulated not only PGE{sub 2} expression, but also reversed the promotional effect of CD14{sup +} monocytes and partially restored CD4{sup +} and CD8{sup +} T cell proliferation and IFN-{gamma} secretion. Our data demonstrate an important role of monocytes in the hUC-MSC-induced immunomodulation, which may have important implications in future efforts to explore the clinical potentials of hUC-MSCs.

Stress, coping and adherence to immunosuppressive medications in kidney transplantation: a comparative study.

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Brito, Daniela Cristina Sampaio de; Marsicano, Elisa Oliveira; Grincenkov, Fabiane Rossi Dos Santos; Colugnati, Fernando Antônio Basile; Lucchetti, Giancarlo; Sanders-Pinheiro, Helady

2016-01-01

: Adherence to medication is a key issue relating to outcomes from transplantation and it is influenced by several factors, such as stress and coping strategies. However, these factors have been poorly explored. We aimed to compare stress and coping strategies between adherent and nonadherent renal transplant recipients who were receiving immunosuppression. : We conducted a comparative, cross-sectional and observational study at a university-based transplantation clinic in Juiz de Fora, Brazil. :Fifty patients were recruited and classified as adherent or nonadherent following administration of the Basel Assessment of Adherence to Immunosuppressive Medications Scale. Stress was evaluated using the Lipp Stress Symptom Inventory for Adults and coping strategies were assessed using the Ways of Coping Scale. : The study included 25 nonadherent patients and 25 controls with a mean age of 44.1 ± 12.8 years and median post-transplantation time of 71.8 months. Stress was present in 50% of the patients. Through simple logistic regression, nonadherence was correlated with palliative coping (OR 3.4; CI: 1.02-11.47; P transplantation patients and should be considered among the strategies for reducing nonadherence.

Comparison of tamarins and marmosets as hosts for GBV-B infections and the effect of immunosuppression on duration of viremia

International Nuclear Information System (INIS)

Lanford, Robert E.; Chavez, Deborah; Notvall, Lena; Brasky, Kathleen M.

2003-01-01

GBV-B virus is a close relative to hepatitis C virus (HCV) that causes hepatitis in tamarins, and thus, is an attractive surrogate model for HCV. In this study, we demonstrate that the host range of GBV-B extends to the common marmoset with an infection profile similar to that observed for tamarins. Marmoset hepatocytes were susceptible to in vitro infection with GBV-B. Virus was efficiently secreted into the medium, and approximately 25% of hepatocytes were positive for NS3 staining. In an attempt to induce persistent infections, tamarins were immunosuppressed with FK506 and inoculated with GBV-B. Although no chronic infections were induced, the duration of viremia was increased in most animals. In one animal, the duration of viremia was extended to 46 weeks, but viral clearance occurred 18 weeks after stopping FK506 therapy. The greater availability of marmosets in comparison to tamarins will greatly facilitate future research efforts with this model

Cyclosporine-A therapy-induced multiple bilateral breast and accessory axillary breast fibroadenomas: a case report

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Darwish Ahmed

2010-08-01

Full Text Available Abstract Introduction Breast adenoma is common. However, in the setting of post-transplantation immune suppression it may be expressed differently. Case presentation A 35-year-old Sudanese woman, with a history of renal transplantation two and half years prior to presentation, was on a single immune suppression therapy in the form of cyclosporine-A since the transplantation. During a regular follow-up visit, she was noticed to have gingival hypertrophy and bilateral breast and axillary swellings. She underwent successful surgical resection of the bilateral fibroadenomas. Conclusions Cyclosporine-A therapy post renal transplantation is associated with an increased incidence of benign breast changes as fibroadenoma. Regular follow-up and appropriate selection of immunosuppressant therapy are essential in the post transplantation management of these patients.

Assessment of immunomodulating action of combined therapy with UHF-hyperthermia in children with osteogenic sarcoma

International Nuclear Information System (INIS)

Neprina, G.S.; Panteleeva, E.S.; Vatin, O.E.; Bizer, V.A.; Bojko, I.N.

1989-01-01

The paper is concerned with immunological evaluation of different stages of combined therapy with local UHF-hyperthermia in children with osteogenic sarcoma. Combined therapy (polychemo- and raditherapy) was shown to cause a decrease in the number of immunocompetent cells, to enhance dysbalance of immunoregulatory T-lymphocytes, to weaken T-lymphocyte function on PHA; immunosuppressive action of combined therapy did not depend on a tumor site. The incorporation of UHF-hyperthermia in the therapeutic scheme weakened the manifestations of secondary immunodeficiency, got back to normal structure of T-lymphocyte population. A favorable immunomodulating effect of hyperthermia was more frequently observed in patients with crural bone tumors. The effect of hyperthermia was revealed after direct influence of thermotherapy but it was absent in continuation of combined treatment

A case of toxic epidermal necrolysis initially affecting the skin site of radiation therapy for an intra-cranial post-transplantation lymphoma

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Tanoue, Toshihide; Egawa, Kiyofumi; Fukushima, Satoshi; Wakasugi, Syoji; Ono, Tomomichi; Yoshida, Shinsuke; Kouchi, Masato; Nishi, Kazuhiko

2006-01-01

We report a case of post-transplantation lymphoma (intra-cranial EBV-related malignant lymphoma) who developed toxic epidermal necrolysis (TEN) during concomitant phenobarbital administration and radiotherapy. The erythema exsudativum multiforme-like eruption first appeared on the site of radiation and extended to approximately 35% of the body surface. After stopping radiation therapy and all medications, including immunosuppressant, anticonvulsant, and diuretic drugs, treatment was successfully administered by systemic corticosteroids including semi-pulse therapy (500 mg of methylpredonisolone sodium succinate for 3 days). (author)

Total lymphoid irradiation assessed for possible enhancement of immunosuppression in hyperimmunized dogs receiving renal allografts

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Sonoda, Kazuhiko (Yamato Seiwa Hospital, Kanagawa (Japan)); Rapaport, F.T.

1992-12-01

With performed antibodies to human leukocyte antigens (HLA) appearing in an increasing number of patients today, hyperimmunization constitutes a major problem in clinical transplantation. In adult beagle dogs hyperimmunized with skin allografts and buffy coat injection, we performed renal allograft transplantation to assess the efficacy of total lymphoid irradiation (TLI) employed as a preoperative measure in combination with cyclosporine (CyA) and methyl-prednisolone (MPL) in effecting immunosuppression. The mean survival period were 6.5 days in dogs withheld preliminary treatment, 9.0 days in the dogs receiving CyA and MPL, 26.7 days in those administered one-stage TLI, and 68 days (terminated by euthanasia) of the dogs given two-stage TLI. TLI administered two stages is considered an effective method of enhancing immunosuppression sufficiently to enable the attenuation of adverse reaction to renal allograft in hyperimmunized recipients. (author).

Total lymphoid irradiation assessed for possible enhancement of immunosuppression in hyperimmunized dogs receiving renal allografts

International Nuclear Information System (INIS)

Sonoda, Kazuhiko; Rapaport, F.T.

1992-01-01

With performed antibodies to human leukocyte antigens (HLA) appearing in an increasing number of patients today, hyperimmunization constitutes a major problem in clinical transplantation. In adult beagle dogs hyperimmunized with skin allografts and buffy coat injection, we performed renal allograft transplantation to assess the efficacy of total lymphoid irradiation (TLI) employed as a preoperative measure in combination with cyclosporine (CyA) and methyl-prednisolone (MPL) in effecting immunosuppression. The mean survival period were 6.5 days in dogs withheld preliminary treatment, 9.0 days in the dogs receiving CyA and MPL, 26.7 days in those administered one-stage TLI, and 68 days (terminated by euthanasia) of the dogs given two-stage TLI. TLI administered two stages is considered an effective method of enhancing immunosuppression sufficiently to enable the attenuation of adverse reaction to renal allograft in hyperimmunized recipients. (author)

The Release of Immunosuppressive Factor(s) in Young Males Following Exercise

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Tian, Ye; Nie, Jinlei; Tong, Tom K.; Baker, Julien S.

2012-01-01

It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years) were taken befo...

Belatacept for Maintenance Immunosuppression in Lung Transplantation

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Christine Hui PharmD

2014-06-01

Full Text Available Belatacept is a novel immunosuppressant that blocks a T-cell costimulation pathway and is approved for use in adult kidney transplant recipients. Its safety and efficacy have not been established after lung transplantation. We present a case of a lung transplant recipient treated with belatacept. A 56-year-old man underwent bilateral lung retransplantation for bronchiolitis obliterans syndrome (BOS. In the third year posttransplant, he developed hemolytic uremic syndrome (HUS attributed to tacrolimus. Tacrolimus was changed to sirolimus. One month later, he presented with worsening renal function and HUS attributed to sirolimus. Plasmapheresis and steroid pulse were initiated with clinical improvement, and sirolimus was switched to belatacept. He experienced no episodes of cellular rejection but developed recurrent BOS. Complications during treatment included anemia and recurrent pneumonias. The safety and efficacy of belatacept in lung transplantation remains unclear; further studies are needed.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

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Schnitzbauer, Andreas A; Adam, Rene; Bechstein, Wolf O; Becker, Thomas; Beckebaum, Susanne; Chazouillères, Olivier; Cillo, Umberto; Colledan, Michele; Fändrich, Fred; Gugenheim, Jean; Hauss, Johann P; Zuelke, Carl; Heise, Michael; Hidalgo, Ernest; Jamieson, Neville; Königsrainer, Alfred; Lamby, Philipp E; Lerut, Jan P; Mäkisalo, Heikki; Margreiter, Raimund; Mazzaferro, Vincenzo; Mutzbauer, Ingrid; Graeb, Christian; Otto, Gerd; Pageaux, Georges-Philippe; Pinna, Antonio D; Pirenne, Jacques; Rizell, Magnus; Rossi, Giorgio; Rostaing, Lionel; Roy, Andre; Turrion, Victor Sanchez; Schmidt, Jan; Rochon, Justine; Troisi, Roberto I; Hoek, Bart van; Valente, Umberto; Wolf, Philippe; Wolters, Heiner; Mirza, Darius F; Scholz, Tim; Steininger, Rudolf; Soderdahl, Gunnar; Strasser, Simone I; Bilbao, Itxarone; Jauch, Karl-Walter; Neuhaus, Peter; Schlitt, Hans J; Geissler, Edward K; Burra, Patrizia; Jong, Koert P de; Duvoux, Christophe; Kneteman, Norman M

2010-01-01

The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 2 1/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

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Roy Andre

2010-05-01

Full Text Available Abstract Background The potential anti-cancer effects of mammalian target of rapamycin (mTOR inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC-free patient survival in liver transplant (LT recipients with a pre-transplant diagnosis of HCC. Methods/Design The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously

De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.

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Hart-Matyas, M; Gareau, A J; Hirsch, G M; Lee, T D G

2015-01-01

Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant. Copyright © 2014 Elsevier B.V. All rights reserved.

The immune-enhancing activity of Cervus nippon mantchuricus extract (NGE) in RAW264.7 macrophage cells and immunosuppressed mice.

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Hong, Se Hyang; Ku, Jin Mo; In Kim, Hyo; Ahn, Chang-Won; Park, Soo-Hyun; Seo, Hye Sook; Shin, Yong Cheol; Ko, Seong-Gyu

2017-09-01

Chemotherapeutics are often used to inhibit the proliferation of cancer cells. However, they can also harm healthy cells and cause side effects such as immunosuppression. Especially traditional oriental medicines long used in Asia, may be beneficial candidates for the alleviation of immune diseases. Cervus nippon mantchuricus extract (NGE) is currently sold in the market as coffee and health drinks. However, NGE was not widely investigated and efficacy remain unclear and essentially nothing is known about their potential immune-regulatory properties. As a result, NGE induced the differentiation of RAW264.7 macrophage cells. NGE-stimulated RAW264.7 macrophage cells elevated cytokines levels and NO production. NGE-stimulated RAW264.7 macrophage cells activated MAPKs and NF-κB signaling pathways. NGE encouraged the immuno-enhancing effects in immunosuppressed short-term treated with NGE mice model. NGE or Red ginseng encouraged the immuno-enhancing effects in immunosuppressed long-term treated with NGE mice model. Our data clearly show that NGE contains immune-enhancing activity and can be used to treat immunodeficiency. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Influence of overall treatment time in a fractionated total lymphoid irradiation as an immunosuppressive therapy in allogeneic bone marrow transplantation in mice

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Waer, M.; Ang, K.K.; Vandeputte, M.; Van der Schueren, E.

1982-01-01

Three groups of C 57 /BL/Ka mice received total lymphoid irradiation (TLI) in a total dose of 34 Gy in three different fractionation schedules. The tolerance of all different schedules was excellent. No difference in the peripheral white blood cell and lymphocyte counts nor the degree of immunosuppression as measured by phytohaemaglutinin or concanavalin A induced blastogenesis and mixed lymphocyte reaction were observed at the end of the treatment and up to 200 days. When bone marrow transplantation was performed one day after the end of each schedule, chimerism without signs of graft versus host disease was induced in all the groups. However, from the results in a limited number of animals it seems that concentrated schedules were less effective for chimerism induction. It has been demonstrated that it is possible to reduce drastically the overall treatment time for TLI before bone marrow transplantation. Further investigations are necessary in order to determine the optimal time-dose-fractionation factors and the different perameters involved in the transplantation

Prevention of Intraabdominal Adhesions by Local and Systemic Administration of Immunosuppressive Drugs

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Peker, Kemal; Inal, Abdullah; Sayar, Ilyas; Sahin, Murat; Gullu, Huriye; Inal, Duriye Gul; Isik, Arda

2013-01-01

Background: Intraperitoneal adhesion formation is a serious postsurgical issue. Adhesions develop after damage to the peritoneum by surgery, irradiation, infection or trauma. Objectives: Using a rat model, we compared the effectiveness of systemic and intraperitoneally administered common immunosuppressive drugs for prevention of postoperative intraperitoneal adhesions. Materials and Methods: Peritoneal adhesions were induced in 98 female Wistar-Albino rats by cecal abrasion and peritoneal excision. Rats were randomly separated into seven groups, each containing fourteen rats, and the standard experimental model was applied to all of rats. 14 days later, rats were euthanized, intraperitoneal adhesions were scored and tissues were examined histologically using hematoxylin/eosin and Masson’s trichrome staining. Results: Throughout the investigation, no animal died during or after surgery. In all of experimental groups, decrease in fibrosis was statistically significant. Decrease in fibrosis was most prominently in intraperitoneal tacrolimus group (P = 0.000), and decrease was least in intraperitoneal cyclosporine group (P = 0.022). Vascular proliferation was significantly decreased in all experimental groups (P < 0.05) except for systemic tacrolimus group (P = 0.139). Most prominent reduction in vascular proliferation was in intraperitoneal tacrolimus group (P = 0.000). Conclusions: Administration of immunosuppressive drugs is effective for prevention of intraperitoneal adhesions. PMID:24693396

Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative

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Marcin Mączyński

2018-06-01

Full Text Available This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10 was synthesized in reaction of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with relevant carbonyl compounds. The isoxazole derivatives were tested in several in vitro models using human cells. The compounds inhibited phytohemagglutinin A (PHA-induced proliferation of peripheral blood mononuclear cells (PBMCs to various degrees. The toxicity of the compounds with regard to a reference A549 cell line was also differential. 5-amino-N′-(2,4-dihydroxyphenylmethylidene-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM3 compound was selected for further investigation because of its lack of toxicity and because it had the strongest antiproliferative activity. The compound was shown to inhibit lipopolysaccharide (LPS-induced tumor necrosis factor (TNF α production in human whole blood cell cultures. In the model of Jurkat cells, MM3 elicited strong increases in the expression of caspases, Fas, and NF-κB1, indicating that a proapoptotic action may account for its immunosuppressive action in the studied models.

Effect of Mesenchymal Stromal Cells on T Cells in a Septic Context: Immunosuppression or Immunostimulation?

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Le Burel, Sébastien; Thepenier, Cédric; Boutin, Laetitia; Lataillade, Jean-Jacques; Peltzer, Juliette

2017-10-15

Sepsis is a complex process, including a first wave of damage partially due to the body's response to pathogens, followed by a phase of immune cell dysfunction. The efficacy of a pharmacological approach facing a rapidly evolving system implies a perfect timing of administration-this difficulty could explain the recent failure of clinical trials. Mesenchymal stromal cells (MSCs) are usually defined as immunosuppressive and their beneficial effects in preclinical models of acute sepsis have been shown to rely partly on such ability. If nonregulated, this phenotype could be harmful in the immunosuppressed context arising hours after sepsis onset. However, MSCs being environment sensitive, we hypothesized that they could reverse their immunosuppressive properties when confronted with suffering immune cells. Our objective was to evaluate the effect of human MSCs on activated human lymphocytes in an in vitro endotoxemia model. Peripheral blood mononuclear cells (PBMCs) underwent a 24-h lipopolysaccharide (LPS) intoxication and were stimulated with phytohemagglutinin (PHA) in contact with MSCs. MSCs induced a differential effect on lymphocytes depending on PBMC intoxication with LPS. Unintoxicated lymphocytes were highly proliferative with PHA and were inhibited by MSCs, whereas LPS-intoxicated lymphocytes showed a low proliferation rate, but were supported by MSCs, even when monocytes were depleted. These data, highlighting MSC plasticity in their immunomodulatory activity, pave the way for further studies investigating the mechanisms of mutual interactions between MSCs and immune cells in sepsis. Thus, MSCs might be able to fight against both early sepsis-induced hyperinflammatory response and later time points of immune dysfunction.

Discrepancies between beliefs and behavior: a prospective study into immunosuppressive medication adherence after kidney transplantation.

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Massey, Emma K; Tielen, Mirjam; Laging, Mirjam; Timman, Reinier; Beck, Denise K; Khemai, Roshni; van Gelder, Teun; Weimar, Willem

2015-02-01

Nonadherence to immunosuppressive medication after kidney transplantation is a behavioral issue and as such it is important to understand the psychological factors that influence this behavior. The aim of this study was to investigate the extent to which goal cognitions, illness perceptions, and treatment beliefs were related to changes in self-reported immunosuppressive medication adherence up to 18 months after transplantation. Interviews were conducted with patients in the outpatient clinic 6 weeks (T1; n=113), 6 months (T2; n=106), and 18 months (T3; n=84) after transplantation. Self-reported adherence was measured using the Basel Assessment of Adherence to Immunosuppressive Medications Scale Interview. Psychological concepts were measured using the Brief Illness Perceptions Questionnaire, Beliefs about Medicines Questionnaire, and questions on the importance of adherence as a personal goal, conflict with other goals, and self-efficacy for goal attainment. Nonadherence significantly increased over time to 31% at T3. Perceived necessity of medication, perceived impact of transplant on life (consequences) and emotional response to transplantation significantly decreased over time. Participants who reported low importance of medication adherence as a personal goal were more likely to become nonadherent over time. Illness perceptions can be described as functional and supportive of adherence which is inconsistent with the pervasive and increasing nonadherence observed. There appears therefore to be a discrepancy between beliefs about adherence and actual behavior. Promoting (intrinsic) motivation for adherence goals and exploring the relative importance in comparison to other personal goals is a potential target for interventions.

[Personalized medicine in transplantation therapy].

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Nakatani, Kaname

2013-05-01

Personalized medicine based on pharmacogenomics is being developed at the clinical stage. Various evidence is accumulating in transplantation therapy. Tacrolimus, a calcineurin inhibitor, is usually used for immunosuppressive therapy after transplantation. Tacrolimus is mainly metabolized by cytochrome P450 isozymes, CYP3A4 and CYP3A5, expressed in the intestine as well as in the liver. Recent studies of pharmacogenomics have reported that several single nucleotide polymorphisms (SNPs) of CYP3A5 are correlated with gene expression and enzyme activity. Phenotypes of CYP3A5 are typed as expressors (*1/*1 and *1/*3) or non-expressors (*3/*3) . In living-donor liver transplantation, CYP3A5 phenotypes could predict the blood concentration of tacrolimus. In particular, preoperative assessment of CYP3A5 genotypes in both recipients (intestine) and donors (graft liver) is required for predicting tacrolimus pharmacokinetics. In kidney transplantation, blood tacrolimus concentrations were significantly different between expressors and non-expressors. Genotyping and phenotyping of recipients were useful to predict blood tacrolimus levels in early phase of post-transplantation. Furthermore, phenotypes of CYP3A5 could predict the initial dose of tacrolimus. Combination therapy was performed after bone marrow transplantation to prevent complications. Genotyping and phenotyping of metabolic enzymes for combination dugs would be useful for predicting drug actions. In conclusion, phenotyping based on pharmacogenomics supports personalized medicine in transplantation therapy. In future, multiplex testing should be developed to support personalized medicine in various fields.

Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks

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Raed Alroughani

2016-01-01

Full Text Available The burden of multiple sclerosis (MS in women of childbearing potential is increasing, with peak incidence around the age of 30 years, increasing incidence and prevalence, and growing female : male ratio. Guidelines recommend early use of disease-modifying therapies (DMTs, which are contraindicated or recommended with considerable caution, during pregnancy/breastfeeding. Many physicians are reluctant to prescribe them for a woman who is/is planning to be pregnant. Interferons are not absolutely contraindicated during pregnancy, since interferon-β appears to lack serious adverse effects in pregnancy, despite a warning in its labelling concerning risk of spontaneous abortion. Glatiramer acetate, natalizumab, and alemtuzumab also may not induce adverse pregnancy outcomes, although natalizumab may induce haematologic abnormalities in newborns. An accelerated elimination procedure is needed for teriflunomide if pregnancy occurs on treatment or if pregnancy is planned. Current evidence supports the contraindication for fingolimod during pregnancy; data on other DMTs remains limited. Increased relapse rates following withdrawal of some DMTs in pregnancy are concerning and require further research. The postpartum period brings increased risk of disease reactivation that needs to be carefully addressed through effective communication between treating physicians and mothers intending to breastfeed. We address the potential for use of the first- and second-line DMTs in pregnancy and lactation.

A Case of Refractory Pulmonary Coccidioidomycosis Successfully Treated with Posaconazole Therapy

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Patel, RH; Pandya, S; Nanjappa, S; Greene, JN

2018-01-01

Coccidioidomycosis is an endemic fungal infection caused by the inhalation of the spores of Coccidioides species. Patients with underlying immunosuppressive illness can contract chronic or disseminated disease which requires prolonged systemic therapy. Pulmonary coccidioidomycosis remains as an illusory and abstruse disease, with increased prevalence that poses as a challenge for clinicians in developing an effective strategy for treatment. Here, we report successful treatment of a refractory case of chronic relapsing pulmonary coccidioidomycosis in a 50-year old woman with a thin-walled cavitary lung lesion who was ultimately treated with posaconazole.

Oral candidiasis in immunosuppressed children and young adults after liver or kidney transplantation.

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Olczak-Kowalczyk, Dorota; Pawłowska, Joanna; Garczewska, Barbara; Smirska, Ewa; Grenda, Ryszard; Syczewska, Małgorzata; Kowalczyk, Wojciech

2010-01-01

Candidiasis is an infectious complication in organ transplant recipients resulting from the patients' immunodeficiency and virulence of fungi pathogens. The purpose of this study was to evaluate the frequency of Candida spp. and identify their presence in the oral lesions of graft recipients. This study included 185 patients, 1.5 to 25.2 years of age (mean = 13.1 +/- 4.2 years) who were receiving combined immunosuppression treatment after kidney or liver transplantation and 70 control subjects. Evaluation included clinical oral examination, mycology, and statistical analysis. Candida spp. colonies were found in the oral mucosa of 63 (34%) graft recipients and in 19 (27%) control subjects. Candida albicans was the most prevalent species. This study showed that, regardless of the type of the organ transplant and immunosuppression, frequent, regular oral follow-up and mycologic tests are recommended. Diagnosing increased density of Candida spp. colonies in the oral cavity will help initiate early antifungal treatment. Candida spp. prevalence in the oral cavity in transplant recipients was higher than in immunocompetent control subjects. Kidney or liver transplantation predisposes one to the development of an increased density of Candida spp. colonies.

The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties.

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Francesca Rossi

Full Text Available Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians. Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes. In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells. We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

International Nuclear Information System (INIS)

Wirsdörfer, Florian; Cappuccini, Federica; Niazman, Muska; Leve, Simone de; Westendorf, Astrid M; Lüdemann, Lutz; Stuschke, Martin; Jendrossek, Verena

2014-01-01

Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease

Global LC/MS Metabolomics Profiling of Calcium Stressed and Immunosuppressant Drug Treated Saccharomyces cerevisiae

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Stefan Jenkins

2013-12-01

Full Text Available Previous studies have shown that calcium stressed Saccharomyces cerevisiae, challenged with immunosuppressant drugs FK506 and Cyclosporin A, responds with comprehensive gene expression changes and attenuation of the generalized calcium stress response. Here, we describe a global metabolomics workflow for investigating the utility of tracking corresponding phenotypic changes. This was achieved by efficiently analyzing relative abundance differences between intracellular metabolite pools from wild-type and calcium stressed cultures, with and without prior immunosuppressant drugs exposure. We used pathway database content from WikiPathways and YeastCyc to facilitate the projection of our metabolomics profiling results onto biological pathways. A key challenge was to increase the coverage of the detected metabolites. This was achieved by applying both reverse phase (RP and aqueous normal phase (ANP chromatographic separations, as well as electrospray ionization (ESI and atmospheric pressure chemical ionization (APCI sources for detection in both ion polarities. Unsupervised principle component analysis (PCA and ANOVA results revealed differentiation between wild-type controls, calcium stressed and immunosuppressant/calcium challenged cells. Untargeted data mining resulted in 247 differentially expressed, annotated metabolites, across at least one pair of conditions. A separate, targeted data mining strategy identified 187 differential, annotated metabolites. All annotated metabolites were subsequently mapped onto curated pathways from YeastCyc and WikiPathways for interactive pathway analysis and visualization. Dozens of pathways showed differential responses to stress conditions based on one or more matches to the list of annotated metabolites or to metabolites that had been identified further by MS/MS. The purine salvage, pantothenate and sulfur amino acid pathways were flagged as being enriched, which is consistent with previously published

The central effect of biological Amines on immunosuppressive effect of restraint stress in rat

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Zeraati F

2000-10-01

Full Text Available The effects of some histaminergic agents were evaluated on stress- induced immunosuppression in immunized nale rats. In rat immunized with sheep red blood cells ( SRBCs. Restraint stress (RS prevented the booster-induced rise in anti-SRBC antibody titre and cell immunity response. Intracerebroventicular (I.C>V injection of histamine (150 µg/rat induced a similar effect with RS. Pretreatment with chlorpheniramine (50 µg/rat reduced the inhibitory effect of Ras on immune function. Also histamine could inhibit the effect of RS on immune function. Also histamine could inhibitory the effect of chlorpheniramine when injected simultaneously. Pretreatment with ranidine (10 µg/rat had not a significant effect. Serotonin (3 µg/rat and dopamine (0.2 µg/rat could reverse the effects of chlorpheniromine when injected with chlorpheniramine (P<0.05. Epinephrine (0.2 µg/rat had not a significant effect. The results indicate that histamine mediates the immunosuppression of restraint stress by influencing the histamine H1 receptor in the brain and this effects of histamine may be modulated by serotoninergic and dopaminergic system.

Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin.

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Deters, M; Hütten, H; Kaever, V

2013-01-15

The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring (3)H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC(50) of 2.8 μM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC(50) 1.1 ng/ml). When curcumin was combined at concentrations of 1.25-2.5 μM with sirolimus at concentrations from 0.63 to 1.25 ng/ml the effects were synergistic. Combination of curcumin (1.25-2.5 μM) with sirolimus (5 ng/ml) showed additive effects. The effects after combination of curcumin at 5 μM with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models. Copyright © 2012 Elsevier GmbH. All rights reserved.

Perspective on future therapy of vasculitis.

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Boumpas, D T; Kritikos, H D; Daskalakis, N G

2000-10-01

This article summarizes recent advances in the management of various vasculitic syndromes and discusses potential new therapies based on a better understanding of their pathogenesis and natural history. Current efforts for optimization of testing for antineutrophil cytoplasmic antibodies and improvement of diagnostic criteria will certainly have a significant impact on future therapy. Biologic agents such as interferon-alpha are already in use in various vasculitides, whereas others, such as inhibitors of tumor necrosis factor-alpha, are in phase I clinical trials. Agents that selectively inhibit distinct steps in the pathogenesis of vasculitis are in preclinical or early clinical stages of development. Newer (mycophenolate mofetil, leflunamide) or older (methotrexate, azathioprine) immunosuppresive agents are finding new roles in the management of vasculitides. For patients with severe vasculitis, short-term use of cytotoxic agents, such as cyclophosphamide, alone or in combination with biologic agents, may expedite remission, which could then be better maintained with other, less toxic (and less expensive) immunosuppressive agents, such as methotrexate, azathioprine, mycophenolate mofetil, and leflunamide. For patients with mild or moderately severe vasculitis, these latter agents alone may be adequate. New therapeutic studies in vasculitis should better address the impact of therapy on health-related quality of life and its long-term toxicity.

Evidence of immunosuppression by Demodex canis.

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Barriga, O O; al-Khalidi, N W; Martin, S; Wyman, M

1992-04-01

Three clinically normal beagles, 3 beagles with localized demodectic mange (LDM), and 3 beagles with generalized demodectic mange (GDM) were investigated simultaneously 1-3 and 4-6 weeks from the appearance of the clinical signs. Blood clinical examination and reactivity of peripheral lymphocytes to Con A and PHA were investigated in the first instance, and reactivity to Con A, PHA, and LPS in the second. Eight aliquots were used in each blastogenesis assay for each dog. All dogs were negative for rheumatoid factor. The results of blastogenesis showed that many observations were distributed non-normally, and that not all dogs in each group responded homogeneously. Comparison of blastogenesis results between dogs demands careful statistical analysis. Responses to mitogens were normal in all dogs at 1-3 weeks except for the LDM dogs that showed an increased response to PHA. Only the response to Con A was moderately inhibited in the LDM dogs at 4-6 weeks. All responses were severely depressed in the GDM dogs at 4-6 weeks. This means that immunosuppression follows rather than precedes the clinical manifestations of GDM, and implies that the phenomenon is induced by the parasite or the host's reaction to it.

Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome.

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Burt, Richard K; Han, Xiaoqiang; Gozdziak, Paula; Yaung, Kim; Morgan, Amy; Clendenan, Allison M; Henry, Jacquelyn; Calvario, Michelle A; Datta, Syamal K; Helenowski, Irene; Schroeder, James

2018-05-31

Some patients with systemic lupus erythematosus (SLE) are refractory to traditional therapies, dependent on chronic corticosteroids, have organ damage, and are at high risk of mortality. In this group of patients, we report outcome at a median of five years after autologous hematopoietic stem cell transplant (HSCT) using two different non-myeloablative regimens. Four patients received a conditioning regimen of cyclophosphamide (200 mg/kg) and alemtuzumab (60 mg), while 26 patients underwent conditioning with cyclophosphamide (200 mg/kg), rATG (Thymoglobulin) (5.5 mg/kg), and rituximab 1000 mg. Unselected peripheral blood stem cells were infused on day 0. There were no treatment related deaths. Of the four patients treated with cyclophosphamide and alemtuzumab, none entered remission. For the 26 patients treated with cyclophosphamide, rATG, and rituximab, disease remission defined as no immune suppressive drugs except hydroxychloroquine and/or 10 mg or less of prednisone a day was 92% at 6 months, 92% at one year, 81% at 2 years, 71% at 3 years, and 62% at 4 and 5 years post-HSCT. Autologous HSCT outcome is dependent on the conditioning regimen but prior organ damage may cause lingering symptoms.

Multipotent mesenchymal stem cells with immunosuppressive activity can be easily isolated from dental pulp

DEFF Research Database (Denmark)

Pierdomenico, Laura; Bonsi, Laura; Calvitti, Mario

2005-01-01

) as a potential source of MSCs instead of bone marrow (BM). METHODS: Flow cytometric analysis showed that DP-MSCs and BM-MSCs were equally SH2, SH3, SH4, CD29 and CD 166 positive. The in vitro proliferative kinetics of MSCs were measured by 3H-thymidine incorporation uptake. The immunosuppressive function of MSCs...

Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus.

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Kwon, H H; Bang, S Y; Won, S; Park, Y; Yi, J H; Joo, Y B; Lee, H S; Bae, S C

2018-01-01

Objectives Avascular necrosis (AVN) is one of the most common causes of organ damage in patients with systemic lupus erythematosus (SLE) and often causes serious physical disability. The aims of this study were to investigate clinical risk factors associated with symptomatic AVN and to analyze their synergistic effects in a large SLE cohort in Korea. Methods Patients with SLE were enrolled and followed from 1998 to 2014 in the Hanyang BAE Lupus cohort, and damage was measured annually according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). AVN was confirmed by imaging study if patients had symptoms. To determine risk factors for AVN, clinical, laboratory and therapeutic variables were analyzed by logistic regression. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) were calculated to measure interactions between significant variables. Results Among 1219 SLE patients, symptomatic AVN was the most common type of musculoskeletal damage (10.8%, n = 132). SLE patients with AVN showed an earlier onset age, demonstrated AVN more commonly in conjunction with certain other clinical manifestations such as renal and neuropsychiatric disorders, and received significantly higher total cumulative corticosteroid dose and immunosuppressive agents than did patients without AVN. However, in multivariable analysis, only two variables including use of a cumulative corticosteroid dose greater than 20 g (odds ratio (OR) 3.62, p = 0.015) and use of immunosuppressants including cyclophosphamide or mycophenolate mofetil (OR 4.51, p AVN. Patients with cumulative corticosteroid dose > 20 g and immunosuppressant use had a 15.44-fold increased risk for AVN, compared with patients without these risk factors ( p AVN in our Korean lupus cohort. Conclusions An individual risk assessment for AVN development should be made prior to and during treatment for SLE

Polyketides with Immunosuppressive Activities from Mangrove Endophytic Fungus Penicillium sp. ZJ-SY₂.

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Liu, Hongju; Chen, Senhua; Liu, Weiyang; Liu, Yayue; Huang, Xishan; She, Zhigang

2016-11-25

Nine polyketides, including two new benzophenone derivatives, peniphenone ( 1 ) and methyl peniphenone ( 2 ), along with seven known xanthones ( 3 - 9 ) were obtained from mangrove endophytic fungus Penicillium sp. ZJ-SY₂ isolated from the leaves of Sonneratia apetala . Their structures were elucidated on the basis of MS, 1D, and 2D NMR data. Compounds 1 , 3 , 5 , and 7 showed potent immunosuppressive activity with IC 50 values ranging from 5.9 to 9.3 μg/mL.

Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

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Laia eGorchs

2015-05-01

Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

Immunosuppressive drugs impairs antibody response of the polysaccharide and conjugated pneumococcal vaccines in patients with Crohn's disease

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Kantsø, Bjørn; Halkjær, Sofie Ingdam; Thomsen, Ole Østergaard

2015-01-01

BACKGROUND: Patients with Crohn's disease (CD) have a higher risk of infectious diseases including pneumococcal infections, and the risk increases with immunotherapy. The primary endpoint of this study was to investigate the specific antibody response to two pneumococcal vaccines in CD patients...... with and without immunosuppressive treatment four weeks post vaccination. METHODS: In a randomized trial of the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the 13-valent pneumococcal conjugated vaccine (PCV13), a group of CD patients treated with immunosuppressive drugs (IS) alone or in combination...... with TNF-α antagonists were compared to a group of CD patients not treated with any of these drugs (untreated). Specific pneumococcal antibody concentrations were measured against 12 serotypes common to the two vaccines before and 4 week after vaccination. RESULTS: PCV13 induced a significantly higher...

Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy.

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Amaral, Teresa; Leiter, Ulrike; Garbe, Claus

2017-12-01

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation. In the metastatic setting, chemotherapy has been the standard treatment. However, two recently published trials with immune checkpoint inhibitors in first and second line showed promising results with a tolerable safety profile and these might become the standard therapy shortly. Somatostatin receptors are expressed in many MCC but such expression is not associated with disease severity. Presently there are no biomarkers predictive of response that could help to better select patients to these new therapies, and additional research is essential.

Antibody induction therapy for lung transplant recipients

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Penninga, Luit; Møller, Christian H; Penninga, Ida Elisabeth Irene

2013-01-01

Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe and effect...... and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation....

Current and future challenges in therapy for antibody-mediated rejection.

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Nair, Nandini; Ball, Timothy; Uber, Patricia A; Mehra, Mandeep R

2011-06-01

Antibody-mediated rejection (AMR) continues to present a challenge for the survival of the cardiac allograft. AMR appears to be on the rise, likely secondary to changing trends in clinical practice, including selection of patients for transplantation on mechanical circulatory support and development of more effective combinations of immunosuppressive drugs against acute cellular rejection. Most current strategies are aimed at treating acute AMR, but the treatment of chronic AMR is still not well defined. Clinically, AMR can often be more severe than cellular rejection and more difficult to treat, often not responding to typical protocols of increased immunosuppression. Complex steps involved in the antibody response allows for several potential targets for therapeutic intervention, including suppression of T and B cells, elimination of circulating antibodies, and inhibition of residual antibodies. Existing evidence suggests a multiregimen approach is the best option. Sustenance of accommodation and induction of tolerance could be viewed as viable options if adequate immune surveillance can be achieved in this setting. This review discusses the challenges in treating AMR and provides a critical analysis of current and possible future therapies. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Healthy rabbits are susceptible to Epstein-Barr virus infection and infected cells proliferate in immunosuppressed animals.

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Khan, Gulfaraz; Ahmed, Waqar; Philip, Pretty S; Ali, Mahmoud H; Adem, Abdu

2015-02-18

Epstein-Barr virus (EBV) is an oncogenic virus implicated in the pathogenesis of several human malignancies. However, due to the lack of a suitable animal model, a number of fundamental questions pertaining to the biology of EBV remain poorly understood. Here, we explore the potential of rabbits as a model for EBV infection and investigate the impact of immunosuppression on viral proliferation and gene expression. Six healthy New Zealand white rabbits were inoculated intravenously with EBV and blood samples collected prior to infection and for 7 weeks post-infection. Three weeks after the last blood collection, animals were immunosuppressed with daily intramuscular injections of cyclosporin A at doses of 20 mg/kg for 15 days and blood collected twice a week from each rabbit. The animals were subsequently sacrificed and tissues from all major organs were collected for subsequent analysis. Following intravenous inoculation, all 6 rabbits seroconverted with raised IgG and IgM titres to EBV, but viral DNA in peripheral blood mononuclear cells (PBMCs) could only be detected intermittently. Following immunosuppression however, EBV DNA could be readily detected in PBMCs from all 4 rabbits that survived the treatment. Quantitative PCR indicated an increase in EBV viral load in PBMCs as the duration of immunosuppression increased. At autopsy, splenomegaly was seen in 3/4 rabbits, but spleens from all 4 rabbit were EBV PCR positive. EBER-in situ hybridization and immunoshistochemistry revealed the presence of a large number of EBER-positive and LMP-1 positive lymphoblasts in the spleens of 3/4 rabbits. To a lesser extent, EBER-positive cells were also seen in the portal tract regions of the liver of these rabbits. Western blotting indicated that EBNA-1 and EBNA-2 were also expressed in the liver and spleen of infected animals. EBV can infect healthy rabbits and the infected cells proliferate when the animals are immunocompromised. The infected cells expressed several EBV

Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

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Siegler, Elizabeth Louise; Wang, Pin

2018-05-01

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

In vivo delivery of miRNAs for cancer therapy: Challenges and strategies⋆

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Chen, Yunching; Gao, Dong-Yu; Huang, Leaf

2016-01-01

MicroRNAs (miRNAs), small non-coding RNAs, can regulate post-transcriptional gene expressions and silence a broad set of target genes. miRNAs, aberrantly expressed in cancer cells, play an important role in modulating gene expressions, thereby regulating downstream signaling pathways and affecting cancer formation and progression. Oncogenes or tumor suppressor genes regulated by miRNAs mediate cell cycle progression, metabolism, cell death, angiogenesis, metastasis and immunosuppression in cancer. Recently, miRNAs have emerged as therapeutic targets or tools and biomarkers for diagnosis and therapy monitoring in cancer. Since miRNAs can regulate multiple cancer-related genes simultaneously, using miRNAs as a therapeutic approach plays an important role in cancer therapy. However, one of the major challenges of miRNA-based cancer therapy is to achieve specific, efficient and safe systemic delivery of therapeutic miRNAs In vivo. This review discusses the key challenges to the development of the carriers for miRNA-based therapy and explores current strategies to systemically deliver miRNAs to cancer without induction of toxicity. PMID:24859533

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.

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Nahas, Myrna R; Rosenblatt, Jacalyn; Lazarus, Hillard M; Avigan, David

2018-02-15

The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. Copyright © 2018 Elsevier Ltd. All rights reserved.

The role of immunosuppression in squamous cell carcinomas arising in seborrheic keratosis.

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Conic, Ruzica Z; Napekoski, Karl; Schuetz, Heidi; Piliang, Melissa; Bergfeld, Wilma; Atanaskova Mesinkovska, Natasha

2017-06-01

Seborrheic keratoses (SK) are common skin neoplasms considered to be benign. Reports of associated squamous cell carcinoma arising within seborrheic keratosis (SCC-SK) have been described. To describe the histopathologic characteristics of SCC-SK and identify predisposing factors in formation of these rare lesions. There were 162 cases of SCC-SK in a span of a decade (2003-2014). All of the histopathologic specimens and medical records were reviewed. Data from these patients were compared to a control group with seborrheic keratosis who were matched by age, sex, and location of lesion from the same time period (n = 162). SCC-SK has the classic histopathologic features of SK, such as hyperkeratosis, parakeratosis, papillomatosis, and pseudohorn cysts. The areas of squamous cell carcinoma were characterized by areas of squamous dysplasia (100%), hypogranulosis (79.6%), squamous eddies (79.6%), solar elastosis (80.9%), and brown pigmentation (59.9%). Patients with a history of immunosuppression had an increased risk for developing SCC-SK (19% vs 3%; P < .01), particularly when inhibition was transplant-associated (10% vs 0%; P < .01). This was a single center, retrospective study. SCC-SK occurs more often in elderly men with a history of immunosuppression associated with organ transplants. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Alemtuzumab Injection

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... room temperature on a counter; and meat, poultry, fish, or eggs that have not been cooked thoroughly. ... victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency ...

Mitoxantrone Therapy for Acute Posterior Multifocal Placoid Pigment Epitheliopathy with Cerebral Vasculitis

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Hélène Massé

2009-01-01

Full Text Available Purpose. To report favorable outcome of a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE associated with cerebral vasculitis after treatment with immunosuppressive therapy by mitoxantrone. Design. Single case report. Method. A 22-year-old man presented with acute isolated bilateral loss of vision revealing APMPPE. Corticosteroid therapy was initiated and visual acuity gradually improved. Seventeen days later, visual function deteriorated again, associated with flu-like syndrome and severe headaches. A relapse of APMPPE was diagnosed, complicated with lymphocytic meningitis and cerebral ischemia. Intravenous therapy with mitoxantrone was performed in combination with methylprednisolone. Results. Headaches disappeared in a few days whereas visual acuity gradually improved and stabilized at 20/40 in the right eye and 20/32 in the left eye. No adverse event was observed. Clinical improvement was confirmed by magnetic resonance imaging. Conclusion. Cerebral vasculitis is the most severe complication of the extraocular manifestations of APMPEE. This diagnosis should be evoked when severe headaches or behavior disorder are associated with APMPEE.

Infectious olecranon and patellar bursitis: short-course adjuvant antibiotic therapy is not a risk factor for recurrence in adult hospitalized patients.

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Perez, Cédric; Huttner, Angela; Assal, Mathieu; Bernard, Louis; Lew, Daniel; Hoffmeyer, Pierre; Uçkay, Ilker

2010-05-01

No evidence-based recommendations exist for the management of infectious bursitis. We examined epidemiology and risk factors for recurrence of septic bursitis. Specifically, we compared outcome in patients receiving bursectomy plus short-course adjuvant antibiotic therapy (7 days). Retrospective study of adult patients with infectious olecranon and patellar bursitis requiring hospitalization at Geneva University Hospital from January 1996 to March 2009. We identified 343 episodes of infectious bursitis (237 olecranon and 106 patellar). Staphylococcus aureus predominated among the 256 cases with an identifiable pathogen (85%). Three hundred and twelve cases (91%) were treated surgically; 142 (41%) with one-stage bursectomy and closure and 146 with two-stage bursectomy. All received antibiotics for a median duration of 13 days with a median intravenous component of 3 days. Cure was achieved in 293 (85%) episodes. Total duration of antibiotic therapy [odds ratio (OR) 0.9; 95% confidence interval (95% CI) 0.8-1.1] showed no association with cure. In multivariate analysis, only immunosuppression was linked to recurrence (OR 5.6; 95% CI 1.9-18.4). Compared with 14 days of antibiotic treatment (OR 0.9; 95% CI 0.1-10.7) was equivalent, as was the intravenous component (OR 1.1; 95% CI 1.0-1.3). In severe infectious bursitis requiring hospitalization, adjuvant antibiotic therapy might be limited to 7 days in non-immunosuppressed patients.

Post-Renal Transplant Diabetes Mellitus in Korean Subjects: Superimposition of Transplant-Related Immunosuppressant Factors on Genetic and Type 2 Diabetic Risk Factors

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Hyun Chul Lee

2012-06-01

Full Text Available Postrenal transplantation diabetes mellitus (PTDM, or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced β-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors.

The treatment of peripheral nerve injuries using irradiated allografts and temporary host immunosuppression (in a rat model)

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Easterling, K.J.; Trumble, T.E. (Yale Univ. School of Medicine, New Haven, CT (USA))

1990-10-01

Irradiation of allografts prior to transplantation and host immunosuppression with cyclosporin-A were studied separately and in combination as means of lessening the rejection of transplanted peripheral nerve tissue. Lewis and Brown Norway rats were used in the animal model, as they differ at both major and minor histocompatibility loci. Sciatic nerve grafts (2.5 cm) were used and the animals were followed for 16 weeks after nerve grafting. The outcome was studied by functional measurements (sensory testing, gait analysis, joint flexion contracture, and muscle weight), as well as by measurements of biochemical and histologic parameters (hydroxyproline concentration and axon counts, respectively). Sensory testing was not reliable because of crossover innervation by the saphenous nerve. Evaluation by standard gait-testing techniques was found to be unsatisfactory. However, the allografted animals receiving cyclosporin-A had significantly smaller flexion contractures, compared to the allografted animals without immunosuppression (17 degrees +/- 12 degrees vs. 44 degrees +/- 13 degrees and 51 degrees +/- 13 degrees, p less than 0.005). Allografted animals receiving short-term cyclosporin-A had contractures that were not significantly different from those seen in isografted control animals (17 degrees +/- 12 degrees vs. 22 degrees +/- 15 degrees, NS). Muscle hydroxyproline concentration analysis revealed a lower hydroxyproline concentration among the allografted groups that received irradiated allografts, compared to groups receiving nonirradiated allogeneic grafts. The studies of muscle hydroxyproline concentration and muscle weight both showed substantial reinnervation, even in allografted animals without pretreatment of the grafts or immunosuppression of the recipient animal.

The treatment of peripheral nerve injuries using irradiated allografts and temporary host immunosuppression (in a rat model)

International Nuclear Information System (INIS)

Easterling, K.J.; Trumble, T.E.

1990-01-01

Irradiation of allografts prior to transplantation and host immunosuppression with cyclosporin-A were studied separately and in combination as means of lessening the rejection of transplanted peripheral nerve tissue. Lewis and Brown Norway rats were used in the animal model, as they differ at both major and minor histocompatibility loci. Sciatic nerve grafts (2.5 cm) were used and the animals were followed for 16 weeks after nerve grafting. The outcome was studied by functional measurements (sensory testing, gait analysis, joint flexion contracture, and muscle weight), as well as by measurements of biochemical and histologic parameters (hydroxyproline concentration and axon counts, respectively). Sensory testing was not reliable because of crossover innervation by the saphenous nerve. Evaluation by standard gait-testing techniques was found to be unsatisfactory. However, the allografted animals receiving cyclosporin-A had significantly smaller flexion contractures, compared to the allografted animals without immunosuppression (17 degrees +/- 12 degrees vs. 44 degrees +/- 13 degrees and 51 degrees +/- 13 degrees, p less than 0.005). Allografted animals receiving short-term cyclosporin-A had contractures that were not significantly different from those seen in isografted control animals (17 degrees +/- 12 degrees vs. 22 degrees +/- 15 degrees, NS). Muscle hydroxyproline concentration analysis revealed a lower hydroxyproline concentration among the allografted groups that received irradiated allografts, compared to groups receiving nonirradiated allogeneic grafts. The studies of muscle hydroxyproline concentration and muscle weight both showed substantial reinnervation, even in allografted animals without pretreatment of the grafts or immunosuppression of the recipient animal

Prototheca zopfii associated diverticulitis in an immunosuppressed host, a case presentation and literature review

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Kyle W. Meinke

2017-11-01

Full Text Available Clinical infection with Prototheca species can present in many ways including cutaneous, bursal, or disseminated forms. Of these clinical forms, protothecal intestinal infections are a very rare occurrence, and there have only been a few documented cases within the medical literature. We present a case of a 67 year old African American male who presented to our veterans hospital with bowel obstruction. The patient has a pertinent medical history of prolonged immunosuppressive therapy for cadaveric renal transplant, Clostridium difficile infection, herpetic perirectal ulcer, and diverticulosis. The patient presented with symptoms of weight loss, left lower quadrant pain, and pencil thin stool. Colonoscopic and barium studies confirmed a complete obstruction at the level of the distal descending colon. Carcinoembryonic levels were within normal limits. The patient underwent a left hemicolectomy, and gross examination of the specimen revealed a markedly thickened bowel wall with multiple diverticula. Histologic examination revealed diverticular disease with associated transmural inflammation and numerous associated dark round structures. The basophilic round structures appeared to contain cell walls and stained positively for fungal stains. Overall, the diagnosis of Prototheca zopfii was made based on the characteristic histopathologic features and the results of the fungal staining pattern. To our knowledge, this is the first reported case of a colonic diverticulitis with involvement by Prototheca zopfii. We present an overview of the biology, epidemiology, histopathologic features, clinical manifestations, and treatment options of Prototheca as it relates to our patient.

Accuracy of C - Reactive protein as a bacterial infection marker in critically immunosuppressed patients: A systematic review and meta-analysis.

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de Oliveira, Vanessa Martins; Moraes, Rafael Barberena; Stein, Airton Tetelbom; Wendland, Eliana Márcia

2017-12-01

There is a need for a better understanding of the role of C-reactive protein (CRP) as a valid marker for the detection of bacterial infections in critically immunosuppressed patients. A high negative predictive value of CRP is also needed to rule out sepsis and bacterial infections in immunocompetent patients. However, few studies have evaluated the performance of CRP in immunocompromised hosts. The aim of the present study was to evaluate the performance of CRP as a marker of infection in critically immunosuppressed patients. The inclusion criterion was immunosuppression for which CRP was used as a bacterial infection marker. Searches were performed in the Cochrane Register, MEDLINE, EMBASE, SCOPUS, Web OF Science, LILACS and CINAHL databases. We applied the Quality Assessment of Diagnostic Accuracy Studies tool 2 (QUADAS 2) to evaluate the quality of the articles and evaluated the test accuracy parameters using hierarchical summary receiver operating characteristic (HSROC) curves and bivariate random effect models. Only 13 of 21 studies produced quantitative results. We analyzed all studies using the random effects method (restricted maximum likelihood) and obtained a joint diagnostic odds ratio (DOR) of 3.04 (95% confidence interval [CI] 1.71-5.40) with heterogeneity (I 2 =91%, Q=181.48, p<0.001). Therefore, a bivariate model was applied. Analyzing the tuberculosis carrier, steroid user, or presence of opportunistic infection subgroups, as described in the proposal, was not possible due to the lack of information on these topics included in the articles. CRP appears to be a good screening tool for sepsis in critically immunosuppressed patients. Submitted PROSPERO 2015: CRD42015019329. Copyright © 2017 Elsevier Inc. All rights reserved.

Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities.

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Xia, An-Liang; Wang, Xiao-Chen; Lu, Yi-Jun; Lu, Xiao-Jie; Sun, Beicheng

2017-10-27

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possibl e solutions and future perspectives.

38 CFR 4.118 - Schedule of ratings-skin.

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2010-07-01

.... Note (3): Take into consideration unretouched color photographs when evaluating under these criteria...-constant systemic therapy such as corticosteroids or other immunosuppressive drugs required during the past..., or; systemic therapy such as corticosteroids or other immunosuppressive drugs required for a total...

The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy.

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Ghiringhelli, François; Apetoh, Lionel

2014-01-01

Preclinical studies have revealed an unexpected ability of the immune system to contribute to the success of chemotherapy and radiotherapy. Anticancer therapies can trigger immune system activation by promoting the release of danger signals from dying tumor cells and/or the elimination of immunosuppressive cells. We have, however, recently discovered that some chemotherapies, such as 5-fluorouracil and gemcitabine, exert conflicting effects on anticancer immune responses. Although 5-fluorouracil and Gem selectively eliminated myeloid-derived suppressive cells in tumor-bearing rodents, these chemotherapies promoted the release of IL-1β and the development of pro-angiogenic IL-17-producing CD4 T cells. The ambivalent effects of chemotherapy on immune responses should thus be carefully considered to design effective combination therapies based on chemotherapy and immune modulators. Herein, we discuss how the initial findings underscoring the key role of the immune system in mediating the antitumor efficacy of anticancer agents could begin to translate into effective therapies in humans.

ATG-Fresenius or daclizumab induction therapy in immunologically high risk kidney recipients: a prospective randomized pilot trial.

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Kim, Min Jeong; Tsinalis, Dimitrios; Franz, Stefan; Binet, Isabelle; Gürke, Lorenz; Mihatsch, Michael J; Steiger, Jürg; Thiel, Gilbert; Dickenmann, Michael

2008-01-01

Despite all the advantages in the immunosuppressive therapy, kidney transplantation in immunologically high risk patients remains a challenge. Ideally, an induction therapy should provide maximal graft protection, while adverse events rate and costs remain as low as possible. Immunologically high risk kidney recipients with CDC-PRA ł 25% within the last 3 years, a positive B-cell CDC-crossmatch or graft loss due to rejection within 3 years following a prior transplantation, were randomized 1:1 to receive ATG-Fresenius (ATG-F) (9 mg/kg day 0; 3 mg/kg day 1-4) or Daclizumab therapy (1 mg/kg day 0, 14, 28, 42, 56) in a pilot study. Additional immunosuppression consisted of cyclosporine, mycophenolate mofetil, and steroids. 11 patients were included in each group. The patient (90% in ATG-F; 100% in Daclizumab) and graft survival (censored for death) (100% in ATG-F; 90% in Daclizumab) and the mean creatinine concentration at 24 months (139+/-68 mol/l in ATG-F; 176+/-103 mol/l in Daclizumab) were similar in both groups. More severe graft rejections (3 vascular rejections in Daclizumab) and adverse events (5.3/patient in ATG-F; 6.7/patient in Daclizumab) were observed in the Daclizumab group. The costs for hospitalization/ day within 24 months were lower in ATG-F (2.32+/-3.51 USD vs. 12.25+/-9.75 USD; p=0.02) resulting in an average cost-difference of more than 10'435 USD /patient. In this pilot trial, both treatments were comparably successful regarding graft and patient outcome.

Multiple Sclerosis: Immunopathology and Treatment Update

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Dargahi, Narges; Katsara, Maria; Tselios, Theodore; Androutsou, Maria-Eleni; Matsoukas, John

2017-01-01

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS. PMID:28686222

Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report

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Yo Komatsuzaki

2017-01-01

Full Text Available Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection.

Genetic variation in the immunosuppression pathway genes and breast cancer: a pooled analysis of 42,510 cases and 40,577 controls from the Breast