Transfusion-associated graft-versus-host disease

International Nuclear Information System (INIS)

Rappeport, J.M.

1990-01-01

The clinical pathologic syndrome of graft-versus-host disease (GVHD) is usually a sequela of bone marrow transplantation. This disorder occurs as a result of recognition by engrafted donor-derived lymphocytes of foreign recipient transplantation antigens. GVHD may also result from engraftment of lymphocytes from other sources, including (1) transfusion of lymphocytes containing blood components, (2) transplacental maternal fetal transfusion, and (3) passive transfer of lymphocytes in solid organ transplantation. The recipients are usually severely immunodeficient and thus incapable of rejecting the transfused lymphocytes. This syndrome may, however, also develop in immunologically competent patients receiving blood products from individuals with histocompatibility antigens not recognized as foreign. 58 refs

Prediction of graft-versus-host disease in humans by donor gene-expression profiling.

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Chantal Baron

2007-01-01

Full Text Available BACKGROUND: Graft-versus-host disease (GVHD results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT. Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be "stronger alloresponders" than others, and consequently more likely to elicit GVHD. METHODS AND FINDINGS: To this end, we measured the gene-expression profiles of CD4(+ and CD8(+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation. CONCLUSIONS: These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.

Ocular manifestations of graft-versus-host disease

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Nassar, Amr; Tabbara, Khalid F.; Aljurf, Mahmoud

2013-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved over the past two decades to become the standard of care for hematologic and lymphoid malignancies. Major ocular complications after allogeneic HSCT have been increasing in number and severity. Graft-versus-host disease (GVHD) remains a major cause of ocular morbidity after allogeneic HSCT. The main objective of this review is to elucidate the ocular complications in patients developing GVHD following HSCT. Ocular complications secondary to GVHD are common and include dry eye syndrome, acquisition of ocular allergy from donors with allergic disorders. Eyelid changes may occur in GVHD leading to scleroderma-like changes. Patients may develop poliosis, madarosis, vitiligo, lagophthalmos, and entropion. The cornea may show filamentary keratitis, superficial punctate keratitis, corneal ulcers, and peripheral corneal melting which may lead to perforation in severe cases. Scleritis may also occur which can be anterior or posterior. Keratoconjunctivis sicca appears to be the most common presentation of GVHD. The lacrimal glands may be involved with mononuclear cell infiltration of both the major and accessory lacrimal glands and decrease in tear production. Severe dry eye syndrome in patients with GVHD may develop conjunctival scarring, keratinization, and cicatrization of the conjunctiva. Therapy of GVHD includes systemic immunosuppression and local therapy. Surgical treatment in refractory cases includes surgical intervention to improve the manifestation of GVHD of the eye. This may include tarsorrhapy, prose lenses, punctal occlusions and corneal transplantation. PMID:24227989

[NKT cells and graft-versus-host disease-review].

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Zhao, Lei; Hao, Sha; Yuan, Wei-Ping; Cheng, Tao

2013-10-01

NKT cells (nature killer T cells), as a regulatory cellular compartment in the immune system, express cell surface markers of T cells and NK cells. It secretes a variety of cytokines that stimulate specific antigens. Through regulating the balance of Th1/Th2, the NKT cells play an important role in prevention and treatment of graft-versus-host disease (GVHD). Its antitumor and anti-infectious effects serve as a basis of its application in allogeneic hematopoietic stem cell transplantation. A better understanding of the biological and immunological features of NKT cell, as well as its specific immune regulatory mechanisms, will further justify the rationales of using NKT cells in the management of GVHD for patients. In this review, the biologic properties, classification, differentiation and development, immune activation of NKT cells as well as the NKT cells and GVHD including the related mechanisms of prevention and treatment of GVHD with NKT cells, NKT cells and tumors, NKT cells and infection, and NKT cells and clinical GVHD are summarized.

Steroid treatment of acute graft-versus-host disease grade I: a randomized trial

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Bacigalupo, Andrea; Milone, Giuseppe; Cupri, Alessandra; Severino, Antonio; Fagioli, Franca; Berger, Massimo; Santarone, Stella; Chiusolo, Patrizia; Sica, Simona; Mammoliti, Sonia; Sorasio, Roberto; Massi, Daniela; Van Lint, Maria Teresa; Raiola, Anna Maria; Gualandi, Francesca

2017-01-01

Patients with acute graft-versus-host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II–IV GvHD. The cumulative incidence of grade II–IV GvHD was 50% in the observation arm and 33% in the treatment arm (P=0.005). However, grade III–IV GvHD was comparable (13% vs. 10%, respectively; P=0.6), and this was tru...

Graft irradiation abrogates graft-versus-host disease in combined pancreas-spleen transplantation

International Nuclear Information System (INIS)

Schulak, J.A.; Sharp, W.J.

1986-01-01

A model of combined pancreas-spleen transplantation (PST) was studied in LBN F1 recipients of Lewis grafts in order to evaluate the efficacy of pretransplant graft irradiation in preventing lethal graft-versus-host disease (GVHD). Recipients of unmodified PST uniformly developed severe GVHD and died (MST = 16.7 +/- 3.8 days). Whole body donor irradiation with either 500 or 250 rad prevented lethal GVHD. Similarly, ex vivo graft irradiation with either 1000 or 500 rad also resulted in normal weight gain, graft function, and host survival for the 6-week study period. Conversely, delay of graft irradiation until 3 days after transplantation failed to prevent this complication (MST = 15.8 +/- 3.7 days). Recipients of irradiated grafts displayed glucose tolerance tests that were identical to those in the control group indicating that the doses of radiation employed in these experiments were not deleterious to islet function. Irradiated spleen grafts appeared histologically normal at 6 weeks after transplantation. Cells derived from these grafts failed to stimulate lymph node enlargement in a popliteal lymph node assay for GVHD, suggesting that these spleens may have become repopulated with host cells. These experiments confirm that PST has the potential to cause lethal GVHD and suggest that pretransplant graft irradiation may be used to prevent its occurrence

Dendritic cell chimerism in oral mucosa of transplanted patients affected by graft-versus-host disease.

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Pérez, Claudio A; Rabanales, Ramón; Rojas-Alcayaga, Gonzalo; Larrondo, Milton; Escobar, Alejandro F; López, Mercedes N; Salazar-Onfray, Flavio; Alfaro, Jorge I; González, Fermín E

2016-02-01

Graft-versus-host disease (GVHD) is one of the main complications after haematopoietic stem cell transplantation. Clinical features of GVHD include either an acute (aGVHD) or a chronic (cGVHD) condition that affects locations such as the oral mucosa. While the involvement of the host's dendritic cells (DCs) has been demonstrated in aGVHD, the origin (donor/host) and mechanisms underlying oral cGVHD have not been completely elucidated. In this study, we intend to determine the origin of DCs present in mucosal tissue biopsies from the oral cavity of transplanted patients affected by cGVHD. We purified DCs, from oral biopsies of three patients with cGVHD, through immunobeads and subsequently performed DNA extraction. The origin of the obtained DCs was determined by PCR amplification of 13 informative short tandem repeat (STR) alleles. We also characterised the DCs phenotype and the inflammatory infiltrate from biopsies of two patients by immunohistochemistry. Clinical and histological features of the biopsies were concordant with oral cGVHD. We identified CD11c-, CD207- and CD1a-positive cells in the epithelium and beneath the basal layer. Purification of DCs from the mucosa of patients affected by post-transplantation cGVHD was >95%. PCR-STR data analysis of DCs DNA showed that 100% of analysed cells were of donor origin in all of the evaluated patients. Our results demonstrate that resident DCs isolated from the oral tissue of allotransplanted patients affected by cGVHD are originated from the donor. Further research will clarify the role of DCs in the development and/or severity of oral cGVHD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An update on the clinical utility of extracorporeal photopheresis in the treatment of graft-versus-host disease

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Salem B

2017-03-01

Full Text Available Baheyeldin Salem,1,2 Jennifer Webb,3 David Alex Jacobsohn1,2 1Blood and Marrow Transplant Program, 2Department of Paediatrics, 3Department of Transfusion Medicine, Children’s National Health System, Washington, DC, USA Abstract: Graft-versus-host disease (GVHD continues to be a major complication following allogeneic hematopoietic cell transplantation (allo-HCT with high morbidity and mortality. Corticosteroids are the first-line treatment for GVHD; however, a substantial number of patients go on to require second-line treatment where no single therapeutic modality has been proven to be the most effective. Extracorporeal photopheresis (ECP is an efficient and established therapy for cutaneous T-cell lymphoma, GVHD, rejection after solid organ transplantation and various autoimmune diseases. Although large randomized trials are limited, there is compelling cumulative data on the efficacy of ECP for GVHD, and the response rates, especially for cutaneous involvement, are encouraging. ECP has an excellent safety profile, a well-documented steroid-sparing effect, proven survival benefit and overall quality-of-life improvement. In many institutions, ECP is commonly regarded as the preferred second-line treatment for GVHD. Keywords: GVHD, ECP, immunosuppressive therapy, IST, apheresis, steroid-refractory ­graft-versus-host disease, hematopoietic cell transplantation, graft versus leukemia effect

Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity.

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Jachiet, M; de Masson, A; Peffault de Latour, R; Rybojad, M; Robin, M; Bourhis, J-H; Xhaard, A; Dhedin, N; Sicre de Fontbrune, F; Suarez, F; Barete, S; Parquet, N; Nguyen, S; Ades, L; Rubio, M-T; Wittnebel, S; Bagot, M; Socié, G; Bouaziz, J-D

2014-07-01

According to the National Institutes of Health classification of chronic graft-versus-host disease (cGVHD), skin ulcers after allogeneic haematopoietic stem-cell transplantation (HSCT) are recorded as having the maximal severity score but published data are scarce. To describe skin ulcers related to cGVHD with an emphasis on clinical findings, associated morbidity, management and evolution. A multicentre retrospective analysis was carried out of patients with a diagnosis of cGVHD skin ulcers. All 25 patients included in the study had sclerotic skin cGVHD and 21 had lichenoid skin lesions associated with the sclerotic skin lesions. Thirteen patients had severe cGVHD without considering the skin, because of the involvement of an extracutaneous organ by cGVHD. The median time from HSCT to the onset of ulcers was 44 months. In addition to scleroderma, initial skin lesions at the site of ulcers were bullous erosive lichen in 21 patients and bullous erosive morphoea in four patients. Fifteen patients had an inaugural oedema. Ulcers were mostly bilateral with a predilection for the lower limbs. They were frequently colonized but few infections occurred. Four patients died during a median follow-up period of 55 months. Chronic graft-versus-host disease skin ulcers occur in patients with sclerodermatous skin cGVHD, are associated with severe cGVHD, often start with bullous lichenoid lesions or bullous morphoea and seem to cause more morbidity than mortality, given the low rate of mortality observed in our series of patients. © 2014 British Association of Dermatologists.

Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions.

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Nishiwaki, Satoshi; Nakayama, Takayuki; Murata, Makoto; Nishida, Tetsuya; Terakura, Seitaro; Saito, Shigeki; Kato, Tomonori; Mizuno, Hiroki; Imahashi, Nobuhiko; Seto, Aika; Ozawa, Yukiyasu; Miyamura, Koichi; Ito, Masafumi; Takeshita, Kyosuke; Kato, Hidefumi; Toyokuni, Shinya; Nagao, Keisuke; Ueda, Ryuzo; Naoe, Tomoki

2014-01-01

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

Therapeutic effects of hydrogen on chronic graft-versus-host disease.

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Qian, Liren; Liu, Xiaopeng; Shen, Jianliang; Zhao, Defeng; Yin, Wenjie

2017-10-01

The incidence of chronic graft-versus-host disease (cGVHD) is rising recent years, which has been the leading cause of non-transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen-rich saline increased survival rate of cGVHD mice. Administration of hydrogen-rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Assessment of dry eye in a GVHD murine model: Approximation through tear osmolarity measurement.

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Martínez-Carrasco, Rafael; Sánchez-Abarca, Luis Ignacio; Nieto-Gómez, Cristina; García, Elisabet Martín; Ramos, Teresa L; Velasco, Almudena; Sánchez-Guijo, Fermín; Aijón, José; Hernández-Galilea, Emiliano

2017-01-01

Dry eye disease is one of the most frequent pathological events that take place in the course of the graft versus host disease (GVHD), and is the main cause of deterioration in quality of life for patients. Thus, demonstration of dry eye signs in murine models of oGVHD is crucial for the validation of these models for the study of the disease. Given the increasing evidence that tear osmolarity is an important player of dry eye disease, our purpose in this study was to validate the use of a reliable method to assess tear osmolarity in mice: the electrical impedance method. Then, we wanted to test its utility with an oGVHD model. Tear volume assessment was also performed, using the phenol red thread test. We found differences in tear osmolarity in mice that received a transplant with cells from bone marrow and spleen (the GVHD group) when compared with mice that only received bone marrow cells (the BM group) at day 7 (362 ± 8 mOsm/l and 345 ± 9 mOsm/l respectively; P dry eye disease, what contributes to give relevance to this model for the study of GVHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chronic graft versus host disease and nephrotic syndrome

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Samia Barbouch

2014-01-01

Full Text Available Disturbed kidney function is a common complication after bone marrow transplantation. Recently, attention has been given to immune-mediated glomerular damage related to graft versus host disease (GVHD. We describe a 19-year-old woman who developed membranous glomerulonephritis after bone marrow transplantation (BMT. Six months later, she developed soft palate, skin and liver lesions considered to be chronic GVHD. Fifteen months after undergoing BMT, this patient presented with nephrotic syndrome. A renal biopsy showed mem-branous glomerulonephritis associated with a focal segmental glomerulosclerosis. She was started on corticosteroid treatment with good outcome.

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

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Tong, Jiefeng; Hu, Renjian; Zhao, Yingying; Xu, Yang; Zhao, Xiaoying; Jin, Xiuming

2017-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

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Pedro Santos e Sousa

2018-05-01

Full Text Available The skin is the most common target organ affected by graft-versus-host disease (GVHD, with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies.

IL-17 Genetic and Immunophenotypic Evaluation in Chronic Graft-versus-Host Disease

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Renata Gonçalves Resende

2014-01-01

Full Text Available Although interleukin-17 (IL-17 is a recently discovered cytokine associated with several autoimmune diseases, its role in the pathogenesis of chronic graft-versus-host disease (cGVHD was not established yet. The objective of this study was to investigate the association of IL17A and IL17F genes polymorphisms and IL-17A and IL-17F levels with cGVHD. IL-17A expression was also investigated in CD4+ T cells of patients with systemic cGVHD. For Part I of the study, fifty-eight allo-HSCT recipients and donors were prospectively studied. Blood samples were obtained to determine IL17A and IL17F genes polymorphisms. Cytokines levels in blood and saliva were assessed by ELISA at days +35 and +100 after HSCT. In Part II, for the immunophenotypic evaluation, eight patients with systemic cGVHD were selected and the expression of IL-17A was evaluated. We found association between recipient AA genotype with systemic cGVHD. No association was observed between IL-17A levels and cGVHD. Lower IL-17A levels in the blood were associated with AA genotype. In flow cytometry analysis, decreased expression of IL-17A was observed in patients with cGVHD after stimulation. In conclusion, IL-17A may have an important role in the development of systemic cGVHD.

New Insight for the Diagnosis of Gastrointestinal Acute Graft-versus-Host Disease

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Florent Malard

2014-01-01

Full Text Available Allogeneic stem cell transplantation (allo-SCT is a curative therapy for different life-threatening malignant and nonmalignant hematologic disorders. Graft-versus-host disease (GVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Early diagnostic of GVHD is essential to initiate treatment as soon as possible. Unfortunately, the diagnosis of GVHD may be difficult to establish, because of the nonspecific nature of the associated symptoms and of the numerous differential diagnosis. This is particularly true regarding gastrointestinal (GI acute GVHD. In the recent years many progress has been made in medical imaging test and endoscopic techniques. The interest of these different techniques in the diagnosis of GI acute GVHD has been evaluated in several studies. With this background we review the contributions, limitations, and future prospect of these techniques in the diagnosis of GI acute GVHD.

Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease.

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Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

2015-08-01

To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). Prospective study. Eighty-four patients diagnosed with chronic ocular GVHD. We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease

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Jiefeng Tong

2017-06-01

Full Text Available Allogeneic hematopoietic stem cell transplantation (HSCT is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses.

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Martires, Kathryn J; Baird, Kristin; Citrin, Deborah E; Hakim, Fran T; Pavletic, Steven Z; Cowen, Edward W

2011-09-01

The mechanisms responsible for the variable manifestations of chronic cutaneous graft-vs-host disease (cGVHD) are poorly understood. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury (isomorphic and isotopic responses), a recognized phenomenon in morphea, suggests a potential common pathway between cGVHD and other sclerotic skin conditions. Four cases of sclerotic-type cGVHD developed at the site of disparate skin injuries (ionizing radiotherapy, repeated needle sticks, central catheter site, and varicella-zoster virus infection). We review the spectrum of previously reported cases of sclerotic and nonsclerotic cGVHD relating to external forces on the skin. Localization of sclerotic-type cGVHD may occur after many types of skin injury, including UV and ionizing radiotherapy, needle sticks, viral infection, and pressure or friction. Recognition of this phenomenon may be helpful for the early diagnosis of sclerotic disease. Recent insights into the immunological consequences of minor skin injury may provide important clues to the underlying pathogenesis of cGVHD-mediated skin disease.

A case of membranous nephropathy as a manifestation of graft-versus-host disease

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Jae Hyun Han

2013-03-01

Full Text Available Nephrotic syndrome (NS rarely occurs after hematopoietic stem cell transplantation (HSCT as a late manifestation of graft-versus-host disease (GVHD. Herein, we report a case of HSCT-associated membranous nephropathy in a female patient with aplastic anemia. The patient received an allogeneic HSCT from her human leukocyte antigen-identical brother following myeloablative conditioning chemotherapy. NS occurred 21 months after HSCT without any concurrent features of chronic GVHD. The patient was treated with prednisolone and cyclosporine after renal biopsy confirmed membranous nephropathy, and achieved complete remission. Our report contradicts previous assumptions that concomitant chronic GVHD is responsible for the development of NS, suggesting that NS can develop as a new, independent manifestation of GVHD.

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

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McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; MacDonald, Kelli P. A.; Hill, Geoffrey R.; Luznik, Leo; Serody, Jonathan S.; Murphy, William J.; Maillard, Ivan; Munn, David H.; Turka, Laurence A.; Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome

2016-01-01

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. PMID:27385791

Pulp Obliteration in a Patient with Sclerodermatous Chronic Graft-versus-Host Disease.

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Gomes, Camilla Borges Ferreira; Treister, Nathaniel Simon; Miller, Brian; Armand, Philippe; Friedland, Bernard

2016-04-01

Dental pulp calcification is a common finding associated with localized dental trauma, genetic disorders, and systemic inflammatory diseases. Chronic graft-versus-host disease (cGVHD) is a frequent complication after allogeneic hematopoietic cell transplantation (allo-HCT) characterized by immune-mediated injury to the skin, mouth, eyes, liver, and other tissues, resulting in significant disability and reduced quality of life. We report a patient with sclerodermatous cGVHD who presented with general pulp calcification in all teeth 5 years after allo-HCT. A review of full mouth dental radiographs obtained just before allo-HCT revealed normal-appearing pulp chambers. Based on prior reports of generalized pulp calcification associated with progressive systemic sclerosis, we hypothesized that the etiology was likely related to the presence of cGVHD with associated vascular and fibrotic tissue changes within the pulp vasculature. Clinicians should consider cGVHD in the differential diagnosis of generalized pulp calcification. Copyright © 2016 American Association of Endodontists. All rights reserved.

The Green Tea Catechin Epigallocatechin Gallate Ameliorates Graft-versus-Host Disease.

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Sabine Westphal

Full Text Available Allogeneic hematopoetic stem cell transplantation (allo-HSCT is a standard treatment for leukemia and other hematologic malignancies. The major complication of allo-HSCT is graft-versus-host-disease (GVHD, a progressive inflammatory illness characterized by donor immune cells attacking the organs of the recipient. Current GVHD prevention and treatment strategies use immune suppressive drugs and/or anti-T cell reagents these can lead to increased risk of infections and tumor relapse. Recent research demonstrated that epigallocatechin gallate (EGCG, a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. EGCG treated allo-HSCT recipients had significantly higher numbers of regulatory T cells in GVHD target organs and in the blood. Furthermore, EGCG treatment resulted in diminished oxidative stress indicated by significant changes of glutathione blood levels as well as glutathione peroxidase in the colon. In summary, our study provides novel evidence demonstrating that EGCG ameliorates lethal GVHD and reduces GVHD-related target organ damage. Possible mechanisms are increased regulatory T cell numbers and reduced oxidative stress.

Graft-versus-host disease and sialodacryoadenitis viral infection in bone marrow transplanted rats

International Nuclear Information System (INIS)

Rossie, K.M.; Sheridan, J.F.; Barthold, S.W.; Tutschka, P.J.

1988-01-01

The effect of a localized viral infection on the occurrence of graft-vs.-host disease (GVHD) was examined in allogeneic rat bone marrow chimeras (ACI/LEW). Animals without clinical evidence of GVHD, 62 days after bone marrow transplant, were infected in salivary and lacrimal glands with sialodacryoadenitis virus (SDAV), and sacrificed 8-25 days postinfection. Using established histologic criteria, GVHD was found more frequently in salivary and lacrimal glands of SDAV-infected chimeras than uninfected chimeras. Skin and oral mucosa, tissues not infected by the virus, showed no differences in occurrence of GVHD, suggesting that the viral infection induced only local and not systemic GVHD. GVHD and SDAV infection, which are histologically similar, were differentiated by examining tissues for SDAV antigen using immunoperoxidase technique. Histologic changes were present for at least 1 week longer than viral antigen, suggesting they represented GVHD rather than viral infection. GVHD and SDAV infection were also differentiated by looking for a histologic feature characteristic of GVHD and not found in SDAV infection (periductal lymphocytic infiltrate). This was found in SDAV-infected chimeras more frequently than uninfected chimeras, suggesting that the viral infection somehow induced GVHD. Results showed a localized increase in the occurrence of GVHD subsequent to localized viral infection

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist.

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Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu; Ko, Huaibin Mabel; Renteria, Anne; Levine, John; Colombel, Jean-Frederic; Ferrara, James

2017-12-01

Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

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Anu Batra

2014-01-01

Full Text Available Autologous graft versus host disease (autoGVHD is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P=0.047. On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells were found to be significantly lower in patients with autoGVHD (P=0.038. HLA-B55 expression was significantly associated with development of autoGVHD (P=0.032. Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

The prevalence and prognostic value of concomitant eosinophilia in chronic graft-versus-host disease after allogeneic stem cell transplantation

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Mortensen, Katrine Brandt; Gerds, Thomas Alexander; Bjerrum, Ole Weis

2014-01-01

The prognostic significance of eosinophilia after myeloablative allogeneic stem cell transplantation (ASCT) remains to be established. Patients, whom developed chronic graft-versus-host disease (cGVHD) after ASCT, were included (n = 142). Eosinophil count was analyzed at cGVHD onset. We observed...... no significant association between EO and the grade of cGVHD, thrombocytopenia, nor extensive skin involvement. Importantly, we observed no significant association between cGVHD with concomitant eosinophilia and long-term clinical outcomes, and subgroup analyses revealed a considerable confounding effect...

Reversal of CD8 T-Cell–Mediated Mucocutaneous Graft-Versus-Host-Like Disease by the JAK Inhibitor Tofacitinib

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Okiyama, Naoko; Furumoto, Yasuko; Villarroel, Vadim A; Linton, Jay T; Tsai, Wanxia L; Gutermuth, Jan; Ghoreschi, Kamran; Gadina, Massimo; O'Shea, John J; Katz, Stephen I

2014-01-01

The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell–mediated mucocutaneous diseases in patients with GVHD. PMID:24213371

Brazilian situation of blood component irradiation practice for the prevention of transfusion associated Graft-versus-Host disease

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Goes, E.G.; Borges, J.C.; Covas, D.T.; Motta, I.

1998-01-01

Transfusion-associated graft-versus-host disease (TA-GVHD) is a usually complication of transfusion of blood component containing T lymphocytes what recently has also involved immunocompetent patient. Gamma irradiation of cellular blood components has been the mainstay against TA-GVHD, nevertheless there is little information in the literature about current transfusion medicine practices regarding gamma irradiation of blood products. This work presents an overview of the Brazilian reality and suggests policies to optimize TA-GVHD prevention. (Author)

Brazilian situation of blood component irradiation practice for the prevention of transfusion associated Graft-versus-Host disease

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Goes, E.G.; Borges, J.C. [EE/COPPE-UFRJ (Brazil); Covas, D.T. [Faculdade deMedicina-USP-RP (Brazil); Motta, I. [Instituto Nacional do Cancer- Rio deJaneiro (Brazil)

1998-12-31

Transfusion-associated graft-versus-host disease (TA-GVHD) is a usually complication of transfusion of blood component containing T lymphocytes what recently has also involved immunocompetent patient. Gamma irradiation of cellular blood components has been the mainstay against TA-GVHD, nevertheless there is little information in the literature about current transfusion medicine practices regarding gamma irradiation of blood products. This work presents an overview of the Brazilian reality and suggests policies to optimize TA-GVHD prevention. (Author)

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

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Baron, F; Labopin, M; Niederwieser, D

2012-01-01

This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk...... of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P...

Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity.

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Grkovic, L; Baird, K; Steinberg, S M; Williams, K M; Pulanic, D; Cowen, E W; Mitchell, S A; Hakim, F T; Martires, K J; Avila, D N; Taylor, T N; Salit, R B; Rowley, S D; Zhang, D; Fowler, D H; Bishop, M R; Gress, R E; Pavletic, S Z

2012-04-01

Chronic graft-versus-host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. In all, 189 adults with cGVHD (33% moderate and 66% severe according to National Institutes of Health (NIH) global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of four prior systemic therapies (PST) for their cGVHD. Lower albumin (P<0.0001), higher C-reactive protein (P = 0.043), higher platelets (P = 0.030) and higher number of PST (P<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (P = 0.021) and higher number of PST (P<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

SEVERE (GRADE III-IV ACUTE GRAFT VERSUS HOST DISEASE AFTER ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION

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Irena Preložnik-Zupan

2002-09-01

Full Text Available Background. Beside greater susceptibility to infections, acute graft host disease is a consequence of the activation of donor T-cells against host antigens. Most common target organs are skin, liver and intestinal mucosis.Methods. In the 6-year period between January 1995 and December 2000, 49 patients were treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT in Transplant unit, Department of Hematology, Clinical Centre Ljubljana. The standard GVHD prophylaxis regimen consisted of cyclosporine and short-course methotrexate. Severe, grade III-IV aGVHD with skin and/or gastrointestinal and/or liver involvement appeared in 16 (32% of the 49 patients.Results. Among the 16 patients with severe aGVHD, 14 had liver involvement, ten gastrointestinal and eight skin involvement. One patient had skin involvement only, the rest of them had combined involvement of two or three organ systems. Routine first-line treatment for aGVHD, given to all 16 pts with severe forms of the disease, was methylprednisolone (MP 2mg/ kg. Six patients with predominant skin involvement responded to MP. Other ten patients with mainly liver and gastrointestinal involvement needed second or even third line aGVHD treatment. These were anti-thymocyte globulin (ATG and/or monoclonal antibodies (OKT3 and/or mycophenolate mofetil (MMF and/or FK506 (tacrolimus. Seven patients died of advanced aGVHD and treatment related infection.Conclusions. Based on our experiences, we conclude that in critically ill patients with severe aGVHD, neutropenia and high risk for opportunistic infection, each day of ineffective MP therapy may have fatal consequences. Simultaneous institution of a combination of corticosteroids and a second-line drug might prove more appropriate for patients with a severe form of aGVHD.

The Role of MicroRNAs in Myeloid Cells during Graft-versus-Host Disease

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Sophia Chen

2018-01-01

Full Text Available The successful treatment of various hematologic diseases with allogeneic hematopoietic cell transplantation is often limited by the occurrence of graft-versus-host disease (GvHD. Several microRNAs (miRs have recently been shown to impact the biology of GvHD by regulating pro- as well as anti-inflammatory target genes. There is increasing evidence that a single miR can have different effects by preferentially targeting certain genes depending on the cell type that the miR is analyzed in. This review will focus on the role of miRs in myeloid cells during the development of acute and chronic GvHD and autoimmune diseases. Because miRs act on the expression of multiple target genes and may thereby influence the immune system at different functional levels, they are potentially attractive targets for the modification of allogeneic immune responses using miR mimics and inhibitors.

Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease.

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Martires, Kathryn J; Baird, Kristin; Steinberg, Seth M; Grkovic, Lana; Joe, Galen O; Williams, Kirsten M; Mitchell, Sandra A; Datiles, Manuel; Hakim, Fran T; Pavletic, Steven Z; Cowen, Edward W

2011-10-13

Chronic GVHD is one of the most severe complications of allogeneic HSCT. The sclerotic skin manifestations of cGVHD (ScGVHD) result from inflammation and fibrosis of the dermis, subcutaneous tissue, or fascia, leading to significant functional disability. Risk factors and clinical markers associated with ScGVHD remain largely unexamined. By using a single-visit, cross-sectional design, we evaluated 206 patients with cGVHD at the National Institutes of Health. Most patients manifested severe (ie, 63% National Institutes of Health score "severe"), refractory disease (median treatments = 4). ScGVHD was detected in 109 (52.9%) patients. ScGVHD was associated with greater platelet count (P < .001) and C3 (P < .001), and decreased forced vital capacity (P = .013). Total body irradiation (TBI) was associated with development of ScGVHD (P = .002). TBI administered in reduced-intensity conditioning was most strongly associated with ScGVHD (14/15 patients, P < .0001). Patients with ScGVHD had significant impairments of joint range of motion and grip strength (P < .001). Greater body surface area involvement was associated with poorer survival (P = .015). We conclude that TBI, particularly in reduced-intensity regimens, may be an important risk factor for ScGVHD. Widespread skin involvement is associated with significant functional impairment, distressing symptoms, and diminished survival. This trial is registered at http://www.clinicaltrials.gov as NCT00331968.

Graft versus host disease in the bone marrow, liver and thymus humanized mouse model.

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Matthew B Greenblatt

Full Text Available Mice bearing a "humanized" immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice. The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc(-/- delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.

Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

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Sydney X Lu

Full Text Available Allogeneic bone marrow transplantation (allo-BMT is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT activity are limited by graft-versus-host-disease (GVHD. Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1 is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models.We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT in mouse models. In vivo, Ceacam1(-/- T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi, CD62L(lo. Additionally, Ceacam1(-/- CD8 T cells had greater expression of the gut-trafficking integrin α(4β(7, though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/- recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/- mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+ lymphoma model was improved in animals receiving Ceacam1(-/- vs. control T cells.We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the

A murine model of graft-versus-host disease induced by allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Hu Jiangwei; Jin Jiangang; Ning Hongmei; Yu Liquan; Feng Kai; Chen Hu; Wang Lisha

2007-01-01

Objective: To establish the model of graft-versus-host disease (GVHD) in mice with allogeneic bone marrow transplantation. Methods: Bone marrow cells were combined with spleen cells of male donor C57BL/6 mice according to different proportions, then were transfused into female postradiation recipient BALB/c mice. General state, life span and histopathology of the recipient mice and detected chimera were observed. Results and Conclusion:The recipient mice groups which accepted above 5 x 10 6 donor spleen cells developed acute GVHD after different peroids of time. The GVHD model in mice after allo-BMT was successfully established. The transfusion of 5 x 10 6 -5 x 10 7 spleen cells may be adequate to establish the murine model of GVHD for the prevention and treatment of GVHD. The number of murine spleen cells can be chosen according to the experimental requirement. (authors)

Granzyme A Is Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease.

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Sarvari Velaga

Full Text Available In our previous work we could identify defects in human regulatory T cells (Tregs likely favoring the development of graft-versus-host disease (GvHD following allogeneic stem cell transplantation (SCT. Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

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Socié, Gérard; Schmoor, Claudia; Bethge, Wolfgang A; Ottinger, Hellmut D; Stelljes, Matthias; Zander, Axel R; Volin, Liisa; Ruutu, Tapani; Heim, Dominik A; Schwerdtfeger, Rainer; Kolbe, Karin; Mayer, Jiri; Maertens, Johan A; Linkesch, Werner; Holler, Ernst; Koza, Vladimir; Bornhäuser, Martin; Einsele, Hermann; Kolb, Hans-Jochem; Bertz, Hartmut; Egger, Matthias; Grishina, Olga; Finke, Jürgen

2011-06-09

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Graft-versus-host disease is enhanced by selective CD73 blockade in mice.

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Long Wang

Full Text Available CD73 functions as an ecto-5'-nucleotidase to produce extracellular adenosine that has anti-inflammatory and immunosuppressive activity. We here demonstrate that CD73 helps control graft-versus-host disease (GVHD in mouse models. Survival of wild-type (WT recipients of either allogeneic donor naïve CD73 knock-out (KO or WT T cells was similar suggesting that donor naïve T cell CD73 did not contribute to GVHD. By contrast, donor CD73 KO CD4(+CD25(+ regulatory T cells (Treg had significantly impaired ability to mitigate GVHD mortality compared to WT Treg, suggesting that CD73 on Treg is critical for GVHD protection. However, compared to donor CD73, recipient CD73 is more effective in limiting GVHD. Pharmacological blockade of A2A receptor exacerbated GVHD in WT recipients, but not in CD73 KO recipients, suggesting that A2 receptor signaling is primarily implicated in CD73-mediated GVHD protection. Moreover, pharmacological blockade of CD73 enzymatic activity induced stronger alloreactive T cell activity, worsened GVHD and enhanced the graft-versus-leukemia (GVL effect. These findings suggest that both donor and recipient CD73 protects against GVHD but also limits GVL effects. Thus, either enhancing or blocking CD73 activity has great potential clinical application in allogeneic bone marrow transplants.

Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/- immunodeficient mice.

NARCIS (Netherlands)

Mutis, T; Rijn, R.S. van; Simonetti, E.R.; Aarts-Riemens, T.; Emmelot, M.E.; Bloois, L. van; Martens, A.; Verdonck, L.F.; Ebeling, S.B.

2006-01-01

PURPOSE: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD.

MAGIC biomarkers predict long term outcomes for steroid-resistant acute GVHD.

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Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol; Reddy, Pavan; Ayuk, Francis; Holler, Ernst; Efebera, Yvonne A; Hogan, William J; Wölfl, Matthias; Qayed, Muna; Hexner, Elizabeth O; Wudhikarn, Kitsada; Ordemann, Rainer; Young, Rachel; Shah, Jay; Hartwell, Matthew J; Chaudhry, Mohammed; Aziz, Mina; Etra, Aaron; Yanik, Gregory A; Kröger, Nicolaus; Weber, Daniela; Chen, Yi-Bin; Nakamura, Ryotaro; Rösler, Wolf; Kitko, Carrie L; Harris, Andrew C; Pulsipher, Michael; Reshef, Ran; Kowalyk, Steven; Morales, George; Torres, Ivan; Özbek, Umut; Ferrara, James L M; Levine, John E

2018-03-15

Acute graft versus host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after one week of therapy often guides further treatment decisions, but long term outcomes vary widely between centers and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken after one week of systemic treatment for GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into test (n=236) and two validation cohorts separated in time (n = 142 and 129, respectively). Initial response to systemic steroids correlated with response at four weeks, one-year non-relapse mortality (NRM) and overall survival (OS). A previously validated algorithm of two MAGIC biomarkers (ST2 and REG3α) consistently separated steroid resistant patients into two groups with dramatically different NRM and OS (p<0.001 for all three cohorts). High biomarker probability, resistance to steroids and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating curves showed the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, p=0.004) and for Minnesota risk (0.72, p=0.005). In conclusion, MAGIC biomarker probabilities generated after one week of systemic treatment for GVHD predict long term outcomes in steroid resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies. Copyright © 2018 American Society of Hematology.

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

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Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

2015-01-15

The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. © 2015 by The American Society of Hematology.

Syngeneic graft-versus-host disease: a report of two cases and literature review.

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Latif, T; Pohlman, B; Kalaycio, M; Sobecks, R; Hsi, E D; Andresen, S; Bolwell, B J

2003-09-01

Rappeport et al first reported the clinical syndrome of graft-versus-host disease (GVHD) in syngeneic bone marrow transplant patients. Recently, there have been more reports of a GVHD-like syndrome in syngeneic bone marrow transplant patients (SGVHD) that may result in significant clinical morbidity. A total of 17 cases of SGVHD in syngeneic bone marrow transplant patients have been reported to date in the medical literature. The current report reviews these cases and presents two additional cases of severe SGVHD that have occurred at our institution.

International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium

Science.gov (United States)

Harris, Andrew C.; Young, Rachel; Devine, Steven; Hogan, William J.; Ayuk, Francis; Bunworasate, Udomsak; Chanswangphuwana, Chantiya; Efebera, Yvonne A.; Holler, Ernst; Litzow, Mark; Ordemann, Rainer; Qayed, Muna; Renteria, Anne S.; Reshef, Ran; Wölfl, Matthias; Chen, Yi-Bin; Goldstein, Steven; Jagasia, Madan; Locatelli, Franco; Mielke, Stephan; Porter, David; Schechter, Tal; Shekhovtsova, Zhanna; Ferrara, James L.M.; Levine, John E.

2015-01-01

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed upon by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance was following discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture which may improve the reproducibility of GVHD clinical trials after further prospective validation. PMID:26386318

Ocular graft versus host disease in allogenic haematopoetic stem cell transplantation in a tertiary care centre in India

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Rehan Khan

2015-01-01

Full Text Available Background & objectives: This study was aimed to report the occurrence of ocular graft versus host disease (oGVHD in allogeneic haematopoietic stem cell transplantation (allo-HSCT patients in a tertiary care hospital setting. Methods: A cross-sectional study of ocular surface of allo-HSCT patients was done. Slit lamp biomicroscopy, symptom score, tear meniscus height, fluorescein tear break-up time, Schirmer′s test I, ocular surface staining, dry eye severity, ocular surface disease index score were done. Indications for allo-HSCT, human leukocyte antigen (HLA matching, GVHD risk factor, systemic manifestation and treatment were also noted. Results: GVHD occurred in 44.4 per cent of 54 allo-HSCT patients (mean age 26.7 ± 12 yr included in the study. GVHD risk factors identified included female gender, relapse, older age of donor, cytomagelo virus (CMV reactivation, and multiparous female donors. oGVHD was noted in 31.5 per cent with mean time to occurrence being 17.8 ± 21.9 months after the allo-HSCT and was observed in 89.5 per cent of chronic GVHD cases. Acute GVHD (oral and dermatological involvement showed a significant association with GVHD in our patients (P< 0.001, 0R 23.0, CI 6.4-82.1. Chronic GVHD was observed to be associated with the occurrence of oGVHD (dry eye (P<0.001, OR = 24.0, CI 0.02 - 0.29. Of the 34 eyes with oGHVD, dry eye of level 3 severity was seen in 16, level 2 in six, level 1 in 12 eyes. Interpretation & conclusions: GVHD occurred in 44.4 per cent of the patients studied in the present study. Acute and chronic GVHD showed a strong association with oGVHD. Dry eye disease due to chronic oGVHD was observed in 17 (31.5% of 54 allo-HSCT patient with chronic oGVHD occurring in 17 (89.4% of chronic GVHD cases in allo-HSCT patients. Our study on oGVHD in post allo-HSCT patients in tertiary care centre points towards the fact that ocular morbidity due to dry eye disease as a result of oGVHD is a cause for concern in these

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report

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Enrico Maffini

2016-08-01

Full Text Available Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD remains a life-threatening complication. Standard treatment is high-dose (HD corticosteroids. Steroid-refractory (SR GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. Case presentation A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34+ cells/kg infused were 8.69 × 106 kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. Conclusions At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

[Mesenchymal stromal cells in the treatment of graft-versus-host disease: where do we stand?].

Science.gov (United States)

Schüle, Silke; Berger, André

2015-11-01

Medicinal products based on mesenchymal stromal cells (MSC) are expected to have a therapeutic benefit in a variety of conditions and, accordingly, are being tested in many clinical studies. The treatment and prevention of graft-versus-host disease (GVHD) is one of the world's most widely studied MSC therapy concepts. So far, one MSC medicinal product has been approved for the treatment of GvHD. This article gives an overview of the particular features related to the production of MSC-based medicinal products, the state of non-clinical research, and the clinical development status of MSCs and the associated challenges, especially in the context of GvHD.

Steroid treatment of acute graft-versus-host disease grade I: a randomized trial.

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Bacigalupo, Andrea; Milone, Giuseppe; Cupri, Alessandra; Severino, Antonio; Fagioli, Franca; Berger, Massimo; Santarone, Stella; Chiusolo, Patrizia; Sica, Simona; Mammoliti, Sonia; Sorasio, Roberto; Massi, Daniela; Van Lint, Maria Teresa; Raiola, Anna Maria; Gualandi, Francesca; Selleri, Carmine; Sormani, Maria Pia; Signori, Alessio; Risitano, Antonio; Bonifazi, Francesca

2017-12-01

Patients with acute graft- versus -host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II-IV GvHD. The cumulative incidence of grade II-IV GvHD was 50% in the observation arm and 33% in the treatment arm ( P =0.005). However, grade III-IV GvHD was comparable (13% vs 10%, respectively; P =0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17% vs 9%). In multivariate analysis, an early interval between transplant and randomization (GvHD. Patients in the observation arm had less infectious bacterial episodes (12 vs 25; P =0.04), less severe infectious fungal episodes (0 vs 3; P =0.04), and less severe adverse events (3 vs 11; P =0.07). At five years, non-relapse mortality was 20% versus 26% ( P =0.2), relapse-related mortality 25% versus 21%, and actuarial survival was 51% versus 41% ( P =0.3) in the observation and treatment arms, respectively. In multivariate analysis, advanced disease phase, older age and an early onset of GvHD were significant negative predictors of survival, independent of the randomization arm. In conclusion, steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III-IV GvHD, and there is no effect on non-relapse mortality and survival. Patients treated with steroids are at a higher risk of developing infections and have more adverse events. ( Trial registered as EUDTRACT 2008-000413-29 ). Copyright© 2017 Ferrata Storti Foundation.

Reduction of fatal graft-versus-host disease by 3H--thymidine suicide of donor cells cultured with host cells

International Nuclear Information System (INIS)

Cheever, M.A.; Einstein, A.B. Jr.; Kempf, R.A.; Fefer, A.

1977-01-01

The effect of the tritiated thymidine ( 3 H-TdR) suicide technique on the ability of donor cells to induce fatal graft-versus-host disease (GVHD) was studied. C57BL/6 (H-2/sup b/) spleen cells were stimulated in vitro with irradiated BALB/c (H-2/sup d/) Moloney lymphoma cells in mixed culture and 3 H-TdR of high-specific activity added to eliminate proliferating cells. The ability of such cells to induce fatal GVHD was assayed by injecting them i.v. into adult BALB/c mice immunosuppressed with cyclophosphamide (180 mg/kg). These cells induced fatal GVHD in fewer mice (52 percent) than did C57BL/6 cells cultured with BALB/c lymphoma cells but without 3 H-TdR (87 percent) and C57BL/6 cells cultured with irradiated C57BL/6 cells with (95 percent) or without 3 H-TdR (86 percent). Thus, the 3 H-TdR suicide technique greatly diminished the ability of cells to induce lethal GVHD

Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

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Balan, A; Lucchini, G; Schmidt, S; Schneider, A; Tramsen, L; Kuçi, S; Meisel, R; Bader, P; Lehrnbecher, T

2014-10-01

Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.

OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model.

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Zhi, Xiao; Xue, Fei; Chen, Wei; Liang, Chao; Liu, Hao; Ma, Tao; Xia, Xuefeng; Hu, Liqiang; Bai, Xueli; Liang, Tingbo

2017-09-01

Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4 + CD25 - T cells into CD4 + CD25 + forkhead box P3 + Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4 + CD25 + T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

Viral infections in acute graft-versus-host disease: a review of diagnostic and therapeutic approaches.

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Tong, Lana X; Worswick, Scott D

2015-04-01

While immunosuppressive therapy for acute graft-versus-host disease (aGVHD) advances, viral reactivation has been found to be an increasingly common complication in these patients. Dermatologists may often be consulted on inpatient services for evaluation. We investigated the literature for the role of viral infections in aGVHD and review the current evidence regarding management. Articles in the public domain regarding aGVHD, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, hepatitis viruses, parvovirus B19, and respiratory viruses were included. Dermatologic findings vary between different viral antigens, and some infections may be a marker for the development of aGVHD or worsen prognosis. The heterogeneous cohorts of the studies reviewed often preclude direct comparison between results. The relationship between viral reactivation and aGVHD may be bidirectional and is worthy of further exploration. Additional studies are needed to determine appropriate prophylaxis and treatment. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: Successful engraftment and mild GVHD

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Wu Yamei

2014-01-01

Full Text Available Haploidentical hematopoietic stem-cell transplantation (haplo-HSCT is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD. Mesenchymal stromal cells (MSCs have been shown to support in vivo normal hematopoiesis and to display potent immunesuppressive effects. We cotransplanted the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs in 21 young people with severe aplastic anemia (SAA undergoing haplo-HSCT without T-cell-depleted. We observed that all patients had sustained hematopoietic engraftment without any adverse UC-MSC infusion-related events. Furthermore, we did not observe any increase in severe aGVHD. These data suggest that UC-MSCs, possibly thanks to their potent immunosuppressive effect on allo-reactive host T lymphocytes escaping the preparative regimen, reduce the risk of graft failure and severe GVHD in haplo-HSCT.

[Ocular graft-versus-host disease: An often misdiagnosed etiology of dry eye syndrome].

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Moyal, L; Adam, R; Akesbi, J; Rodallec, F T; Nordmann, J-P

2017-02-01

To report a case of severe ocular graft-versus-host disease (GVHD) after cataract surgery. Observational case report. We describe the case of a 59-year-old man with postoperative corneal ulcer on his only functional eye. His past history reported allogenic bone marrow transplant. His visual acuity (VA) was limited to hand motions. Slit lamp examination revealed diffuse conjunctival hyperemia, severe blepharitis, Meibomian dysfunction, total corneal opacification with epithelial and stromal keratitis and neovascular invasion. Because of the severe dry eye symptoms and history of allogenic hematological stem cell transplantation, ocular GVHD was diagnosed. Functional and anatomical improvement occurred rapidly with topical cyclosporine 2%, with improved VA after treatment. With any severe dry eye syndrome in the context of allogenic bone marrow transplant, ocular GVHD must be considered. For planned ocular surgery, we recommend adding cyclosporine 0.1% treatment before and after surgery to prevent severe ocular GVHD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Critical Appraisal of Extracorporeal Photopheresis as a Treatment Modality for Acute and Chronic Graft-Versus-Host Disease

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Hind Rafei

2017-10-01

Full Text Available Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT due to high risk of disabling morbidity and mortality. Extracorporeal photopheresis (ECP has promising effects in controlling steroid-refractory GVHD, both acute and chronic, and it has been studied extensively. Its putative immunomodulatory mechanisms, while not immunosuppressive, position ECP as an attractive treatment strategy for GVHD patients who are already receiving global immunosuppression. However, ECP is relatively underutilized due in part to limited access and time commitment. Here, we review the recent findings on the ECP efficacy in both acute and chronic GVHD, primarily for steroid-refractory status, and we critically appraise its benefits. We also explore salient considerations on the optimal use of ECP in the treatment of refractory GVHD.

Preventing transfusion-associated graft-versus-host disease: state of the art

Directory of Open Access Journals (Sweden)

Fast LD

2015-01-01

Full Text Available Loren D Fast Division of Hematology/Oncology, Rhode Island Hospital and Warren Alpert School of Medicine at Brown University, Providence, RI, USA Abstract: The transfer of pathogens and the induction of immune responses are deleterious consequences that can result from the transfusion of blood products. Transfusion-associated graft-versus-host disease (TA-GVHD, the most severe immune consequence, occurs when recipient immune responses are incapable of effectively eliminating donor leukocytes, permitting unabated responses of the donor T lymphocytes. Currently, prevention of TA-GVHD is routinely accomplished by exposing blood products to γ-irradiation in order to prevent donor T cell proliferation. Alternative protocols are being developed to meet the challenges associated with the use of γ-irradiation. Use of pathogen reduction protocols, which interfere with nucleic acid replication by modifying nucleic acids, are increasing. Comparison of pathogen reduction protocols with γ-irradiation have found that both protocols are equally effective in preventing T lymphocyte proliferation and GVHD responses when testing in both in vitro and in vivo models. The potential use of pathogen reduction protocols to treat whole blood prior to separation into its components could provide a cost-effective method for preventing TA-GVHD in the future. Keywords: blood transfusion, GVHD, pathogen reduction, irradiation

The Role of B Cell Targeting in Chronic Graft-Versus-Host Disease

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Ruben Rhoades

2017-10-01

Full Text Available Chronic graft-versus-host disease (cGVHD is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously felt to be a T cell disease has more recently been shown to involve activation of both T and B cells, as well as a number of cytokines. With a better understanding of its pathophysiology have come more expansive preclinical and clinical trials, many focused on B cell signaling. This report briefly reviews our current understanding of cGVHD pathophysiology and reviews clinical and preclinical trials with B cell-targeted agents.

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT.

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Choi, Sung Won; Braun, Thomas; Henig, Israel; Gatza, Erin; Magenau, John; Parkin, Brian; Pawarode, Attaphol; Riwes, Mary; Yanik, Greg; Dinarello, Charles A; Reddy, Pavan

2017-10-12

The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 ( P = .028) and GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568. © 2017 by The American Society of Hematology.

Induction of a glucocorticoid-sensitive F1-anti-parental mechanism that affects engraftment during graft-versus-host disease.

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You-Ten, K E; Seemayer, T A; Wisse, B; Bertley, F M; Lapp, W S

1995-07-01

Studies have shown that graft-vs-host disease (GVHD) in animal models induces persistent elevated levels of circulating adrenal glucocorticoids. In this report, we investigated the effects of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing (ADX) unirradiated (C57BL/6 x A)F1 (B6AF1) mice before GVHD induction. GVHD was induced by injection of 20 x 10(6) A strain parental lymphoid cells into B6AF1 mice. Our results demonstrated that non-ADX recipient mice experienced features characteristic of GVHD on day 13, which became progressively more severe by days 18 to 21. The GVHD features included severe immunosuppression, reversal in the host splenic CD4+/CD8+ ratio, histopathologic lesions in different tissues, and high parental cell chimerism in the spleens and lymph nodes. In contrast, ADX F1 recipient mice experienced GVHD features on day 13 similar to their non-ADX counterparts; however, ADX animals recovered rapidly from GVHD by days 18 to 21. Flow cytometry showed that, although a relatively high frequency of parental cells was detected in the spleens and lymph nodes of ADX mice on day 13, nearly all of the parental cells in the peripheral lymphoid organs disappeared on days 18 to 21, the time of recovery from GVHD. The marked reduction of parental cells and recovery from GVHD were prevented by treating ADX F1 mice with either exogenous glucocorticoid, anti-asialoGM1, or anti-CD8, but not anti-NK1.1 Ab. These results suggest that a dramatic recovery from GVHD was induced by a cell-mediated, steroid-sensitive F1-anti-parental mechanism. The F1-anti-parental phenomenon described herein is different from classical hybrid resistance.

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.

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Miklos, David; Cutler, Corey S; Arora, Mukta; Waller, Edmund K; Jagasia, Madan; Pusic, Iskra; Flowers, Mary E; Logan, Aaron C; Nakamura, Ryotaro; Blazar, Bruce R; Li, Yunfeng; Chang, Stephen; Lal, Indu; Dubovsky, Jason; James, Danelle F; Styles, Lori; Jaglowski, Samantha

2017-11-23

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. © 2017 by The American Society of Hematology.

[Detection of NK and NKT cells in peripheral blood of patients with cGVHD and its significance].

Science.gov (United States)

Zhou, Mao-Hua; Wang, Chun-Miao; Gong, Cai-Ping; Luo, Yin; Zhang, Min

2012-10-01

The aim of this study was to investigate the correlation of NK and NKT cells in peripheral blood of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) with chronic graft-versus-host disease (cGVHD). 64 patients undergoing allo-HSCT in Guangdong Provincial People Hospital were studied retrospectively. Among 64 cases, 21 cases were did not develop with cGVHD, 43 cases (mild 15, moderate 18, severe 10) were recorded with cGVHD. The frequency of NK and NKT cells in peripheral blood of patients were measured by flow cytometry. The counts of NK and NKT cells were measured by automatic five sort hematology cyto-analyser (LH-750). The frequency and counts of NK and NKT cells between patients with non-cGVHD and patients with different status of cGVHD were analysed. The results indicated that as compared with the non-cGVHD patients, the frequency and counts of NK cells in patients with cGVHD obviously reduced (P NKT cells were did not changed significantly. The frequency and counts of NK cells gradually decreased within the different status of cGVHD, the frequency and counts of NK cells in severe-cGVHD were significantly lower than that in mild-cGVHD. It is concluded that NK cells may play an important role in the incidence and development of cGVHD. The detection of frequency and counts of NK cells should be helpful to early diagnose cGVHD and provide valuable clues for assessing the severity of illnesses. NKT cells may have little effect on the incidence and development of cGVHD.

Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial

NARCIS (Netherlands)

Choi, S.W.; Braun, T.; Chang, L.; Ferrara, J.L.; Pawarode, A.; Magenau, J.M.; Hou, G.; Beumer, J.H.; Levine, J.E.; Goldstein, S.; Couriel, D.R.; Stockerl-Goldstein, K.; Krijanovski, O.I.; Kitko, C.; Yanik, G.A.; Lehmann, M.H.; Tawara, I.; Sun, Y; Paczesny, S.; Mapara, M.Y.; Dinarello, C.A.; Dipersio, J.F.; Reddy, P.

2014-01-01

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and

Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

OpenAIRE

Scroggins, Sabrina M.; Olivier, Alicia K.; Meyerholz, David K.; Schlueter, Annette J.

2013-01-01

Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate thi...

IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects.

Science.gov (United States)

Liu, Y; Wu, Y; Wang, Y; Cai, Y; Hu, B; Bao, G; Fang, H; Zhao, L; Ma, S; Cheng, Q; Song, Y; Liu, Y; Zhu, Z; Chang, H; Yu, X; Sun, A; Zhang, Y; Vignali, D A A; Wu, D; Liu, H

2015-04-01

IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4(+) effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4(+)Foxp3(+) Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4(+) T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.

Science.gov (United States)

Holtan, Shernan G; Khera, Nandita; Levine, John E; Chai, Xiaoyu; Storer, Barry; Liu, Hien D; Inamoto, Yoshihiro; Chen, George L; Mayer, Sebastian; Arora, Mukta; Palmer, Jeanne; Flowers, Mary E D; Cutler, Corey S; Lukez, Alexander; Arai, Sally; Lazaryan, Aleksandr; Newell, Laura F; Krupski, Christa; Jagasia, Madan H; Pusic, Iskra; Wood, William; Renteria, Anne S; Yanik, Gregory; Hogan, William J; Hexner, Elizabeth; Ayuk, Francis; Holler, Ernst; Watanaboonyongcharoen, Phandee; Efebera, Yvonne A; Ferrara, James L M; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel; Lee, Stephanie J; Pidala, Joseph

2016-11-10

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD. © 2016 by The American Society of Hematology.

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

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Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S; D'Souza, Aloma; Nishikii, Hidekazu; Chuang, Hui-Yen; Ilovich, Ohad; Lin, Chih-Feng; Reeves, Robert; Shuhendler, Adam; Hoehne, Aileen; Chan, Carmel T; Baker, Jeanette; Yaghoubi, Shahriar S; VanBrocklin, Henry F; Hawkins, Randall; Franc, Benjamin L; Jivan, Salma; Slater, James B; Verdin, Emily F; Gao, Kenneth T; Benjamin, Jonathan; Negrin, Robert; Gambhir, Sanjiv Sam

2017-06-01

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR . ©2017 American Association for Cancer Research.

Mechanism of low GVHD incidence in umbilical cord blood transplantation

International Nuclear Information System (INIS)

Zhang Zhanying; Zhu Xuezhen; Zhang Lansheng; Zhu Shoupeng

2000-01-01

Objective: To compare the immunological function between umbilical cord blood (UCB) and peripheral blood, and to explore the mechanism of low incidence of graft-versus host disease (GVHD) in UCB transplantation. Methods: The proliferation assay, NK cell killing activity assay and immunologic fluorescence double label technique were used to study four sear effect on T cell immunologic function. Results: UCB serum could reduce K 562 cell activity, compared to that of adult serum. Furthermore, adult serum will enhanced the percentage of HLA-DR expression of T cells on PHA-stimulated PBMC, whereas fetal serum has no such effect. Both adult and fetal serum enhanced mitogen-specific T cell proliferation, the peak proliferative response could be reached with adult serum but not with fetal serum. Conclusion: There must be some soluble factors secreted into serum, which play a role in T cell activation and associate with the incidence of GVHD

Endoscopic and Histological Findings Are Predicted by Fecal Calprotectin in Acute Intestinal Graft-Versus-Host-Disease.

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Adam, Birgit; Koldehoff, Michael; Ditschkowski, Markus; Gromke, Tanja; Hlinka, Michal; Trenschel, Rudolf; Kordeals, Lambros; Steckel, Nina K; Beelen, Dietrich W; Liebregts, Tobias

2016-07-01

Gastrointestinal graft-versus-host-disease (GI-GVHD) is a major cause of nonrelapse mortality after hematopoietic stem cell transplantation (HSCT) necessitating endoscopic examinations and biopsies for diagnosis. Fecal calprotectin (CPT) has been widely used in gastrointestinal inflammation, but comprehensive data in GI-GVHD are lacking. We aimed to identify an association of CPT with endoscopic findings, mucosal damage and symptoms for diagnosing and monitoring acute GI-GVHD. Symptoms were prospectively evaluated in 110 consecutive HSCT recipients by standardized questionnaires and Bristol Stool Scale (BSS). CPT was assayed by ELISA. Symptom assessment and CPT were performed weekly and with onset of first symptoms. GVHD was diagnosed according to the Glucksberg criteria and by endoscopic biopsies. Patients with GI-GVHD received standard high-dose corticosteroid therapy and follow-up CPT, and symptom evaluation was performed after 28 days. Patients not responding to steroid treatment were re-evaluated by colonoscopy. GI-GVHD was diagnosed in 40 patients. Twelve patients with GI symptoms and CMV colitis and 24 patients with isolated skin GVHD were included as control subjects. CPT was significantly higher in GI-GVHD compared to skin GVHD and CMV colitis. Endoscopic findings, histological grading, abdominal cramps, diarrhea, urgency and BSS correlated with CPT. At follow-up, CPT correlated with abdominal cramps, diarrhea, urgency and BSS. In steroid refractory patients, CPT level was still significantly associated with severity of mucosal damage. CPT predicts endoscopic and histological findings in GI-GVHD and correlates with lower GI symptoms. It enables to discriminate GVHD from CMV colitis and to monitor therapeutic success.

Emerging technologies for oral diagnostics: lessons from chronic graft-versus-host disease

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Mays, Jacqueline W.; Ambatipudi, Kiran S.; Bassim, Carol W.; Melvin, James E.

2013-05-01

Saliva is a protein-rich oral fluid that contains information about systemic and oral-specific disease pathogenesis and diagnosis. Technologies are emerging to improve detection of protein components of human saliva for use not only in biomarker discovery, but also for the illumination of pathways involved in oral disease. These include the optimization of liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) analysis of saliva in health and disease. Downstream of saliva component identification and validation comes the complex task of connecting salivary proteomic data to biological function, disease state, and other clinical patient information in a meaningful way. Augmentation of database information with biological expertise is crucial for effective analysis of potential biomarkers and disease pathways in order to improve diagnosis and identify putative therapeutic targets. This presentation will use LC-MS/MS analysis of saliva from chronic Graft-versus-Host disease (cGVHD) patients to illustrate these principles, and includes a discussion of the complex clinical and diagnostic issues related to proteomics and biomarker research in cGVHD.

Wireless capsule endoscopy for diagnosis of acute intestinal graft-versus-host disease.

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Neumann, Susanne; Schoppmeyer, Konrad; Lange, Thoralf; Wiedmann, Marcus; Golsong, Johannes; Tannapfel, Andrea; Mossner, Joachim; Niederwieser, Dietger; Caca, Karel

2007-03-01

The small intestine is the most common location of intestinal graft-versus-host disease (GVHD). EGD with duodenal biopsies yields the highest diagnostic sensitivity, but the jejunum and ileum are not accessible by regular endoscopy. In contrast, wireless capsule endoscopy (WCE) is a noninvasive imaging procedure offering complete evaluation of the small intestine. The objective was to compare the diagnostic value of EGD, including biopsies, with the results of WCE in patients with acute intestinal symptoms who received allogeneic blood stem cell transplantation and to analyze the appearance and distribution of acute intestinal GVHD lesions in these patients. An investigator-blinded, single-center prospective study. Patients with acute intestinal symptoms after allogeneic stem cell transplantation underwent both EGD and WCE within 24 hours. Clinical data were recorded during 2 months of follow-up. Fourteen consecutive patients with clinical symptoms of acute intestinal GVHD were recruited. In 1 patient, the capsule remained in the stomach and was removed endoscopically. In 7 of 13 patients who could be evaluated, acute intestinal GVHD was diagnosed by EGD with biopsies, but 3 of these would have been missed by EGD alone. In all 7 patients with histologically confirmed acute intestinal GVHD, WCE revealed typical signs of GVHD. Lesions were scattered throughout the small intestine, but were most accentuated in the ileum. This study had a small number of patients. WCE, which is less invasive than EGD with biopsies, showed a comparable sensitivity and a high negative predictive value for diagnosing acute intestinal GVHD. It may be helpful to avoid repeated endoscopic procedures in patients who have undergone stem cell transplantation.

alpha-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

NARCIS (Netherlands)

Marcondes, A.M.; Karoopongse, E.; Lesnikova, M.; Margineantu, D.; Welte, T.; Dinarello, C.A.; Hockenbery, D.; Janciauskiene, S.; Deeg, H.J.

2014-01-01

Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma alpha-1-antitrypsin (AAT) levels in human donors and the

Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?

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Morris, Edward S; MacDonald, Kelli P A; Hill, Geoffrey R

2006-05-01

The separation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains the "holy grail" of allogeneic stem cell transplantation, and improvements are urgently needed to allow more effective therapy of malignant disease. The use of G-CSF-mobilized peripheral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demonstrated that G-CSF modulates donor T cell function before transplantation, promoting T(H)2 differentiation and regulatory T cell function. In addition, the expansion of immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (DCs) favors the maintenance of this pattern of T cell differentiation after transplantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cytolytic pathways of the CD8(+) T cells that are critical for effective GVL. Recently, it has been demonstrated that modification of G-CSF, either by pegylation of the native cytokine or conjugation to Flt-3L, results in the expansion and activation of donor iNKT cells, which significantly augment CD8(+) T cell-mediated cytotoxicity and GVL effects after transplantation. Given that these cytokines also enhance the expansion of regulatory T cells and APCs, they further separate GVHD and GVL, offering potential clinical advantages for the transplant recipient.

Effective and less invasive diagnostic strategy for gastrointestinal GVHD

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Endo, Katsuya; Fujishima, Fumiyoshi; Kuroha, Masatake; Moroi, Rintaro; Onodera, Motoyuki; Naito, Takeo; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Shimosegawa, Tooru

2018-01-01

Background and study aims  Rectosigmoidoscopy with biopsy has been regarded to be a useful procedure to diagnose gastrointestinal graft-versus-host disease (GVHD). However, little is known about the specific colonoscopic features of gastrointestinal GVHD. In this study, we focused on the 4 unique colonoscopic findings – orange peel appearance, spotty redness, small mucosal sloughing, and diffuse mucosal defect – which are possible specific findings of gastrointestinal GVHD. We aimed to estimate the usefulness of these four unique colonoscopic findings in the rectosigmoid portion to diagnose gastrointestinal GVHD. Patients and methods  Seventy patients who were histologically diagnosed with gastrointestinal GVHD at our institute were retrospectively enrolled. Colonoscopic findings were reviewed, focusing on the four characteristic findings. The percentage of the positive cases for the characteristic findings was calculated. The final scoping portion and the number of cases showing any of the four characteristic findings in the rectosigmoid portion were also evaluated. The relationships between biopsy sites and the histological findings were also evaluated. Results  Orange peel appearance was observed in 66 cases (94.3 %). Spotty redness was observed in 45 cases (64.3 %). Small mucosal sloughing was observed in 49 cases (70.0 %). Diffuse mucosal defect was observed in six cases (8.6 %). The number of cases that were concurrently positive for one, two, and three findings were 16 (20.8 %), 20 (26.0 %), and 34 (48.6 %), respectively. Fifty-eight cases (82.9 %) were investigated up to the rectosigmoid portion, and 12 (17.1 %) were investigated beyond the sigmoid colon. All of the cases showed at least 1 of the 4 characteristics in the rectosigmoid portion. The percentage of crypt apoptosis in the biopsy specimen from orange peel appearance, spotty redness, small mucosal sloughing, and diffuse mucosal defect were 87.5 %, 83.3 %, 87.2�

Vitamin D levels and their associations with survival and major disease outcomes in a large cohort of patients with chronic graft-vs-host disease

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Katić, Mašenjka; Pirsl, Filip; Steinberg, Seth M.; Dobbin, Marnie; Curtis, Lauren M.; Pulanić, Dražen; Desnica, Lana; Titarenko, Irina; Pavletic, Steven Z.

2016-01-01

Aim To identify the factors associated with vitamin D status in patients with chronic graft-vs-host disease (cGVHD) and evaluate the association between serum vitamin D (25(OH)D) levels and cGVHD characteristics and clinical outcomes defined by the National Institutes of Health (NIH) criteria. Methods 310 cGVHD patients enrolled in the NIH cGVHD natural history study (clinicaltrials.gov: NCT00092235) were analyzed. Univariate analysis and multiple logistic regression were used to determine the associations between various parameters and 25(OH)D levels, dichotomized into categorical variables: ≤20 and >20 ng/mL, and as a continuous parameter. Multiple logistic regression was used to develop a predictive model for low vitamin D. Survival analysis and association between cGVHD outcomes and 25(OH)D as a continuous as well as categorical variable: ≤20 and >20 ng/mL; <50 and ≥50 ng/mL, and among three ordered categories: ≤20, 20-50, and ≥50 ng/mL, was performed. PMID:27374829

Ocular manifestations of graft-versus-host disease: 10 years’ experience

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Lin X

2015-07-01

Full Text Available Xihui Lin, Harrison Dwight Cavanagh Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA Purpose: To evaluate the ocular presentation, treatment, and clinical course of graft-versus-host disease (GVHD. Design: Retrospective case series. Participants: Two hundred and forty-nine patients with systemic GVHD were included in the study. Methods: Ocular and systemic data were collected from 2003 to 2013. Main outcome measures: Mortality, visual acuity, and response of ocular symptoms. Results: Sixty-four patients had ocular manifestations (25.7%. At presentation, the mean age was 44.5 years and mean latency was 16.4 months. The most common presentations were keratoconjunctivitis sicca, cataract, blepharitis, ocular hypertension, and filamentary keratitis. Visual acuity at presentation was 20/49; at the worst point in the disease was 20/115; and at most recent visit was 20/63. When topical anti-inflammatory drops were used in addition to tears, 54.3% of patients’ ocular symptoms stabilized. When autologous serum was used in addition, 80% stabilized. The overall 10-year mortality of GVHD was 29.7%. For those with ocular involvement, it was 21.9%. Conclusion: Systemic GVHD has a high mortality rate, but ocular involvement does not suggest a worse prognosis. The main ocular presentations were keratoconjunctivitis sicca, cataracts, and ocular hypertension. Dry eyes in this population were very severe with overall worsening in visual acuity. However, with a step-wise approach involving topical anti-inflammatory medications and autologous serum tears, ocular symptoms do improve. It is important to monitor these patients closely, as they are prone to serious ocular complications such as corneal perforation and endophthalmitis. Keywords: dry eye, keratitis, corneal ulceration

Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease.

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Hedrich, Christian Michael; Fiebig, Barbara; Hahn, Gabriele; Suttorp, Meinolf; Gahr, Manfred

2011-07-01

Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature.

Segmentation of skin lesions in chronic graft versus host disease photographs with fully convolutional networks

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Wang, Jianing; Chen, Fuyao; Dellalana, Laura E.; Jagasia, Madan H.; Tkaczyk, Eric R.; Dawant, Benoit M.

2018-02-01

Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT) and commonly affects the skin, resulting in distressing patient morbidity. The percentage of involved body surface area (BSA) is commonly used for diagnosing and scoring the severity of cGVHD. However, the segmentation of the involved BSA from patient whole body serial photography is challenging because (1) it is difficult to design traditional segmentation method that rely on hand crafted features as the appearance of cGVHD lesions can be drastically different from patient to patient; (2) to the best of our knowledge, currently there is no publicavailable labelled image set of cGVHD skin for training deep networks to segment the involved BSA. In this preliminary study we create a small labelled image set of skin cGVHD, and we explore the possibility to use a fully convolutional neural network (FCN) to segment the skin lesion in the images. We use a commercial stereoscopic Vectra H1 camera (Canfield Scientific) to acquire 400 3D photographs of 17 cGVHD patients aged between 22 and 72. A rotational data augmentation process is then applied, which rotates the 3D photos through 10 predefined angles, producing one 2D projection image at each position. This results in 4000 2D images that constitute our cGVHD image set. A FCN model is trained and tested using our images. We show that our method achieves encouraging results for segmenting cGVHD skin lesion in photographic images.

Utility of Endoscopic Examination in the Diagnosis of Acute Graft-versus-Host Disease in the Lower Gastrointestinal Tract

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Kosuke Nomura

2017-01-01

Full Text Available Background and Aims. We retrospectively investigated the incidence of acute graft-versus-host disease (GVHD in the lower gastrointestinal (GI tract and the diagnostic accuracy of endoscopy. Methods. Of 1231 patients who underwent allogeneic hematopoietic stem cell transplantation between January 2005 and December 2014, 186 of whom underwent colonoscopy and biopsy and had no cytomegalovirus infection. The endoscopic findings and histologic diagnosis from these 186 patients were retrospectively analyzed. Results. Based on the histopathological findings, 171 patients were diagnosed with GVHD, accounting for 13.9% of all transplant recipients. Useful endoscopic findings for the diagnosis of GVHD were atrophy of the ileocecal valve and villous atrophy in the terminal ileum and tortoise shell-like mucosae, edema, and low vascular permeability in the colon. Even when no mucosal abnormality was observed, the incidence of GVHD was 78.9% in the terminal ileum and 75.0% in the colon. Furthermore, patients with mucosal exfoliation, although infrequent, were all diagnosed with grade 3/4 GVHD. Conclusions. It is important to perform endoscopy proactively for the early diagnosis of GVHD, and biopsy should be performed even when no abnormality is observed. In addition, because patients with mucosal exfoliation are extremely likely to have grade 3/4 GVHD, early treatment should be initiated.

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.

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Hartwell, Matthew J; Özbek, Umut; Holler, Ernst; Renteria, Anne S; Major-Monfried, Hannah; Reddy, Pavan; Aziz, Mina; Hogan, William J; Ayuk, Francis; Efebera, Yvonne A; Hexner, Elizabeth O; Bunworasate, Udomsak; Qayed, Muna; Ordemann, Rainer; Wölfl, Matthias; Mielke, Stephan; Pawarode, Attaphol; Chen, Yi-Bin; Devine, Steven; Harris, Andrew C; Jagasia, Madan; Kitko, Carrie L; Litzow, Mark R; Kröger, Nicolaus; Locatelli, Franco; Morales, George; Nakamura, Ryotaro; Reshef, Ran; Rösler, Wolf; Weber, Daniela; Wudhikarn, Kitsada; Yanik, Gregory A; Levine, John E; Ferrara, James L M

2017-02-09

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( n = 309) and validation set ( n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

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Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Cyclosporin-Methotrexate Compared with Cyclosporin-Methotrexate-Methylprednisolone Therapy for the Prophylaxis of Acute Graft-Versus Host Disease

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Khattab, N.F.

2010-01-01

Acute graft-versus host (GVHD) disease is a common immunologic complication, which occurs in 40-50% of the recipients of allogenic stem cell transplantation (SCT). The role of corticosteroid in the prevention of GVHD is not well established. We report here a study to determine whether the addition of methylprednisolone to the combination of cyclosporine (CSA) and methotrexate (MTX), methylp-rednisolone (MP) for the prophylaxis of acute GVHD would further decrease the incidence of acute GVHD. A group of patients (25 patients with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received CSA/MTX/MP started from 2004 to 2008, were compared to a historical group of patients (19 patient with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received GVHD prophylaxis in the form of CSA/MTX only from 1999 to 2003). The primary endpoint in this study was the develop-ment of GVHD and the secondary end point was overall and disease free survival. Both groups of patients were matched for age, sex, donor recipient sex, low risk patients and high risk patients. Although the incidence of acute GVHD in the MP -ve group was 35% versus 24% in the MP+ve group, there was no significant difference between them. The overall survival showed a significant difference between the 2 groups (p<0.05). It was 48% for the 2 drug regimen (CSA/MTX) vs. 81% for the three drug regimen (CSA/MTX/MP). There was a significant decrease in the relapse rate in patients on CSA/MTX/MP (p<0.05). In conclusion, the addition of MP (methylprednis-olone) to the combination of CSA/MTX did not affect the incidence of acute GVHD significantly in allogeneic SCT but surprisingly the incidence of survival and relapse was markedly increased and decreased respectively

Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease.

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Kawasaki, Yasufumi; Sato, Kazuya; Hayakawa, Hiroko; Takayama, Norihito; Nakano, Hirofumi; Ito, Ryoji; Mashima, Kiyomi; Oh, Iekuni; Minakata, Daisuke; Yamasaki, Ryoko; Morita, Kaoru; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Fujiwara, Shin-Ichiro; Ohmine, Ken; Muroi, Kazuo; Kanda, Yoshinobu

2018-04-17

Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4 + and CD8 + T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rg null mice. CD4 + T cells and, to a lesser extent, CD8 + T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4 + T cells also supported the activation and proliferation of CD8 + T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4 + T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4 + T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC) +/+ mice but not in MHC -/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD. Copyright © 2018. Published by Elsevier Inc.

Topical tacrolimus and periodontal therapy in the management of a case of oral chronic GVHD characterized by specific gingival localization.

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Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G

2014-01-01

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management.

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Zantomio, D; Grigg, A P; MacGregor, L; Panek-Hudson, Y; Szer, J; Ayton, R

2006-10-01

Female genital tract graft-versus-host disease (GVHD) is an under-recognized complication of allogeneic stem cell transplantation impacting on quality of life. We describe a prospective surveillance programme for female genital GVHD to better characterize incidence, risk factors and clinical features and the impact of a structured intervention policy. A retrospective audit was conducted on the medical records of all female transplant recipients surviving at least 6 months at a single centre over a 5-year period. Patients commenced topical vaginal oestrogen early post transplant with hormone replacement as appropriate for age, prior menopausal status and co-morbidities. A genital tract management programme included regular gynaecological review and self-maintenance of vaginal capacity by dilator or intercourse. The incidence of genital GVHD was 35% (95% confidence interval (CI) (25, 50%)) at 1 year and 49% (95% CI (36, 63%)) at 2 years. Topical therapy was effective in most cases; no patient required surgical intervention to divide vaginal adhesions. The main risk factor was stem cell source with peripheral blood progenitor cells posing a higher risk than marrow (hazard ratio=3.07 (1.22, 7.73), P=0.017). Extensive GVHD in other organs was a common association. We conclude that female genital GVHD is common, and early detection and commencement of topical immunosuppression with dilator use appears to be highly effective at preventing progression.

Thoracic air-leakage syndrome in allogeneic stem cell transplant recipients as a late complication of chronic graft-versus-host disease: A case report

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Park, Jae Wook; Kim, Song Soo; Jo, Daeg Yeon; Yun, Hwan Jung; Lee, Hyo Jin; Kim, Jin Hwan [Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon (Korea, Republic of)

2016-08-15

Air-leakage syndrome associated with graft-versus-host disease (GVHD) is a rare complication, but it is also reported as an independent predictor of a worse survival rate after stem cell transplantation. We report two cases of air-leakage syndrome associated with GVHD after allogeneic stem cell transplantation in acute leukemia patients who presented with spontaneous pneumomediastinum and subcutaneous emphysema, and finally death due to respiratory failure seven to eight months later.

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells

International Nuclear Information System (INIS)

Kawakami, Kentaro; Minami, Naoki; Matsuura, Minoru; Iida, Tomoya; Toyonaga, Takahiko; Nagaishi, Kanna; Arimura, Yoshiaki; Fujimiya, Mineko; Uede, Toshimitsu; Nakase, Hiroshi

2017-01-01

Background and aims: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. Methods: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. Results: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. Conclusion: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway. - Highlights: • A lack of osteopontin in donor cells exacerbated clinical gastrointestinal GVHD. • Donor cells lacking

Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases

Directory of Open Access Journals (Sweden)

Wernicke Caroline M

2011-08-01

Full Text Available Abstract Severe acute graft versus host disease (GvHD is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results. We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children. Our meta-analysis demonstrates that the overall response-rate is high (73.8% and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively. These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.

Incidence and Pattern of Graft-versus-Host Disease in Patients Undergoing Allogeneic Transplantation after Nonmyeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin

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Lauren Veltri

2013-01-01

Full Text Available Nonmyeloablative (NMA conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG has been shown to protect against acute graft-versus-host disease (GVHD. We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG (. GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI of grade II–IV acute GVHD at day +100 was 28.6% and 38.1% at day +180. The CI for grade III-IV acute GVHD was 28.6% at day +180. CI of chronic GVHD was 45.2% at 1 year. The CI of disease relapse was 9.5% at 1 year. The rate of nonrelapse mortality (NRM was 0% at day +100 and only 9.5% at 1 year. The overall and progression free survival at 1 year was 81% and 80.4%, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD.

Defecation of a colon cast as a rare presentation of acute graft-versus-host disease

International Nuclear Information System (INIS)

Al Ashgar, Hamad; Peedikayil, Musthafa; Chaudhri, Naeem; AlGhamdi, Abdulmonem

2009-01-01

Diffuse involvement of the gastrointestinal tract by graft versus host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplant (HSCT). Gastrointestinal GVHD usually presents 3 or more weeks after HSCT and is characterized by profuse diarrhea, anorexia, nausea, vomiting, abdominal pain and gastrointestinal bleeding. We report a case of a 23 year old male who had undergone allogeneic HSCT and presented with bloody diarrhea on the 90th day post-HSCT. On the fourth day of admission, the patient passed per rectum a 27-cm long pinkish colored fleshy material recognized as a colon cast. Sigmoidoscopy showed a congested and erythematous rectum with the remaining portion of the colon cast attached to the proximal part of the sigmoid colon. A biopsy from the rectal wall was suggestive of grade 4 GVHD. The patient was treated with methylprednisolone, cyclosporine and mycophenolate mofetil, with a partial response (diarrhea and abdominal pain improved), but then he developed multiple other medical complications and died after 3 months. (author)

Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

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Davide Conrotto

2014-01-01

Full Text Available Background. Chronic graft versus host disease (cGVHD is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

MR findings in patients with disabling musculocutaneous chronic graft-versus-host disease

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Horger, M.; Boss, A.; Claussen, C.D. [Eberhard-Karls-University, Department of Diagnostic Radiology, Tuebingen (Germany); Bethge, W.; Faul, C.; Vogel, W. [Eberhard-Karls-University, Department of Internal Medicine-Oncology, Tuebingen (Germany); Fierlbeck, G. [Eberhard-Karls-University, Department of Dermatology, Tuebingen (Germany); Bornemann, A. [Eberhard-Karls-University, Insitute for Brain Research, Tuebingen (Germany)

2008-10-15

To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia). In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n = 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities. MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis. (orig.)

MR findings in patients with disabling musculocutaneous chronic graft-versus-host disease

International Nuclear Information System (INIS)

Horger, M.; Boss, A.; Claussen, C.D.; Bethge, W.; Faul, C.; Vogel, W.; Fierlbeck, G.; Bornemann, A.

2008-01-01

To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia). In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities. MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis. (orig.)

Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester

International Nuclear Information System (INIS)

Charley, M.; Thiele, D.L.; Bennett, M.; Lipsky, P.E.

1986-01-01

Graft vs. host disease (GVHD) remains one of the main problems associated with bone marrow transplantation. The current studies were undertaken to determine whether treatment of the donor inoculum with the anticytotoxic cell compound L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) would alter the development of GVHD in a murine model. Irradiated recipient mice transplanted with a mixture of control bone marrow and spleen cells from naive semiallogeneic donors died rapidly from GVHD, whereas the recipients of cells incubated with 250 microM Leu-Leu-OMe all survived. In addition, Leu-Leu-OMe treatment of cells obtained from donors immunized against host alloantigens resulted in significantly prolonged survival. Phenotypic characterization of spleen cells from the various groups of mice that had received Leu-Leu-OMe-treated cells and survived consistently revealed the donor phenotype. Treatment of marrow cells with 250 microM Leu-Leu-OMe appeared to have no adverse effects on stem cell function. Erythropoiesis was undiminished, as assayed by splenic 5-iodo-2'-deoxyuridine- 125 I uptake. Moreover, granulocytic and megakaryocytic regeneration were histologically equivalent in the spleens of recipients of control or Leu-Leu-OMe-treated cells. Treatment of the donor inoculum with Leu-Leu-OMe thus prevents GVHD in this murine strain combination with no apparent stem cell toxicity

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

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Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

2016-12-01

Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.

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Simms-Waldrip, Tiffany R; Sunkersett, Gauri; Coughlin, Laura A; Savani, Milan R; Arana, Carlos; Kim, Jiwoong; Kim, Minsoo; Zhan, Xiaowei; Greenberg, David E; Xie, Yang; Davies, Stella M; Koh, Andrew Y

2017-05-01

Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n = 8, and Cincinnati Children's Hospital, n = 7) who developed GVHD showed a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC) compared with those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (P = .003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Science.gov (United States)

Ussowicz, M; Musiał, J; Mielcarek, M; Tomaszewska, A; Nasiłowska-Adamska, B; Kałwak, K; Gorczyńska, E; Mariańska, B; Chybicka, A

2013-11-01

Steroid-refractory graft-versus-host disease (GVHD) remains a challenging therapeutic problem after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical effect of extracorporeal photopheresis (ECP), and its impact on intensivity of immunosuppresive therapy in allogeneic HSCT patients. In this study 443 Therakos ECP procedures were performed in 21 patients after allogeneic HSCT with acute (aGVHD, 8 patients) or chronic (cGVHD, 13 patients) therapy-refractory GVHD. The median age at ECP onset was 20.5 years (range, 10-55). Venous access was provided by a nontunelized central venous catheter (12 patients) or 9.6-French portacath (9 patients). In the cGVHD group 9/13 patients were improved with a 4-year overall survival rate of 67.7%. ECP led to steroid discontinuation in 6 and substantial dose reduction in 5 patients. The prednisone dose equivalent per kilogram body weight decreased from 0.32 mg to 0.07 mg after therapy. Therapy of aGVHD led to complete or partial symptom remission in 3/9 subjects. The change in steroid dose in the aGVHD group was not significant, there were no long-term survivors. Portacath access was well tolerated and provided adequate blood flow rates. The ECP therapy significantly reduced the rates of remissions with steroid discontinuation among cGVHD but not aGVHD patients. Rare ECP-related complications were either catheter related or anticoagulation induced during ECP procedures. Photopheresis was a safe, effective method to treat steroid-resistant cGVHD. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice

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Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G.; Pidala, Joseph; Yu, Xue-Zhong

2015-01-01

Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically. PMID:26348529

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

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Steven D Schutt

Full Text Available Bruton's Tyrosine Kinase (BTK and IL-2 Inducible T-cell Kinase (ITK are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR signaling and T cell receptor (TCR signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD. We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT. We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD, where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis.

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Jo Nadine Fleming

2009-07-01

Full Text Available The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD resembles the appearance of fibrosis in scleroderma (SSc. Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc.We analyzed skin biopsies of normal controls (n = 24, patients with SSc (n = 30 and c-GVHD with dermal fibrosis (n = 133. Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001 average vessels in SSc biopsies (9.8 when compared with c-GVHD (16.5. Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05, respectively. In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies.The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.

Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease

KAUST Repository

Kim, YongHwan

2018-05-22

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.

Murine cytomegalovirus immediate-early 1 gene expression correlates with increased GVHD after allogeneic hematopoietic cell transplantation in recipients reactivating from latent infection.

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Senthilnathan Palaniyandi

Full Text Available The success of allogeneic (allo hematopoietic cell transplantation (HCT is limited by its treatment related complications, mostly graft versus host disease (GVHD and fungal and viral infections. CMV reactivation after HCT has been associated with increased morbidity and mortality, and a causal relation between GVHD, immunosuppressive therapy and vice versa has been postulated. Using a low GVHD severity murine HCT model, we assessed the role of MCMV reactivation and GVHD development. BALB/c mice were infected with either murine CMV (MCMV or mock and monitored for 25 weeks to establish latency, followed by sublethal irradiation conditioning and infusion of bone marrow plus splenocytes from either syngeneic (syn BALB/c or allo B10.D2 donors. Engraftment of allo donor cells was confirmed by PCR for D2Mit265 gene product size. Day+100 mortality and overall GVHD severity in allo MCMV pre-infected recipients was higher than in allo mock controls. Pathologic changes of lung and liver GVHD in immediate-early gene 1 (IE1 positive recipients were significantly increased compared to mock controls, and were only slightly increased in IE1 negative. No significant gut injury was seen in any group. Aggravated lung injury in IE1 positive recipients correlated with higher BAL cell counts both for total cells and for CD4+ T cells when compared with mock controls, and also with protein expression of lung IFN-gamma and liver TNF. No evidence for CMV specific morphologic changes was seen on histopathology in any organ of IE1 positive recipients, suggesting that CMV reactivation is related to increased GVHD severity but does not require active CMV disease, strengthening the concept of a reciprocal relationship between CMV and GVHD.

Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-

NARCIS (Netherlands)

Epstein, Joel B.; Raber-Durlacher, Judith E.; Huysmans, Marie-Charlotte; Schoordijk, Maria C. E.; Cheng, Jerry E.; Bensadoun, Rene-Jean; Arany, Praveen R.

2018-01-01

Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.

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Gideon Steinbach

Full Text Available Severe intestinal graft-vs-host disease (GVHD after allogeneic hematopoietic cell transplantation (HCT causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3, would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3 in the duodenum or colon. We observed that 8 of 12 patients (67% had a complete remission (CR of GVHD and survived more than 1 year (median 5 years when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80% had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with

Photobiomodulation therapy alleviates tissue fibroses associated with chronic Graft-Versus-Host Disease : Two case reports and putative anti-fibrotic roles of TGF-β

NARCIS (Netherlands)

Epstein, J.B.; Raber-Durlacher, J.E.; Huysmans, M.C.; Schoordijk, M.C.E.; Cheng, J.E.; Bensadoun, R.J.; Arany, P.R.

2018-01-01

Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

Science.gov (United States)

Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D; Lombardi, Giovanna; Nestle, Frank O

2012-01-01

The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the NOD-scid IL-2Rγ(null) (NSG) and BALB/c-Rag2(null) IL-2Rγ(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD.

Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

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Niwa Ali

Full Text Available The occurrence of Graft-versus-Host Disease (GvHD is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice" are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null, notably the NOD-scid IL-2Rγ(null (NSG and BALB/c-Rag2(null IL-2Rγ(null (BRG mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+ compartment and higher engraftment levels of CD3(+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM phenotype and high levels of cutaneous lymphocyte antigen (CLA expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM-cell driven GvHD.

Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation

OpenAIRE

Dander, Erica; De Lorenzo, Paola; Bottazzi, Barbara; Quarello, Paola; Vinci, Paola; Balduzzi, Adriana; Masciocchi, Francesca; Bonanomi, Sonia; Cappuzzello, Claudia; Prunotto, Giulia; Pavan, Fabio; Pasqualini, Fabio; Sironi, Marina; Cuccovillo, Ivan; Leone, Roberto

2016-01-01

Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute G...

Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease.

Science.gov (United States)

Hammami, Muhammad Bader; Al-Taee, Ahmad; Meeks, Marshall; Fesler, Mark; Hurley, M Yadira; Cao, Dengfeng; Lai, Jin-Ping

2017-04-01

Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity. We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft-versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies. High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis.

Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD

International Nuclear Information System (INIS)

Sykes, M.; Sheard, M.; Sachs, D.H.

1988-01-01

The opposing problems of graft-vs-host disease (GVHD) and failure of alloengraftment present major obstacles to the application of bone marrow transplantation (BMT) across complete MHC barriers. The addition of syngeneic T-cell-depleted (TCD) bone marrow (BM) to untreated fully allogeneic marrow inocula in lethally irradiated mice has been previously shown to provide protection from GVHD. We have used this model to study the effects of allogeneic T cells on levels of chimerism in recipients of mixed marrow inocula. The results indicate that T cells in allogeneic BM inocula eliminate both coadministered recipient-strain and radioresistant host hematopoietic elements to produce complete allogeneic chimerism without clinical GVHD. To determine the role of GVH reactivity in this phenomenon, we performed similar studies in an F1 into parent combination, in which the genetic potential for GVHD is lacking. The presence of T cells in F1 marrow inocula led to predominant repopulation with F1 lymphocytes in such chimeras, even when coadministered with TCD-recipient-strain BM. These results imply that the ability of allogeneic BM cells removed by T cell depletion to increase levels of allochimerism may be mediated by a population which is distinct from that which produces GVHD. These results may have implications for clinical BM transplantation

Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

Science.gov (United States)

Kawamura, Koji; Nakasone, Hideki; Kurosawa, Saiko; Yoshimura, Kazuki; Misaki, Yukiko; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Kimura, Shun-Ichi; Tanihara, Aki; Kako, Shinichi; Kanamori, Heiwa; Mori, Takehiko; Takahashi, Satoshi; Taniguchi, Shuichi; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-02-21

The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

GVHD after HLA-matched sibling BMT or PBSCT: Comparison of North American Caucasian and Japanese Populations

Science.gov (United States)

Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

2016-01-01

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow (BM) transplantation is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BM or peripheral blood stem cell (PBSC) transplantations from an HLA-matched sibling for leukemia were eligible. BM was used in 13% and 53% of Caucasian and Japanese patients, respectively. In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grades III–IV acute GVHD was significantly lower in Japanese than in Caucasian patients (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57–0.96), which resulted in lower risk of non-relapse mortality in Japanese patients (HR 0.69, 95% CI 0.54–0.89). The risk of relapse was also lower in this group. Lower risk of non-relapse mortality and relapse resulted in lower overall mortality rates among Japanese patients. In conclusion, irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, which results in lower risk of non-relapse mortality. PMID:26762681

Anti-CD3 Antibody Ameliorates Transfusion-Associated Graft-Versus-Host Disease in a Chemotherapy-Based Mouse Model With Busulfan and Fludarabine

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Xiaofan Li

2017-05-01

Full Text Available ABSTRACT To establish a transfusion-associated graft-versus-host disease (TA-GVHD mouse model with busulfan and fludarabine for effective treatment evaluation. BALB/c (H-2d mice were injected with busulfan (15 mg/kg and fludarabine (30 mg/kg twice a day for 4 days. The mice were transfused with 106 T cell-depleted bone marrow (TCD-BM and cells in different groups 3 days after chemotherapy: syngeneic BALB/c, MHC minor mismatch DBA/2 (H-2d, or MHC major mismatch C57BL/6(H2-b. Recipient BALB/c mice were injected with either blood only or blood+splenocyte. TA-GVHD was monitored in terms of body weight loss, clinical scores, and survival. Dexamethasone (50 mg/kg, cyclophosphamide (50 mg/kg, cyclosporine A (30 mg/kg, and anti-CD3 (1 mg/kg were injected to each group to examine the treatments. Blood transfusion alone is insufficient to induce TA-GVHD in a chemotherapy-based mouse model. A MHC-mismatched TA-GVHD model can be induced by splenocyte and blood transfusion. This MHC-mismatched TA-GVHD model was resistant to dexamethasone treatment. Treatment based on anti-CD3 monoclonal antibody slightly ameliorated TA-GVHD. Treatment effectiveness was associated with T-cell depletion following activation by anti-CD3. Busulfan and fludarabine chemotherapy regimen can be used to establish a TA-GVHD mouse model. Anti-CD3 monoclonal antibody is a potential alternative to treat TA-GVHD.

Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

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Håkon Reikvam

2018-01-01

Full Text Available Chronic graft versus host disease (cGVHD is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15–66 years transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days. Thirty-one of the 51 patients (61% had cGVHD 1 year posttransplant. The affected organs were (number of patients liver/bile duct (23, eyes (15, gastrointestinal tract (14, skin (13, mouth (10, lungs (3, and urogenital tract (1. We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs and high metabolite levels, and the last

Lethal graft-versus-host disease: modification with allogeneic cultured donor cells

International Nuclear Information System (INIS)

Mauch, P.; Lipton, J.M.; Hamilton, B.; Obbagy, J.; Kudisch, M.; Nathan, D.; Hellman, S.

1984-01-01

The use of the bone marrow culture technique was studied as a means to prepare donor marrow for bone marrow transplantation to avoid lethal graft-versus-host disease (GVHD). Preliminary experiments demonstrated the rapid loss of theta-positive cells in such cultures, so that theta-positive cells were not detected after 6 days. Initial experiments in C3H/HeJ (H-2k, Hbbd) recipients prepared with 900 rad demonstrated improved survival when 3-day cultured C57BL/6 (H-2b, Hbbs) donor cells were used in place of hind limb marrow for transplantation. However, hemoglobin typing of recipient animals revealed only short-term donor engraftment, with competitive repopulation of recipient marrow occurring. Subsequent experiments were done in 1,200-rad prepared recipients, with long-term donor engraftment demonstrated. The majority of 1,200-rad prepared animals receiving cultured allogeneic cells died of GVHD, but animals receiving 28-day cultured cells had an improved 90-day survival and a delay in GVHD development over animals receiving hind limb marrow or marrow from shorter times in culture. In addition, animals receiving anti-theta-treated, 3-day nonadherent cells had an improved survival (44%) over animals receiving anti-theta-treated hind limb marrow (20%). These experiments demonstrate modest benefit for the use of cultured cells in bone marrow transplantation across major H-2 histocompatibility complex differences

Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome-results from a large single-center study.

Science.gov (United States)

Berger, Massimo; Albiani, Roberto; Sini, Bruno; Fagioli, Franca

2015-04-01

Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response. © 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

Long-term engraftment, graft-vs.-host disease, and immunologic reconstitution after experimental transplantation of allogeneic peripheral blood cells from G-CSF-treated donors.

Science.gov (United States)

Pan, L; Bressler, S; Cooke, K R; Krenger, W; Karandikar, M; Ferrara, J L

1996-10-01

Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated donors showed complete donor engraftment within 1 month, which was sustained until the end of the observation period. In contrast, recipients of T cell-depleted splenocytes showed slower donor engraftment and persistent donor/host chimerism. In addition, lymphocyte phenotype and function in mice receiving splenocytes from G-CSF-treated donors was significantly restored by day 100 after transplantation. Thus, the use of G-CSF-mobilized PBPC may provide significant advantages to conventional BMT by reducing GVHD without impairing long-term engraftment and immunologic reconstruction.

Efficacy and Safety of Topical Corticosteroids for Management of Oral Chronic Graft versus Host Disease

OpenAIRE

Elsaadany, Basma Abdelaleem; Ahmed, Eman Magdy; Aghbary, Sana Maher Hasan

2017-01-01

Background. Oral chronic graft versus host disease (cGVHD) is a major complication in transplantation community, a problem that can be addressed with topical intervention. Topical corticosteroids are the first line of treatment although the choice remains challenging as none of the available treatments is supported by strong clinical evidence. Objective. This systematic review aims to determine the clinical efficacy and safety of topical corticosteroids for the management of the mucosal alter...

T-cell chimerism is valuable in predicting early mortality in steroid-resistant acute graft-versus-host disease after myeloablative allogeneic cell transplantation

DEFF Research Database (Denmark)

Minculescu, Lia; Madsen, Hans O.; Sengeløv, Henrik

2014-01-01

The main aim of this study was to evaluate the impact of early T-cell chimerism status on the incidence and clinical course of acute graft-versus-host disease (aGVHD) in allogeneic transplant recipients after myeloablative conditioning. Of 62 patients, 38 (61%) had complete T-cell donor chimerism...

Effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

International Nuclear Information System (INIS)

Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

1983-01-01

Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. 51 Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras

Immune competence of splenic lymphocytes following graft-vs-host disease in mouse allogeneic radiation chimeras

International Nuclear Information System (INIS)

Urso, P.; Gengozian, N.

1977-01-01

The abnormal immune response of long-term mouse allogeneic chimeras is reflected by qualitative deficiencies in either T or B lymphocytes. The present study was undertaken to determine if a relationship existed between the severity of graft-vs-host disease (GVHD) that these animals had experienced and a functional defect in either the T or B cell population. The in vitro PFC response of chimera spleen cells to sheep red blood cells (SRBC) was evaluated in the presence of normal T or B lymphocytes 4 to 8 months after marrow transplantation and well beyond the GVHD period. In an analysis of several different allogeneic radiation chimeras, our results showed no relationship between the severity of GVHD experienced and the immunologic capacity of either T or B cells. Thus, different chimera combinations showing similar degrees of GVHD were functionally deficient in one or the other of these two cells types or both with no apparent predilection for abnormality in either population. In examining the quantitative in vitro PFC response to sheep RBC by spleen cells from individual chimeras, we found that the number of PFC formed was related to the severity of GVHD experienced by that animal. A general relationship between severity of GVHD and PFC capacity may also exist between chimeras of different genetic combinations. However, this relationship is not precise since gross exceptions occur. Our results, although documenting further the qualitative abnormalities in T and/or B lymphocytes of radiation chimeras, do not reveal the factor or mechanisms by which these cells are made unresponsive. It is suggested that the tolerance-inducing mechanism of these animals, whether it be humoral blocking factors or suppressor cells, is in some way interfering with the collaboration of T and B cells for antibody production

Donor genotype in the Interleukin-7 receptor α-chain predicts risk of graft-versus-host disease and cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

DEFF Research Database (Denmark)

Kielsen, Katrine; Enevold, Christian; Heilmann, Carsten

2018-01-01

The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for de novo T cell generation in thymus.......1-3.8, P = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1-3.6, P = 0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR = 2.4, 95% CI = 1.2-4.3, P.......7, 95% CI = 1.2-2.3, P = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3-4.0, P = 0.0047), but was not associated with the risk of relapse (P = 0.35). In conclusion, the IL-7Rα rs6897932 genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality...

Antibodies against human cytomegalovirus late protein UL94 in the pathogenesis of scleroderma-like skin lesions in chronic graft-versus-host disease.

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Pastano, Rocco; Dell'Agnola, Chiara; Bason, Caterina; Gigli, Federica; Rabascio, Cristina; Puccetti, Antonio; Tinazzi, Elisa; Cetto, Gianluigi; Peccatori, Fedro; Martinelli, Giovanni; Lunardi, Claudio

2012-09-01

Human cytomegalovirus (hCMV) infection and its reactivation correlate both with the increased risk and with the worsening of graft-versus-host disease (GVHD). Because scleroderma-like skin lesions can occur in chronic GVHD (cGVHD) in allogeneic stem-cell transplant (HCT) patients and hCMV is relevant in the pathogenesis of systemic sclerosis (SSc), we evaluated the possible pathogenetic link between hCMV and skin cGVHD. Plasma from 18 HCT patients was tested for anti-UL94 and/or anti-NAG-2 antibodies, identified in SSc patients, by direct ELISA assays. Both donors and recipients were anti-hCMV IgG positive, without autoimmune diseases. Patients' purified anti-UL94 and anti-NAG-2 IgG binding to human umbilical endothelial cells (HUVECs) and fibroblasts was performed by FACS analysis and ELISA test. HUVECs apoptosis and fibroblasts proliferation induced by patients' anti-NAG-2 antibodies were measured by DNA fragmentation and cell viability, respectively. About 11/18 patients developed cGVHD and all of them showed skin involvement, ranging from diffuse SSc-like lesions to limited erythema. Eight of eleven cGVHD patients were positive for anti-UL94 and/or anti-NAG-2 antibodies. Remarkably, 4/5 patients who developed diffuse or limited SSc-like lesions had antibodies directed against both UL94 and NAG-2; their anti-NAG-2 IgG-bound HUVECs and fibroblasts induce both endothelial cell apoptosis and fibroblasts proliferation, similar to that induced by purified anti-UL94 and anti-NAG-2 antibodies obtained from SSc patients. In conclusion, our data suggest a pathogenetic link between hCMV infection and scleroderma-like skin cGVHD in HCT patients through a mechanism of molecular mimicry between UL94 viral protein and NAG-2 molecule, as observed in patients with SSc.

CD4+CD25highCD127low Regulatory T Cells in Peripheral Blood Are Not an Independent Factor for Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

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Jolanta B. Perz

2012-01-01

Full Text Available Background. The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (HSCT largely relies on the graft-versus-leukemia (GVL effect. Uncontrolled graft-versus-host disease (GVHD is a feared complication of HSCT. Regulatory T cells (Treg are a subset of CD4+ T-helper cells believed to maintain tolerance after HSCT. It remains unclear whether low peripheral blood Treg have an impact on the risk for acute (aGVHD and chronic GVHD (cGVHD. Methods. In this paper we enumerated the CD4+CD25highCD127low Treg in the peripheral blood of 84 patients after at least 150 days from HSCT and in 20 healthy age-matched controls. Results. Although similar mean lymphocyte counts were found in patients and controls, CD3+CD4+ T-cell counts were significantly lower in patients. Patients also had significantly lower Treg percentages among lymphocytes as compared to controls. Patients with cGVHD had even higher percentages of Treg if compared to patients without cGVHD. In multivariate analysis, Treg percentages were not an independent factor for cGVHD. Conclusions. This paper did not show a relation between deficient peripheral blood Treg and cGVHD, therefore cGVHD does not seem to occur as a result of peripheral Treg paucity.

Modified extracorporeal photopheresis with cells from a healthy donor for acute graft-versus-host disease in a mouse model.

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Holger Budde

Full Text Available Graft-versus-host disease (GvHD is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles.We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup.We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor's genetic background we could not observe a statistically significant therapeutic effect.Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor's genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation.

CD24(hi)CD27⁺ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.

Science.gov (United States)

de Masson, Adèle; Bouaziz, Jean-David; Le Buanec, Hélène; Robin, Marie; O'Meara, Alix; Parquet, Nathalie; Rybojad, Michel; Hau, Estelle; Monfort, Jean-Benoît; Branchtein, Mylène; Michonneau, David; Dessirier, Valérie; Sicre de Fontbrune, Flore; Bergeron, Anne; Itzykson, Raphaël; Dhédin, Nathalie; Bengoufa, Djaouida; Peffault de Latour, Régis; Xhaard, Aliénor; Bagot, Martine; Bensussan, Armand; Socié, Gérard

2015-03-12

Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. © 2015 by The American Society of Hematology.

Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease?

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Neil Dunavin

2017-07-01

Full Text Available After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute graft-versus-host disease (GVHD. While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies.

Wharton’s Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease

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Joseph P. McGuirk

2015-04-01

Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT, a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD. The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ-derived mesenchymal stromal cells (MSCs as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

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Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

2018-06-15

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

Radiation-induced mouse chimeras: a cellular analysis of the major lymphoid compartments, factors affecting lethal graft versus host disease and host-tumor interactions

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Almaraz, R.

1981-01-01

The major lymphoid compartments of allogeneic bone marrow chimeras were evaluated for the extent of cell chimerism and distribution of Thy 1 and la bearing cells. These chimeras contained lymphoid cell primarily of donor origin. The bone marrow compartment was a mixture of host and donor origin cells. The distribution of Thy 1 and la bearing cells was similar as in normal mice. The effect of adult thymectomy alone or followed by whole-body irradiation and bone marrow reconstitution on the distribution of the Thy 1 positive cells was also investigated. Thymectomy with or without WBI and bone marrow reconstitution significantly lowered the number of Thy 1 bearing cells in the blood and spleen. The number of la bearing cells did not appear to be affected by thymectomy. The role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation induced fully allogeneic mouse chimeras was studied. Mice reconstituted with allogeneic bone marrow from bled donors had a statistically lower incidence of GVHD than those reconstituted with bone marrow from unbled donors. Addition of mature peripheral lymphocytes from blood to the reconstituting bone marrow cells from bled donors reduplicated the high incidence of lethal GVHD. It was demonstrated that the bone marrow of mice not exsanguinated prior to harvesting of bone marrow contained significant numbers of peripheral contaminating cells in the harvested bone marrow. The role of suppressor cell elimination in resisting tumor growth was investigated using radiation induced mouse chimeras. Local effects of irradiation alone at the site of tumor inoculation could account for this lack of growth

Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation.

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Kanate, Abraham S; Hari, Parameswaran N; Pasquini, Marcelo C; Visotcky, Alexis; Ahn, Kwang W; Boyd, Jennifer; Guru Murthy, Guru Subramanian; Rizzo, J Douglas; Saber, Wael; Drobyski, William; Michaelis, Laura; Atallah, Ehab; Carlson, Karen S; D'Souza, Anita; Fenske, Timothy S; Cumpston, Aaron; Bunner, Pamela; Craig, Michael; Horowitz, Mary M; Hamadani, Mehdi

2017-08-01

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in

HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease.

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Li, Jun; Heinrichs, Jessica; Haarberg, Kelley; Semple, Kenrick; Veerapathran, Anandharaman; Liu, Chen; Anasetti, Claudio; Yu, Xue-Zhong

2015-07-15

Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent→F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect. Copyright © 2015 by The American Association of Immunologists, Inc.

Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis.

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Cutler, C; Giri, S; Jeyapalan, S; Paniagua, D; Viswanathan, A; Antin, J H

2001-08-15

Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P=.006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P <.001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P <.001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

Graft-Versus-Host-Disease

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... however you can Daughter's dying wish became mother's motivation Be The Match Blog Stories Anna, transplant recipient ... any symptoms of GVHD , tell your transplant doctor right away. Chronic GVHD: Usually develops 3-6 months ...

Dry Eye Disease Incidence Associated with Chronic Graft-Host Disease: Nonconcurrent Cohort Study (An American Ophthalmological Society Thesis)

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Mian, Shahzad I.; De la Parra-Colín, Paola; De Melo-Franco, Rafael; Johnson, Christopher; Barrientos-Gutierrez, Tonatiuh

2015-01-01

Purpose: To determine if chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with stable or progressive dry eye disease and to determine the true incidence in patients with no prior history of dry eye disease. Methods: A nonconcurrent cohort study at a single institution with 136 patients who had no previous history of dry eye disease before HSCT. Survival analysis was used to estimate dry eye disease incidence. The incidence rate was calculated using life tables as the number of observed dry eye disease cases divided by the person-time at risk accumulated by the cohort. Transition probabilities were calculated from time of transplant to time of diagnosis, and then to last recorded visit. Results: Incidence rate was 0.8 cases of dry eye disease per person-year, and half of the population at risk developed dry eye disease during the first 10 months post transplant. Time to develop dry eye disease was 2.5 months for mild dry eye disease, 9.6 months for moderate dry eye disease, and 13.2 months for severe dry eye disease. In terms of cumulative incidence, 73% of subjects developed dry eye disease (50% mild, 16% moderate, and 7% severe) at the time of diagnosis. Conclusions: Our findings suggest that dry eye disease associated with cGVHD is an extremely frequent event and shows a wide spectrum of severity, with a mild form presenting early and a moderate to severe form presenting later after HSCT. These findings need to be studied further to elucidate if these are two different pathophysiological entities or just different expressions of the same pathology. PMID:27507907

Single nucleotide polymorphism of CC chemokine ligand 5 promoter gene in recipients may predict the risk of chronic graft-versus-host disease and its severity after allogeneic transplantation.

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Kim, Dong Hwan; Jung, Hee Du; Lee, Nan Young; Sohn, Sang Kyun

2007-10-15

Leukocyte trafficking, regulated by chemokine ligands and their receptors, involves in the pathogenesis of graft-versus-host disease (GVHD) including CC ligand 5 (CCL5) or CC receptor 5 (CCR5). The current study analyzed the association of acute or chronic GVHD (cGVHD) with the CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) of recipients and donors. We evaluated the SNPs of CCL5 promoter gene at position -28 (rs1800825)/-403 (rs2107538) and CCR5 gene at 59029 (rs1799987) in 72 recipients and donors using polymerase chain reaction/RFLP (Restriction Fragment Length Polymorphism) methods. With a median follow up of 924 days for survivors (range 48-2,360 days), the CG genotype of CCL5 gene at position -28 in recipients was significantly associated with a higher incidence of cGVHD (P=0.004), extensive cGVHD (P=0.038 by Seattle's criteria), and severe grade of cGVHD at presentation (P=0.017 by prognostic grading by Apkek et al.) compared to CC genotype. In terms of haplotype analysis, the recipients with AG haplotype of CCL5 gene also showed a higher incidence of cGVHD (P=0.003), extensive cGVHD (P=0.023), and more severe grade of cGVHD (P=0.020). However, there was no association of CCL5/CCR5 SNPs with acute GVHD. The donors' genotype of CCL5/CCR5 was not associated with the risk of cGVHD. The CCL5 promoter gene polymorphism of recipients was associated with the risk of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.

The effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

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Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

1983-01-01

Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. 51 Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras. These results raise the possibility that the fulminant GVHD seen in human marrow transplantation is in part due to the major contamination of bone marrow with peripheral blood that results from the techniques currently used for human bone marrow harvest

Distribution and clonality of the vα and vβ T-cell receptor repertoire of regulatory T cells in leukemia patients with and without graft versus host disease.

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Jin, Zhenyi; Wu, Xiuli; Chen, Shaohua; Yang, Lijian; Liu, Qifa; Li, Yangqiu

2014-03-01

Graft versus host disease (GVHD) is the main complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent data indicated that regulatory T (Treg) cells might relate to GVHD, and such functions might be mediated by certain T-cell receptor (TCR) subfamily of Treg cells. Thus, we analyzed the distribution and clonality of the TCR Vα and Vβ repertoire of Treg cells from leukemia patients with and without GVHD after allo-HSCT. Numerous TCR Vα subfamilies, including Vα1, Vα9, Vα13, Vα16-19, and Vα24-29, were absent in Treg cells after allo-HSCT. The usage numbers for the TCR Vα and Vβ subfamilies in Treg cells from patients without GVHD appeared more widely. The expression frequencies of Vα10 or Vα20 between both groups were significantly different. Moreover, the expression frequency of TCR Vβ2 subfamily in patients without GVHD was significantly higher than that in patients with GVHD. Oligoclonally expanded TCR Vα and Vβ Treg cells were identified in a few samples in both groups. Restricted utilization of the Vα and Vβ subfamilies and the absence of some important TCR rearrangements in Treg cells may be related to GVHD due to a lower regulating function of Treg subfamilies.

RANTES polymorphisms and the risk of graft-versus-host disease in human leukocyte antigen-matched sibling allogeneic hematopoietic stem cell transplantation.

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Shin, Dong-Yeop; Kim, Inho; Kim, Jin Hee; Lee, Yun-Gyoo; Kang, Eun Joo; Cho, Hyeon Jin; Lee, Kyung-Hun; Kim, Hye Jin; Park, Eun-Hee; Lee, Jong-Eun; Bae, Ji-Yeon; See, Cha Ja; Yoon, Sung-Soo; Park, Sung Sup; Han, Kyou-Sup; Park, Myoung Hee; Hong, Yun-Chul; Park, Seonyang; Kim, Byoung Kook

2013-01-01

We investigated the association between RANTES (regulated upon activation, normal T cell expressed and secreted) polymorphisms and clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Three RANTES gene polymorphisms, i.e., -403G/A (rs2107538), -28C/G (rs2280788) and In1.1T/C (rs2280789), were genotyped, and the effects of the genotypes and haplotypes of RANTES on clinical outcomes were analyzed. The competing risk regression analysis was used to investigate the relationship between the polymorphisms and the cumulative risk of graft-versus-host disease (GVHD). An AGC haplotype in a recessive model showed significant harmful effects on the cumulative risk of acute GVHD and relapse-free survival (adjusted hazard ratios 2.42 and 2.71, 95% confidence intervals 1.29-4.55 and 1.30-5.64; p = 0.018 and 0.024, respectively), whereas a GCT haplotype did not. RANTES polymorphisms were not significantly associated with overall survival and the risk of chronic GVHD. This study suggests that RANTES polymorphisms might be associated with the occurrence of acute GVHD rather than of chronic GVHD and also of relapse-free survival in the patients treated with allo-HSCT. Further larger prospective investigations are needed to establish the role of RANTES polymorphisms in patients treated with allo-HSCT. Copyright © 2012 S. Karger AG, Basel.

Novel Concept of CD4-Mediated Activation of Regulatory T Cells for the Treatment of Graft-Versus-Host Disease

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Janine Schlöder

2017-11-01

Full Text Available Allogeneic hematopoietic stem cell transplantation is the only curative treatment option for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of a graft-versus-host disease (GvHD after transplantation is a high risk and a severe complication with high morbidity and mortality causing therapeutic challenges. Current pharmacological therapies of GvHD lead to generalized immunosuppression followed by severe adverse side effects including infections and relapse of leukemia. Several novel cell-based immunomodulatory strategies for treatment or prevention of GvHD have been developed. Herein, thymus-derived regulatory T cells (tTreg, essential for the maintenance of peripheral immunologic tolerance, are in the focus of investigation. However, due to the limited number of tTreg in the peripheral blood, a complex, time- and cost-intensive in vitro expansion protocol is necessary for the production of an efficient cellular therapeutic. We demonstrated that activation of tTreg using the CD4-binding human immunodeficiency virus-1 protein gp120 leads to a substantially increased suppressor activity of tTreg without the need for additional expansion. Gp120-activated tTreg prevent GvHD development in a preclinical humanized mouse model. In addition, gp120 is not only effective in prevention but also in therapy of GvHD by suppressing all clinical symptoms and improving survival of treated mice. These data indicate that tTreg activation by gp120 is a feasible and potent strategy for significant functional improvement of tTreg as cellular therapeutic for GvHD treatment without the need of complicated, time-intensive, and expensive in vitro expansion of isolated tTreg.

Graft versus host disease in a rat small bowel transplant model after T-cell depleted donor specific bone marrow infusion

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Bakonyi Neto Alexandre

2003-01-01

Full Text Available Low cytoreductive regimen of irradiation associated to unmodified bone marrow infusion (UBM does not prevent the occurrence of graft versus host disease (GVHD after transplant. PURPOSE: In this study we evaluated the potential advantages of a long-term immunossupression and T-cell depleted bone marrow infusion (TCDBMI in preventing the occurrence of GVHD after small bowel transplantation (SBTx. METHODS: Heterotopic SBTX was performed with Lewis rats as recipients and DA as donors and distributed into 5 groups according to the irradiation, duration of immunossupression and the use of UBM or TCDBMI: G1 (n=6, without irradiation and G2 (n=9, G3 (n=4, G4 (n=5 and G5 (n=6 was given 250 rd of irradiation. Groups 1,2,4 and G3 and 5 were infused with 100 x 10(6 UBM and TCDBM respectively. Animals in G1, 2, 3 were immunossupressed with 1mg/ FK506/Kg/IM for 5 days and G4 and G5 for 15 days. Anti CD3 monoclonal antibodies and immunomagnetic beads were used for T-cell depletion.Animals were examined for rejection, GVHD, chimerism characterization and ileal and skin biopsies. RESULTS: Minimal to mild rejection was observed in all groups; however, GVHD were present only in irradiated groups. Long-term immunossupression changed the severity of GVHD in G4 and G5. Rejection was the cause of death in G1 while GVHD in G2, 3, 4 and 5, not avoided by the use of TCDBMI. Total chimerism and T-cell chimerism was statistically higher in irradiated groups when compared to G1. CONCLUSION: Extended immunossupression associated to low dose of irradiation decrease the severity of GVHD, not avoided by the use of TCDBMI.

Graft-Versus-Host Disease after Liver Transplantation Complicated by Systemic Aspergillosis with Pancarditis

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Joseph Romagnuolo

2000-01-01

Full Text Available Acute graft-versus-host disease (GVHD is a common complication after bone marrow transplantation, with characteristic rash and diarrhea being the most common features. After liver transplantation, however, this phenomenon is very rare. Most transplant patients are on a variety of medications, including immunosuppressants; therefore, the differential diagnosis of skin rash or diarrhea is broad. A 37-year-old man who underwent liver transplantation for primary biliary cirrhosis, and developed a rash and watery diarrhea, is presented. Skin and colonic biopsies confirmed acute GVHD. A pulse of intravenous steroids was given. The skin rash improved, but he developed pancytopenia. His course was complicated by central line infection, jugular and subclavian vein thrombosis, pseudomembranous colitis, recurrent bacteremia, cholestasis on total parenteral nutrition and cytomegalovirus infection. After the onset of pleuritic chest pain and clinical sepsis, spiral computed tomography scan of his chest and abdomen revealed septic infarcts in multiple organs. Despite empirical treatment with amphotericin B, he died of multiorgan dysfunction syndrome within 72 h. Autopsy revealed systemic aspergillosis with pancarditis, endocardial vegetations, and septic pulmonary, splenic, hepatic and renal infarcts. The pathogenesis and experience with this rare, but often fatal, complication of liver transplantation are reviewed. In contrast to GVHD after bone marrow transplantation, pancytopenia is common and liver dysfunction is rare. One should have a high level of suspicion in the liver transplant recipient presenting with rash and/or diarrhea.

Graft-Versus-Host Disease in Adolescents and Young Adults (15-24 Years Old) After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia in First Complete Remission.

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Vignon, Marguerite; Andreoli, Annalisa; Dhédin, Nathalie; Lengliné, Etienne; Masson, Emeline; Robin, Marie; Granier, Clémence; Larghero, Jérôme; Schlageter, Marie-Hélène; de Latour, Régis Peffault; Socié, Gérard; Boissel, Nicolas

2017-06-01

Adolescents and young adults (AYAs) with cancer are a unique group of patients in terms of disease incidence and biology, outcome, and psychosocial needs. This study aims to correlate the risk of graft-versus-host disease (GvHD) and age in a population of children and young adults with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). We analyzed the outcome of 153 consecutive children (<15 years), AYAs (15-24 years), and adults (25-35 years) with lymphoblastic or myeloid acute leukemia in first CR who underwent HSCT with matched donors after myeloablative conditioning. GvHD prophylaxis was methotrexate and cyclosporine A (CsA) in all patients. The cumulative incidence of grade II-IV acute GvHD (aGvHD) was significantly higher in AYA patients than in children (subdistribution hazard ratio (SHR), 2.04, p = 0.005) or adults (SHR 1.59, p = 0.048). Both gut and skin aGvHD occurred more frequently in AYA patients. Increasing CsA blood levels with age could not fully account for this difference. No difference in terms of grade III-IV aGvHD was observed. Chronic GvHD was more frequent in AYAs (SHR 2.81, p = 0.007) and adults (SHR 2.31, p = 0.033) than in children. No difference in terms of nonrelated mortality and overall survival was observed among the age subgroups. Since GvHD occurrence is strongly correlated to quality of life, specific attention should be paid to AYAs undergoing HSCT. Further studies should investigate the reasons for the excess of GvHD observed in this population.

Modulation and Apoptosis of Neutrophil Granulocytes by Extracorporeal Photopheresis in the Treatment of Chronic Graft-Versus-Host Disease.

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Cindy Franklin

Full Text Available Chronic graft-versus-host disease (cGVHD is a common side effect of allogeneic stem cell transplantation and a major cause of morbidity and mortality in affected patients. Especially skin, eyes and oral mucosa are affected. This can lead to pain and functional impairment. Extracorporeal photopheresis (ECP is an effective immunomodulatory therapy with minimal side effects but its mode of action is still largely unknown. The objective of the present study was to examine the effects of ECP on neutrophil granulocytes in patients with cGVHD. Analysis of leukocytes from cGVHD patients obtained from the ECP device during treatment showed that neutrophil granulocytes account for the majority of cells treated during ECP. Neutrophils from healthy donors treated in vitro with 8-methoxypsoralen and UVA light as well as neutrophils from buffy coats of patients with cGVHD treated by ECP showed increased apoptosis and decreased half-life. In remaining non-apoptotic cells chemoirradiation resulted in loss of activation markers and reduced effector functions. This was accompanied by an increase in extracellular arginase-1 activity. Additional comparison of neutrophils isolated from blood of cGVHD patients before and 24h after ECP revealed a decreased half-life and reduction of effector functions of post-ECP neutrophils ex vivo. These observations strongly suggest that ECP induces both apoptosis and physiological changes in neutrophils and that these changes also take place in vivo. This study is the first to show that ECP modulates apoptosis and inflammatory activity in neutrophil granulocytes, indicating that neutrophils may significantly contribute to the overall immunomodulatory effects attributed to this treatment.

FTY720 ameliorates murine sclerodermatous chronic graft-versus-host disease by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin.

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Huu, Doanh Le; Matsushita, Takashi; Jin, Guihua; Hamaguchi, Yasuhito; Hasegawa, Minoru; Takehara, Kazuhiko; Fujimoto, Manabu

2013-06-01

Sphingosine 1-phosphate (S1P) exerts a variety of activities in immune, inflammatory, and vascular systems. S1P plays an important role in systemic sclerosis (SSc) pathogenesis. Regulation of S1P in fibrotic diseases as well as in SSc was recently reported. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases. Murine sclerodermatous chronic graft-versus-host disease (GVHD) is a model for human sclerodermatous chronic GVHD and SSc. We undertook this study to investigate the effects of FTY720 in murine sclerodermatous chronic GVHD. FTY720 was orally administered to allogeneic recipient mice from day 0 to day 20 (short-term, early-treatment group), from day 0 to day 42 (full-term, early-treatment group), or from day 22 to day 42 (delayed-treatment group) after bone marrow transplantation. Delayed administration of FTY720 attenuated, and early administration of FTY720 inhibited, the severity and fibrosis in murine sclerodermatous chronic GVHD. With early treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, Treg cells, and Breg cells. Vascular damage in chronic GVHD was inhibited by FTY720 through down-regulating serum levels of S1P and soluble E-selectin. FTY720 inhibited infiltration of immune cells into skin. Moreover, FTY720 diminished the expression of messenger RNA for monocyte chemotactic protein 1, macrophage inflammatory protein 1α, RANTES, tumor necrosis factor α, interferon-γ, interleukin-6 (IL-6), IL-10, IL-17A, and transforming growth factor β1 in the skin. FTY720 suppressed the immune response by promoting the expansion of regulatory cells and reducing vascular damage and infiltration of immune cells into the skin. Taken together, these results have important implications for the potential use of FTY720 in the treatment of sclerodermatous chronic GVHD and SSc in humans. Copyright © 2013 by the American College of Rheumatology.

Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survival Rate.

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Park, Sung-Soo; Kwak, Dae Hun; Jeon, Young-Woo; Yoon, Jae-Ho; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Kim, Hee-Je; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Min, Woo-Sung; Lee, Jong Wook

2017-09-01

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute

Safety and efficacy of autologous serum eye drop for treatment of dry eyes in graft-versus-host disease.

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Azari, Amir A; Karadag, Remzi; Kanavi, Mozhgan Rezaei; Nehls, Sarah; Barney, Neal; Kim, Kyungmann; Longo, Walter; Hematti, Peiman; Juckett, Mark

2017-06-01

To evaluate the treatment of autologous serum eye drops (ASED) on dry eyes in patients with graft-versus-host disease (GVHD). A retrospective chart review of 35 patients with a history of ocular GVHD following hematopoietic stem cell transplantation that used ASED to alleviate dry eye symptoms was performed. Patients were categorized into three different groups. If patients had available ophthalmic data before and after starting treatment was group 1 (n = 14), had available ophthalmic data after starting treatment in group 2 (n = 10) and had available ophthalmic data before treatment or did not have any data after starting treatment in group 3 (n = 11). Data were collected on patient's age, gender, primary diagnosis, visual acuity and fluorescein corneal staining were collected on individual eyes in order to evaluate the efficacy of the ASED on alleviating dry eye-related signs and symptoms. No adverse ocular effect from the ASED was found in our series (except one fungal keratitis). All patients reported either improvement (55%) or stability (45%) in their ocular symptoms upon the use of ASED. In patients with available data before and after starting treatment, the corneal staining score improved by a median of 1 (p = 0.003) and the LogMAR visual acuity had a non-significant improvement. In our study, ASED used by patients with ocular GVHD were both safe and effective. ASED should be considered in patients with GVHD who suffer from dry eyes.

Is the presence of 6 or fewer crypt apoptotic bodies sufficient for diagnosis of graft versus host disease? A decade of experience at a single institution.

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Lin, Jingmei; Fan, Rong; Zhao, Zijin; Cummings, Oscar W; Chen, Shaoxiong

2013-04-01

Histopathology assessment is crucial for the diagnosis of graft versus host disease (GVHD), as the presence of crypt apoptosis is the cardinal criterion required. However, crypt apoptosis is not limited to GVHD; it also occurs in other conditions such as infection, drug reaction, or inflammatory reactions unrelated to GVHD. To better determine whether the presence of 6 or fewer apoptotic bodies is sufficient for the diagnosis of GVHD, we retrospectively reviewed 78 colon biopsies from 66 patients who received either hematopoietic stem cell (HSCT) or cord blood cell transplantation and whose colon biopsies exhibited apoptotic bodies. Among them, 41 cases contained 6 or fewer apoptotic bodies in the colon biopsy. These biopsies were compared with 141 colon biopsy controls that showed no significant pathologic changes as well as 16 colon biopsies with cytomegalovirus colitis from patients without a history of bone marrow transplantation. Among the 41 cases reviewed, 7 patients had coexisting GVHD in other organs (skin or liver). However, gastrointestinal symptoms of at least 4 HSCT patients whose colon biopsies contained 6 or fewer apoptotic bodies completely resolved in the absence of further intervention for GVHD. The discrepancy between pathologic findings and the clinical course may be due to confounding factors, such as infection or medication-induced injury. Our data suggest that identifying 6 or fewer crypt apoptotic bodies in colon biopsies from HSCT patients is worth reporting in order to alert the clinicians of the possibility of GVHD but not sufficient to render a diagnosis on the pathologic grounds alone. The colon biopsies containing 6 or fewer apoptotic bodies represent a heterogenous group. We suggest this group to be classified as indeterminate for GVHD, instead of diagnosing GVHD outright. Synthesis of all clinical, endoscopic, and pathologic information, including the status of infection, coexisting GVHD involvement in the other organs, and

Pharmacogenetics of steroid-responsive acute graft-versus-host disease.

Science.gov (United States)

Arora, Mukta; Weisdorf, Daniel J; Shanley, Ryan M; Thyagarajan, Bharat

2017-05-01

Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Quantitative computed tomography assessment of graft-versus-host disease-related bronchiolitis obliterans in children: A pilot feasibility study

International Nuclear Information System (INIS)

Kim, Hyun Gi; Shin, Hyun Joo; Kim, Myung-Joon; Lee, Mi-Jung; Kim, Yoon Hee; Sohn, Myung Hyun; Kim, Kyung Won; Lyu, Chuhl Joo

2015-01-01

To suggest a simple method that can quantify air trapping from chest CT in children with graft-versus-host disease (GVHD)-related bronchiolitis obliterans (BO). This institutional review board-approved retrospective study included eight GVHD-related BO patients (age, 6 - 17 years) who underwent both 31 CTs of variable settings and pulmonary function tests (PFT). The attenuation values of lung parenchyma in normal (An) and air trapping (Aa) areas were obtained. Individualized threshold [(An + Aa)/2] and fixed threshold of -950 HU were set for air trapping quantification. Spearman correlation analysis and generalized linear mixed models were used for statistical analysis. The mean value of individualized threshold was -830.2 ± 48.3 HU. The mean air trapping lung volume percentage with individualized threshold and -950 HU were 45.4 ± 18.9 % and 1.4 ± 1.9 %, respectively. The air trapping lung volume percentage with individualized threshold showed a significant negative correlation with the PFT of FEV1/FVC% in all data (γ = -0.795, P <.001) and in the correction of repetition (γ = -0.837, P =.010). We suggest a simple and individualized threshold attenuation setting method for air trapping quantification insusceptible to CT imaging protocols or respiratory phase control in children with GVHD-related BO. (orig.)

Quantitative computed tomography assessment of graft-versus-host disease-related bronchiolitis obliterans in children: A pilot feasibility study

Energy Technology Data Exchange (ETDEWEB)

Kim, Hyun Gi [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Severance Children' s Hospital, Seoul (Korea, Republic of); Ajou University Medical Center, Department of Radiology, Ajou University School of Medicine, Suwon (Korea, Republic of); Shin, Hyun Joo; Kim, Myung-Joon; Lee, Mi-Jung [Yonsei University College of Medicine, Department of Radiology and Research Institute of Radiological Science, Severance Children' s Hospital, Seoul (Korea, Republic of); Kim, Yoon Hee; Sohn, Myung Hyun; Kim, Kyung Won [Yonsei University College of Medicine, Department of Pediatrics and Institute of Allergy, Severance Children' s Hospital, Seoul (Korea, Republic of); Lyu, Chuhl Joo [Yonsei University College of Medicine, Department of Pediatric Hematology and Oncology, Severance Children' s Hospital, Seoul (Korea, Republic of)

2015-10-15

To suggest a simple method that can quantify air trapping from chest CT in children with graft-versus-host disease (GVHD)-related bronchiolitis obliterans (BO). This institutional review board-approved retrospective study included eight GVHD-related BO patients (age, 6 - 17 years) who underwent both 31 CTs of variable settings and pulmonary function tests (PFT). The attenuation values of lung parenchyma in normal (An) and air trapping (Aa) areas were obtained. Individualized threshold [(An + Aa)/2] and fixed threshold of -950 HU were set for air trapping quantification. Spearman correlation analysis and generalized linear mixed models were used for statistical analysis. The mean value of individualized threshold was -830.2 ± 48.3 HU. The mean air trapping lung volume percentage with individualized threshold and -950 HU were 45.4 ± 18.9 % and 1.4 ± 1.9 %, respectively. The air trapping lung volume percentage with individualized threshold showed a significant negative correlation with the PFT of FEV1/FVC% in all data (γ = -0.795, P <.001) and in the correction of repetition (γ = -0.837, P =.010). We suggest a simple and individualized threshold attenuation setting method for air trapping quantification insusceptible to CT imaging protocols or respiratory phase control in children with GVHD-related BO. (orig.)

Increased incidence of murine graft-versus-host disease after allogeneic bone marrow transplantation by previous infusion of syngeneic bone marrow cells

International Nuclear Information System (INIS)

Waer, M.; Ang, K.K.; van der Schueren, E.; Vandeputte, M.

1984-01-01

Different groups of BALB/c mice received supralethal total-body irradiation (TBI; 8.5 Gy, day 0). When 30 x 10(6) allogeneic (C57B1) bone marrow (BM) cells were infused with or without 10 x 10(6) syngeneic (BALB/c) bM cells on day 1, many animals (60%) died from graft-versus-host disease (GVHD). Typing of peripheral blood leukocytes for donor antigens showed that, respectively, 22/22 and 17/21 of the mice in both groups became chimeric. When syngeneic bone marrow was given on day 1 and allogeneic bone marrow on day 2 after TBI, a similar number of animals (21/23) became chimeric, but GVHD occurred more frequently in this group (25/26 mice, P less than 0.01). When the syngeneic bone marrow cells were replaced by spleen cells, or when the transplantation of allogeneic bone marrow was delayed till days 3 or 6 after TBI, almost all mice rejected the allogeneic BM graft and became long-term survivors. BALB/c mice receiving 30 x 10(6) C57B1 BM cells after 17 daily fractions of 0.2 Gy of total lymphoid irradiation (TLI), showed a high incidence of chimerism (15/17) and in none of the latter animals was GVHD observed. Despite the high incidence of GVHD in the mice receiving allogeneic BM after TBI and syngeneic BM transplantation, as compared with mice prepared with TLI which do not develop GVHD, suppressor cells were as easily induced after TBI and syngeneic BM transplantation as after TLI

In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

International Nuclear Information System (INIS)

Lum, L.G.; Seigneuret, M.C.; Storb, R.F.; Witherspoon, R.P.; Thomas, E.D.

1981-01-01

Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation

C-Reactive Protein Levels at Diagnosis of Acute Graft-versus-Host Disease Predict Steroid-Refractory Disease, Treatment-Related Mortality, and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation

DEFF Research Database (Denmark)

Minculescu, Lia; Kornblit, Brian Thomas; Friis, Lone Smidstrups

2018-01-01

, and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line...... of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2 mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid......-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between patients who developed steroid-refractory disease compared with those who responded to high-dose corticosteroid therapy (odds ratio, 1.50; 95% confidence interval, 1...

Mechanism of donor to host tolerance in rat bone marrow chimeras

International Nuclear Information System (INIS)

Tutschka, P.; Schwerdtfeger, R.; Slavin, R.; Santos, G.

1977-01-01

Lewis rats were conditioned with cyclophosphamide and grafted with AgB incompatible bone marrow. They were examined 250 days after transplantation and demonstrated to be healthy complete chimeras. Marrow cells from these chimeras were infused into lethally irradiated ACI, Lewis and BN recipients. Graft-versus-host disease occurred only in the BN rats. Other chimeric rats were given no treatment, busulfan, CY, or total body irradiation prior to the infusion of normal ACI BM. GvHD occurred only in animals given CY or TBI. Normal Lewis rats were conditioned with TBI and given ACI BM. In addition, they received whole blood, irradiated blood, or serum from chimeric rats. GvHD developed in all animals except those given unirradiated chimeric blood. These studies suggest that suppressor cell populations, sensitive to immunosuppression, are likely the fundamental mechanism of recovery from GvHD

Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

Directory of Open Access Journals (Sweden)

Bart eVaes

2012-11-01

Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes

International Nuclear Information System (INIS)

Rolink, A.G.; Gleichmann, E.

1983-01-01

Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. We analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. When nonirradiated F1 mice were used as the recipients, we found unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients but were capable of inducing a vigorous formation of SLE-like autoantibodies and severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. The sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and then comparing donor-cell inocula that contained similar numbers of T lymphocytes. Donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients unseparated donor T cells were superior to T cell subsets in inducing LGVHD. In contrast Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells

The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

Energy Technology Data Exchange (ETDEWEB)

Frassoni, F; Bacigalupo, A [Ospedale San Martino (Italy). Centro Trapianti Midollo Osseo; Scarpati, D [Univ. di Genova (Italy). Ist. di Radiologia; and others

1989-10-01

One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author).

The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Frassoni, F.; Bacigalupo, A.; Scarpati, D.

1989-01-01

One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author)

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Directory of Open Access Journals (Sweden)

Rehan Mujeeb Faridi

Full Text Available Allogeneic hematopoietic cell transplantation (HCT can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs and 'validation' (146 pairs cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD, chronic GVHD needing systemic therapy (cGVHD and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS, cGVHD & relapse free survival (cGRFS and overall survival (OS] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17 and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11. High incidence of cGVHD associated with KIR genotype mismatching was

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Science.gov (United States)

Faridi, Rehan Mujeeb; Kemp, Taylor J; Dharmani-Khan, Poonam; Lewis, Victor; Tripathi, Gaurav; Rajalingam, Raja; Daly, Andrew; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable

Engraftment of allogeneic bone marrow without graft-versus-host disease in mongrel dogs using total lymphoid irradiation

International Nuclear Information System (INIS)

Gottlieb, M.; Strober, S.; Hoppe, R.T.; Grumet, F.C.; Kaplan, H.S.

1980-01-01

We achieved long-term engraftment of unmatched bone marrow (BM) in dogs without graft-versus-host disease (GVHD) using a regimen of total lymphoid irradiation (TLI) which could be applied clinically. Twelve normal adult mongrel dogs were given TLI in 18 fractions of 100 rad each (total dose, 1800 rad) over 4 weeks to mantle and abdominal fields in continuity. Nine of the 12 were transfused with one or two random donor whole blood transfusions during the irradiation regimen to determine the risk of sensitization after the onset of immunosuppression. A mean (+- SD) of 0.71 +- 0.54 x 10 9 BM cells/kg of recipient body weight from unrelated sex-mismatched donors was infused within 24 h of the 18th irradiation fraction. Engraftment was assessed by demonstration of donor-type sex chromosomes in spontaneous metaphase spreads of recipient marrow aspirates, and by the appearance of donor-type red blood cells antigens (DEA) in the recipients' blood. Three untransfused and nine transfused recipients were shown to be stable mixed BM chimeras during a followup period of 2 to 11 months after transplantation. Blood transfusion during TLI did not result in graft rejection. We observed no clinical signs of acute or chronic GVHD. TLI has minimal toxicity when compared with conditioning regimens currently used in BM transplantation for aplastic anemia. Potential advantages of the TLI regimen include the opportunity to use unmatched marrow donors and protection from GVHD

Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.

Science.gov (United States)

Wolf, Dietlinde; Barreras, Henry; Bader, Cameron S; Copsel, Sabrina; Lightbourn, Casey O; Pfeiffer, Brent J; Altman, Norman H; Podack, Eckhard R; Komanduri, Krishna V; Levy, Robert B

2017-05-01

Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice

International Nuclear Information System (INIS)

Guo, Yixian; Zhang, Lanfang; Wan, Suigui; Sun, Xuejing; Wu, Yongxia; Yu, Xue-Zhong; Xia, Chang-Qing

2014-01-01

Highlights: • Injection of UVB-irradiated iDCs induces alloantigen tolerance. • This alloantigen tolerance may be associated regulatory T cell induction. • Tolerant mice serve as bone marrow donors reduces GVHD to their F1 recipients in allo-HSCT. • Tolerance is maintained in F1 recipients for long time post HSCT. - Abstract: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H × Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT

Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice

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Guo, Yixian; Zhang, Lanfang; Wan, Suigui; Sun, Xuejing; Wu, Yongxia [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Yu, Xue-Zhong [Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425 (United States); Xia, Chang-Qing, E-mail: cqx65@yahoo.com [Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

2014-04-18

Highlights: • Injection of UVB-irradiated iDCs induces alloantigen tolerance. • This alloantigen tolerance may be associated regulatory T cell induction. • Tolerant mice serve as bone marrow donors reduces GVHD to their F1 recipients in allo-HSCT. • Tolerance is maintained in F1 recipients for long time post HSCT. - Abstract: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H × Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT.

Use of telecobalt-therapy in transfusion-associated graft-versus-host disease

International Nuclear Information System (INIS)

Goes, Evamberto Garcia de

1999-08-01

The transfusion-associated Graft-Versus-Host Disease (TA-GVHD) is prevented through the irradiation of blood components before transfusion. This work started with a diagnostic about blood irradiation practices in Brazil, through the application of a questionnaire to 56 regional blood centers, and showed that the majority of the regional blood centers have no means to irradiate their own blood components. This survey have also shown that 62,5% of the regional blood centers have local facilities to irradiate their own blood components, through the use of telecobalt-therapy services. Assuming the use of telecobalt-therapy equipment as an alternative solution to the Brazilian blood irradiation problem, the development of an appropriate technique allowed a good quality for irradiated blood. A prototype of a thermic box was made in acrylic and foam, and an automated system of data acquisition, kept the temperature of blood components bellow 6 deg C, during irradiation. Phantoms built using polystyrene plastic represented blood volume routinely irradiated by the regional blood centers. The distribution of doses on the phantoms volumes determined with LiF-100 thermoluminescent dosimeters, were represented in terms of isodoses curves. The doses distributions on the phantom with higher dimensions, 30 x 30 x 20 cm, changed from a minimum relative dose of 80% up to a maximum of 106%. An investigation concerning effects of Cobalt-60 gamma radiation on red blood cells, irradiated and stored, showed increase in potassium levels, up to the tenth day, in blood units irradiated at 3,00 cGy. Surveillance of the reduction in the capacity of T-Cells proliferation as a function of dose, using Limiting Dilution Analysis, showed that a minimum of 2,500 cGy is necessary to prevent TA-GVHD. Methodology developed in this work guarantee good quality for blood irradiated with telecobalt-therapy equipment, a valid alternative for Brazilian institutions which have available only this technique

Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.

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Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo; Hayase, Eiko; Takahashi, Shuichiro; Miyazaki, Miyono; Minomi, Kenjiro; Onozawa, Masahiro; Niitsu, Yoshiro; Teshima, Takanori

2018-03-29

Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80 + macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47 + myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47 + myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47 + myofibroblasts without inducing immunosuppression. © 2018 by The American Society of Hematology.

Chronic graft-versus-host disease in the rat radiation chimera: I. clinical features, hematology, histology, and immunopathology in long-term chimeras

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Beschorner, W.E.; Tutschka, P.J.; Santos, G.W.

1982-04-01

The clinical features, pathology, and immunopathology of chronic graft-versus-host disease (GVHD) developing in the long-term rat radiation chimera are described. At 6 to 12 months post-transplant, the previously stable ACI/LEW chimeras developed patchy to diffuse severe hair loss and thickened skin folds, and had microscopic features resembling scleroderma, Sjogren's syndrome, and chronic hepatitis. Skin histology showed dermal inflammation and acanthosis with atrophy of the appendages, with progression to dermal sclerosis. The liver revealed chronic hepatitis with bile duct injury and proliferation and periportal piecemeal necrosis. The tongue had considerable submucosal inflammation, muscular necrosis, and atrophy and arteritis. The serous salivary glands, lacrimal glands, and bronchi had lymphocytic inflammation and injury to duct, acinar, and mucosal columnar epithelium. The thymus had lymphocyte depletion of the medulla with prominent epithelium. The spleen and lymph nodes had poorly developed germinal centers but increased numbers of plasma cells. IgM was observed along the basement membrane and around the basal cells of the skin and tongue and along the basement membrane of the bile ducts. IgM was present also in the arteries of the tongue. Immunoglobulins eluted from the skin, cross-reacted with the bile duct epithelium and usually with both ACI and Lewis skin. Increased titers of speckled antinuclear antibodies were present in the serum of rats with chronic (GVHD). Chronic GVHD in the long-term rat radiation chimera is very similar to human chronic GVHD and is a potentially excellent model for autoimmune disorders including scleroderma, Sjorgren's syndrome, and chronic hepatitis.

Chronic graft-versus-host disease in the rat radiation chimera: I. clinical features, hematology, histology, and immunopathology in long-term chimeras

International Nuclear Information System (INIS)

Beschorner, W.E.; Tutschka, P.J.; Santos, G.W.

1982-01-01

The clinical features, pathology, and immunopathology of chronic graft-versus-host disease (GVHD) developing in the long-term rat radiation chimera are described. At 6 to 12 months post-transplant, the previously stable ACI/LEW chimeras developed patchy to diffuse severe hair loss and thickened skin folds, and had microscopic features resembling scleroderma, Sjogren's syndrome, and chronic hepatitis. Skin histology showed dermal inflammation and acanthosis with atrophy of the appendages, with progression to dermal sclerosis. The liver revealed chronic hepatitis with bile duct injury and proliferation and periportal piecemeal necrosis. The tongue had considerable submucosal inflammation, muscular necrosis, and atrophy and arteritis. The serous salivary glands, lacrimal glands, and bronchi had lymphocytic inflammation and injury to duct, acinar, and mucosal columnar epithelium. The thymus had lymphocyte depletion of the medulla with prominent epithelium. The spleen and lymph nodes had poorly developed germinal centers but increased numbers of plasma cells. IgM was observed along the basement membrane and around the basal cells of the skin and tongue and along the basement membrane of the bile ducts. IgM was present also in the arteries of the tongue. Immunoglobulins eluted from the skin, cross-reacted with the bile duct epithelium and usually with both ACI and Lewis skin. Increased titers of speckled antinuclear antibodies were present in the serum of rats with chronic (GVHD). Chronic GVHD in the long-term rat radiation chimera is very similar to human chronic GVHD and is a potentially excellent model for autoimmune disorders including scleroderma, Sjorgren's syndrome, and chronic hepatitis

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

Science.gov (United States)

Schneidewind, Laila; Neumann, Thomas; Knoll, Florian; Zimmermann, Kathrin; Smola, Sigrun; Schmidt, Christian Andreas; Krüger, William

2017-01-01

The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed. We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years. Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death. We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding. © 2017 S. Karger AG, Basel.

A Single-Center Pilot Prospective Study of Topical Application of Platelet-Derived Eye Drops for Patients with Ocular Chronic Graft-versus-Host Disease.

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Zallio, Francesco; Mazzucco, Laura; Monaco, Federico; Astori, Maria Rosa; Passera, Roberto; Drago, Giovanna; Tamiazzo, Stefania; Rapetti, Manuela; Dolcino, Daniela; Guaschino, Roberto; Pini, Massimo; Ladetto, Marco

2016-09-01

Ocular involvement of chronic graft-versus-host disease (cGVHD) is a complication that occurs in up to 60% of patients after allogeneic hematopoietic stem cell transplantation. Conventional therapeutic options include medical and surgical procedures that are administered depending on the severity of the condition, but most of them have provided unsatisfactory results and, to date, there is no consensus about treatment. We considered that topical application of a platelet lysate, administered as eye drops, might be considered an alternative worthwhile of investigation to treat ocular surface disorders in patients suffering from cGVHD. Therefore, we conducted a single-center prospective pilot study to assess the efficacy and safety of using eye drops made from reconstituted lysed platelet concentrate. Twenty-six patients with ocular cGVHD were eligible for the study; all but 2 completed their scheduled 1-year treatment and complied with the hematologic and ophthalmic regimen. At their first assessment interviews, after 30 days of treatment, 91% of patients reported an improvement in their symptoms and for 32%, substantive objective differences were measured. Remission of corneal damage was seen for 86% of our cohort, and improved National Institutes of Health scores for 73%, of whom 8% achieved the best score of 0 (ie, non-dry eye). Similar results were seen at later time points. Comparing outcomes for our patient cohort to those determined retrospectively for patients in our institutional database revealed a 5-year overall survival (OS) of 65%. This OS is comparable to patients with limited cGVHD (75%) and is superior to that of patients with nonocular extensive cGVHD or without cGVHD (30% and 59%, respectively) (P = .013). Our results suggest that platelet-derived eye drops are a safe, practical, and well-tolerated therapeutic option that offers substantial benefits for most patients affected by ocular cGVHD at onset. The favorable OS of our patient cohort

Three-dimensional structure discrepancy between HLA alleles for effective prediction of aGVHD severity and optimal selection of recipient-donor pairs: a proof-of-concept study.

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Han, Hongxing; Yuan, Fang; Sun, Yuying; Liu, Jinfeng; Liu, Shuguang; Luo, Yuan; Liang, Fei; Liu, Nan; Long, Juan; Zhao, Xiao; Kong, Fanhua; Xi, Yongzhi

2015-11-24

The optimal selection of recipient-donor pair and accurate prediction of acute graft-versus-host disease (aGVHD) severity are always the two most crucial works in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which currently rests mostly with HLA compatibility, the most polymorphic loci in the human genome, in clinic. Thus, there is an urgent need for a rapid and reliable quantitative system for optimal recipient-donor pairs selection and accurate prediction of aGVHD severity prior to allo-HSCT. For these reasons, we have developed a new selection/prediction system for optimal recipient-donor selection and effective prediction of aGVHD severity based on HLA three-dimensional (3D) structure modeling (HLA-TDSM) discrepancy, and applied this system in a pilot randomized clinical allo-HSCT study. The 37 patient-donor pairs in the study were typed at low- and high-resolution levels for HLA-A/-B/-DRB1/-DQB1 loci. HLA-TDSM system covering the 10000 alleles in HLA class I and II consists of the revised local and coordinate root-mean-square deviation (RMSD) values for each locus. Its accuracy and reliability were confirmed using stably transfected Hmy2.CIR-HLA-B cells, TCR Vβ gene scan, and antigen-specific alloreactive cytotoxic lymphocytes. Based on the preliminary results, we theoretically defined all HLA acceptable versus unacceptable mismatched alleles. More importantly, HLA-TDSM enabled a successful retrospective verification and prospective prediction for aGVHD severity in a pilot randomized clinical allo-HSCT study of 32 recipient-donor transplant pairs. There was a strong direct correlation between single/total revised RMSD and aGVHD severity (92% in retrospective group vs 95% in prospective group). These results seem to be closely related to the 3D structure discrepancy of mismatched HLA-alleles, but not the number or loci of mismatched HLA-alleles. Our data first provide the proof-of-concept that HLA-TDSM is essential for optimal selection of

Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

Science.gov (United States)

Scroggins, Sabrina M; Olivier, Alicia K; Meyerholz, David K; Schlueter, Annette J

2013-01-01

Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months) and older (14-18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may

Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation.

Directory of Open Access Journals (Sweden)

Sabrina M Scroggins

Full Text Available Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD is often a fatal complication following hematopoietic stem cell transplant (HSCT. Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg in young bone marrow transplanted (BMT mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months and older (14-18 months DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2, mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died, there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival compared to young DCreg-treated BMT mice (90% survival. To investigate differences between dendritic cells (DC in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and

A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease

Science.gov (United States)

Zhou, Vivian; Agle, Kimberle; Chen, Xiao; Beres, Amy; Komorowski, Richard; Belle, Ludovic; Taylor, Carolyn; Zhu, Fenlu; Haribhai, Dipica; Williams, Calvin B.; Verbsky, James; Blumenschein, Wendy; Sadekova, Svetlana; Bowman, Eddie; Ballantyne, Christie; Weaver, Casey; Serody, David A.; Vincent, Benjamin; Serody, Jonathan; Cua, Daniel J.; Drobyski, William R.

2016-01-01

Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell–mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin–expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non–Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10–regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers. PMID:27500496

Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party.

Science.gov (United States)

Paviglianiti, Annalisa; Dalle, Jean Hugues; Ayas, Mouhab; Boelens, Jan Jaap; Volt, Fernanda; Iori, Anna Paola; de Souza, Mair Pedro; Diaz, Miguel Angel; Michel, Gerard; Locatelli, Franco; Jubert, Charlotte; Yakoub-Agha, Ibrahim; Bittencourt, Henrique; Bertrand, Yves; Kenzey, Chantal; Tozatto Maio, Karina; Hayashi, Hiromi; Rocha, Vanderson; Bader, Peter; Gluckman, Eliane; Ruggeri, Annalisa

2018-04-01

Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio,  1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Treatment of whole blood with riboflavin plus ultraviolet light, an alternative to gamma irradiation in the prevention of transfusion-associated graft-versus-host disease?

Science.gov (United States)

Fast, Loren D; Nevola, Martha; Tavares, Jennifer; Reddy, Heather L; Goodrich, Ray P; Marschner, Susanne

2013-02-01

Exposure of blood products to gamma irradiation is currently the standard of care in the prevention of transfusion-associated graft-versus-host disease (TA-GVHD). Regulatory, technical, and clinical challenges associated with the use of gamma irradiators are driving efforts to develop alternatives. Pathogen reduction methods were initially developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and white blood cells (WBCs). To date, systems for pathogen and WBC inactivation of products containing red blood cells are less well established than those for platelets and plasma. In this study, the in vitro and in vivo function of WBCs present in whole blood after exposure to riboflavin plus ultraviolet light (Rb-UV) was examined and compared to responses of WBCs obtained from untreated or gamma-irradiated blood by measuring proliferation, cytokine production, activation, and antigen presentation and xenogeneic (X-)GVHD responses in an in vivo mouse model. In vitro studies demonstrated that treatment of whole blood with Rb-UV was as effective as gamma irradiation in preventing WBC proliferation, but was more effective in preventing antigen presentation, cytokine production, and T-cell activation. Consistent with in vitro findings, treatment with Rb-UV was as effective as gamma irradiation in preventing X-GVHD, a mouse model for TA-GVHD. The ability to effectively inactivate WBCs in fresh whole blood using Rb-UV, prior to separation into components, provides the transfusion medicine community with a potential alternative to gamma irradiation. © 2012 American Association of Blood Banks.

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

Science.gov (United States)

Styczynski, Jan; Tridello, Gloria; Gil, Lidia; Ljungman, Per; Hoek, Jennifer; Iacobelli, Simona; Ward, Katherine N; Cordonnier, Catherine; Einsele, Hermann; Socie, Gerard; Milpied, Noel; Veelken, Hendrik; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Maertens, Johan; Blaise, Didier; Cornelissen, Jan; Michallet, Mauricette; Daguindau, Etienne; Petersen, Eefke; Passweg, Jakob; Greinix, Hildegard; Duarte, Rafael F; Kröger, Nicolaus; Dreger, Peter; Mohty, Mohamad; Nagler, Arnon; Cesaro, Simone

2016-07-01

We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. © 2016 by American Society of Clinical Oncology.

Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation.

Science.gov (United States)

Soiffer, Robert J; Kim, Haesook T; McGuirk, Joseph; Horwitz, Mitchell E; Johnston, Laura; Patnaik, Mrinal M; Rybka, Witold; Artz, Andrew; Porter, David L; Shea, Thomas C; Boyer, Michael W; Maziarz, Richard T; Shaughnessy, Paul J; Gergis, Usama; Safah, Hana; Reshef, Ran; DiPersio, John F; Stiff, Patrick J; Vusirikala, Madhuri; Szer, Jeff; Holter, Jennifer; Levine, James D; Martin, Paul J; Pidala, Joseph A; Lewis, Ian D; Ho, Vincent T; Alyea, Edwin P; Ritz, Jerome; Glavin, Frank; Westervelt, Peter; Jagasia, Madan H; Chen, Yi-Bin

2017-12-20

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease.

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Tobin, L M; Healy, M E; English, K; Mahon, B P

2013-05-01

Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchymal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on delivery of human peripheral blood mononuclear cells (PBMC) to non-obese diabetic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rγ(null) (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-γ-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimerism, as CD45(+) and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3(+) T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4(+) T cell proliferation and reduction of human tumour necrosis factor-α in serum. © 2012 British Society for Immunology.

UVB pretreatment of rat bone marrow allografts. Prevention of GVHD and induction of allochimerism and donor-specific unresponsiveness

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Chabot, J.A.; Pepino, P.; Wasfie, T.; Stegall, M.D.; Marboe, C.; Hardy, M.A.

1990-01-01

Ultraviolet B irradiation has been used to pretreat blood and islets to prevent subsequent graft rejection. In this study the optimal dose of UVB irradiation of bone marrow was determined in syngeneic recipients and was subsequently applied to in-vitro treatment of bone marrow allografts. UVB pretreatment of donor bone marrow inoculum led to complete prevention of GVHD in allogeneic rat recipients without major marrow or other toxicity. Long-standing recipients of allogeneic UVB-BM became stable adult chimeras. The recipients of allogeneic BM were populated by donor-type peripheral blood lymphocytes and did not reject host or donor-type heart grafts. The BM allograft recipients were immunocompetent as measured by their ability to normally reject third-party cardiac allografts. We suggest that the prevention of GVHD and induction of stable chimerism in adult recipients of allogeneic UVB-BM may be mediated by suppressor mechanisms

UVB pretreatment of rat bone marrow allografts. Prevention of GVHD and induction of allochimerism and donor-specific unresponsiveness

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Chabot, J.A.; Pepino, P.; Wasfie, T.; Stegall, M.D.; Marboe, C.; Hardy, M.A. (Columbia Univ. College of Physicians and Surgeons, New York, NY (USA))

1990-05-01

Ultraviolet B irradiation has been used to pretreat blood and islets to prevent subsequent graft rejection. In this study the optimal dose of UVB irradiation of bone marrow was determined in syngeneic recipients and was subsequently applied to in-vitro treatment of bone marrow allografts. UVB pretreatment of donor bone marrow inoculum led to complete prevention of GVHD in allogeneic rat recipients without major marrow or other toxicity. Long-standing recipients of allogeneic UVB-BM became stable adult chimeras. The recipients of allogeneic BM were populated by donor-type peripheral blood lymphocytes and did not reject host or donor-type heart grafts. The BM allograft recipients were immunocompetent as measured by their ability to normally reject third-party cardiac allografts. We suggest that the prevention of GVHD and induction of stable chimerism in adult recipients of allogeneic UVB-BM may be mediated by suppressor mechanisms.

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4(+) T-cells.

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Fricke, Stephan; Hilger, Nadja; Fricke, Christian; Schönfelder, Uta; Behre, Gerhard; Ruschpler, Peter; Boldt, Andreas; Oelkrug, Christopher; Sack, Ulrich; Emmrich, Frank

2014-06-01

This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG1 simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG1 was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG1 short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG1 before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG1 anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).

The Genotype of the Donor for the (GTn Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

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Víctor Noriega

Full Text Available The FOXP3 gene encodes for a protein (Foxp3 involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT15 for the (GTn polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021; without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

Platelet lysate mucohadesive formulation to treat oral mucositis in graft versus host disease patients: a new therapeutic approach.

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Del Fante, Claudia; Perotti, Cesare; Bonferoni, Maria Cristina; Rossi, Silvia; Sandri, Giuseppina; Ferrari, Franca; Scudeller, Luigia; Caramella, Carla Marcella

2011-09-01

Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2-8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.

Clinical-Grade-Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell-Dependent Graft-versus-Leukemia Effect in Murine Models.

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Del Papa, Beatrice; Ruggeri, Loredana; Urbani, Elena; Baldoni, Stefano; Cecchini, Debora; Zei, Tiziana; Iacucci Ostini, Roberta; Crescenzi, Barbara; Carotti, Alessandra; Pierini, Antonio; Sportoletti, Paolo; Di Bartolomeo, Paolo; Falzetti, Franca; Mecucci, Cristina; Velardi, Andrea; Martelli, Massimo F; Di Ianni, Mauro

2017-11-01

We developed a good manufacturing practices-compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial

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Locatelli, Franco; Bernardo, Maria Ester; Bertaina, Alice; Rognoni, Carla; Comoli, Patrizia; Rovelli, Attilio; Pession, Andrea; Fagioli, Franca; Favre, Claudio; Lanino, Edoardo; Giorgiani, Giovanna; Merli, Pietro; Pagliara, Daria; Prete, Arcangelo; Zecca, Marco

2017-01-01

Background Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immunemediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II–IV acute graft-versus-host disease (GVHD). Methods We conducted a multicentre, randomised, open-label, p...

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor.

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Nowak, Jacek; Nestorowicz, Klaudia; Graczyk-Pol, Elzbieta; Mika-Witkowska, Renata; Rogatko-Koros, Marta; Jaskula, Emilia; Koscinska, Katarzyna; Madej, Sylwia; Tomaszewska, Agnieszka; Nasilowska-Adamska, Barbara; Szczepinski, Andrzej; Halaburda, Kazimierz; Dybko, Jaroslaw; Kuliczkowski, Kazimierz; Czerw, Tomasz; Giebel, Sebastian; Holowiecki, Jerzy; Baranska, Malgorzata; Pieczonka, Anna; Wachowiak, Jacek; Czyz, Anna; Gil, Lidia; Lojko-Dankowska, Anna; Komarnicki, Mieczyslaw; Bieniaszewska, Maria; Kucharska, Agnieszka; Hellmann, Andrzej; Gronkowska, Anna; Jedrzejczak, Wieslaw W; Markiewicz, Miroslaw; Koclega, Anna; Kyrcz-Krzemien, Slawomira; Mielcarek, Monika; Kalwak, Krzysztof; Styczynski, Jan; Wysocki, Mariusz; Drabko, Katarzyna; Wojcik, Beata; Kowalczyk, Jerzy; Gozdzik, Jolanta; Pawliczak, Daria; Gwozdowicz, Slawomir; Dziopa, Joanna; Szlendak, Urszula; Witkowska, Agnieszka; Zubala, Marta; Gawron, Agnieszka; Warzocha, Krzysztof; Lange, Andrzej

2018-06-01

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT. Copyright © 2018. Published by Elsevier Inc.

Nursing challenges caring for bone marrow transplantation patients with graft versus host disease.

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Neumann, Joyce

2017-12-01

Nursing care of blood and marrow transplantation (BMT) patients is complicated. Nursing considerations of BMT patients with GVHD require an additional set of skills and knowledge that include side effects, both expected and less common, assessment skills, treatment administration, both standard and novel, and acute or intensive care. Nursing care of BMT patients with skin GVHD will be determined by the degree of skin alteration with distinct decisions made about hygiene, both topical and systemic treatment, infection prevention, relief of discomfort, functional ability (ADL) and body image alteration. The nurse needs to have knowledge about assessment criteria for acute and chronic (NIH) assessment with special attention to skin (presence of rash, texture, mobility), joint mobility, mouth care, dressings, and skin care products. Nursing consideration of gastrointestinal GVHD includes importance of accurate intake and output, obtaining culture, fluid and electrolyte imbalance, nutrition, treatment, and skin care. Complication of GVHD treatment, namely effects of steroids require experts from many disciplines to provide comprehensive care. Caring and advocating for GVHD patients may include preparing for outcomes that are undesirable and impact the patient's quality of life and mortality. BMT survivorship programs are a major source of patient education about chronic GVHD for patients after treatment. Caring for BMT patients, especially those experiencing GVHD, takes a knowledgeable, committed, and caring team of healthcare providers. Workshops like this are vital in providing information and networking to keep providers around the region and globe engaged in this critical work. Copyright © 2017. Published by Elsevier B.V.

High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse.

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Machaczka, Maciej; Johansson, Jan-Erik; Remberger, Mats; Hallböök, Helene; Lazarevic, Vladimir Lj; Wahlin, Björn Engelbrekt; Omar, Hamdy; Wahlin, Anders; Juliusson, Gunnar; Kimby, Eva; Hägglund, Hans

2013-12-01

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.

Enfermedad injerto vs hospedero postransfusional en un paciente con leucemia linfoblástica aguda Graft vs host disease after transfusion in a patient with acute linfoblastic leukemia

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TR Nijamin

Full Text Available La enfermedad injerto vs hospedero (EICH es un proceso inmunológico, desencadenado por linfocitos T de un donante inmunocompetente, que reaccionan contra los tejidos de un receptor inmunocomprometido. Esto origina daño multiorgánico severo en el agente receptor. Las manifestaciones cutáneas son un signo clínico relevante en períodos tempranos. La EICH postranfusional (EICH-PT es una entidad poco frecuente y con alta tasa de mortalidad, que se observa en pacientes luego de transfusiones con hemoderivados no irradiados. Los corticoides son el pilar fundamental del tratamiento, una vez instalado el cuadro. La prevención con leucorreducción e irradiación de los componentes sanguíneos, constituye el sustento primordial para evitar su desarrollo. Presentamos un paciente de 5 años de edad, con un diagnóstico de leucemia linfoblástica aguda de alto riesgo, de múltiples transfusiones de glóbulos rojos sin tratamiento radiante previo, a quien se le realiza el diagnóstico dermatológico e histopatológico de EICH aguda postransfusional.Graft vs host disease (GVHD is a process triggered by immune T cells, that react immunocompetent donor tissue against a recipient immunocompromised. This causes severe multiorgan damage in the receiving agent. Cutaneous manifestations are an important clinical sign in early periods. Postranfusional GVHD (GVHD-PT is a rare entity with high mortality rate, observed in patients after transfusion with blood products not previously irradiated. Corticosteroids are the mainstay of treatment after installation of the box, however prevention with leukoreduction and irradiation of blood components remains the mainstay to prevent its development. We present a patient 5 years of age, diagnosed with acute lymphoblastic leukemia at high risk with a history of multiple transfusions of red blood cells without prior radiation treatment, who is performed dermatological and histopathological diagnosis posttransfusion acute GVHD.

Shift of graft-versus-host-disease target organ tropism by dietary vitamin A.

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Christian Koenecke

Full Text Available Gut-homing of donor T cells is causative for the development of intestinal GvHD in recipients of allogeneic hematopoietic stem cell transplantation (HSCT. Expression of the gut-specific homing receptors integrin-α4β7 and chemokine receptor CCR9 on T cells is imprinted in gut-associated lymphoid tissues (GALT under the influence of the vitamin A metabolite retinoic acid. Here we addressed the role of vitamin A deficiency in HSCT-recipients for donor T cell migration in the course of experimental GvHD. Vitamin A-deficient (VAD mice were prepared by feeding them a vitamin A-depleted diet. Experiments were performed in a C57BL/6 into BALB/c model of acute GvHD. We found that expression of integrin-α4β7 and CCR9 in GALT was reduced in VAD recipients after HSCT. Competitive in vivo homing assays showed that allogeneic T cells primed in VAD mice did not home as efficiently to the intestine as T cells primed in mice fed with standard diet (STD. The course of GvHD was ameliorated in VAD HSCT-recipients and, consequently, their survival was prolonged compared to recipients receiving STD. However, VAD-recipients were not protected and died of clinical GvHD. We found reduced numbers of donor T cells in the intestine but increased cell counts and tissue damage in other organs of VAD-recipients. Furthermore, we observed high IFN-γ(+CD4(+ and low FoxP3(+CD4(+ frequencies of total donor CD4(+ T cells in VAD as compared to STD recipients. Taken together, these results indicate that dietary vitamin A deficiency in HSCT-recipients changed target organ tropism in GvHD but also resulted in fatal inflammation after HSCT.

Antilymphocytic antibodies and marrow transplantation. VIII. Recipient conditioning with Clq-affine monoclonal anti-pan T antibodies prevents GVHD in homozygous fully mismatched mice

International Nuclear Information System (INIS)

Thierfelder, S.; Kummer, U.; Schuh, R.; Mysliwietz, J.

1986-01-01

An approach to suppressing secondary disease with antibodies was studied that differed from conventional antibody treatment of donor marrow in vitro. It consisted of the selection of anti-Thy-1 antibodies with high affinity for Clq, the first subunit of the complement cascade, and a single injection of such antibodies into prospective irradiated marrow recipients. Monoclonal mouse IgM and rat IgG 2c antibodies of high titers in complement-dependent test systems but with low affinity for Clq caused little immunosuppression. Monoclonal rat IgG2b or mouse IgG2a anti-Thy-1 antibodies with high affinity for Clq prevented acute and chronic mortality of graft-v-host disease (GVHD), however, when injected in irradiated CBA or AKR mice prior to C57BL/6 spleen and/or bone marrow cell transfusion. This treatment simultaneously suppressed residual host-v-graft reactivity of the irradiated mice, so that permanent hematopoietic engraftment ensued even at 5 or 6 Gy. Full chimerism and specific tolerance were obtained. Primary immune response to SRBC was clearly depressed in the chimeras; secondary immune response was not. Clearance of T cell antibody activity (greater than 6 days), timing, and dose of injected antibody, as well as other modalities of the conditioning treatment that may have contributed to the remarkable immunosuppression, are discussed

Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia.

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Gaziev, J; Isgrò, A; Marziali, M; Daniele, N; Gallucci, C; Sodani, P; Simone, M D; Adorno, G; Paciaroni, K; Andreani, M; Lanti, A; Del Proposto, G; Testi, M; De Angelis, G; Roveda, A; Alfieri, C; Saltarelli, F; Lucarelli, G

2012-01-01

We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 × 10(6)/kg) and CD34(+) (4 × 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD.

Freeze and Thaw of CD4+CD25+Foxp3+ Regulatory T Cells Results in Loss of CD62L Expression and a Reduced Capacity to Protect against Graft-versus-Host Disease.

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Mareike Florek

Full Text Available The adoptive transfer of CD4+CD25+Foxp3+ regulatory T cells (Tregs in murine models of allogeneic hematopoietic cell transplantation (HCT has been shown to protect recipient mice from lethal acute graft-versus-host disease (GVHD and this approach is being actively investigated in human clinical trials. Here, we examined the effects of cryopreservation on Tregs. We found that freeze and thaw of murine and human Tregs is associated with reduced expression of L-selectin (CD62L, which was previously established to be an important factor that contributes to the in vivo protective effects of Tregs. Frozen and thawed murine Tregs showed a reduced capacity to bind to the CD62L binding partner MADCAM1 in vitro as well as an impaired homing to secondary lymphoid organs in vivo. Upon adoptive transfer frozen and thawed Tregs failed to protect against lethal GVHD compared with fresh Tregs in a murine model of allogeneic HCT across major histocompatibility barriers. In summary, the direct administration of adoptively transferred frozen and thawed Tregs adversely affects their immunosuppressive potential which is an important factor to consider in the clinical implementation of Treg immunotherapies.

Comparisons Between Allogeneic Peripheral Blood Stem Cell Transplantation and Allogeneic Bone Marrow Transplantation in Adult Hematologic Disease: A Single Center Experience

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Yi-Chang Liu

2003-11-01

Full Text Available This retrospective study compared the outcomes in 32 adult patients with hematologic diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, severe aplastic anemia who received allogeneic bone marrow transplantation (BMT, n = 14; median age, 28 years or allogeneic peripheral blood stem cell transplantation (PBSCT, n = 18; median age, 29 years from human leukocyte antigen-identical sibling donors. Median follow-up was 58 months in BMT recipients and 18 months in PBSCT recipients. Neutrophil (median, Day 8 vs Day 13, p < 0.001 and platelet engraftment (median, Day 9 vs Day 17, p < 0.001 was faster in the PBSCT group than in the BMT group. Patients receiving PBSCT required less platelet transfusion than those receiving BMT (median, 54 units vs 144 units, p < 0.001, but there was no significant difference in red cell transfusion. At 100 days, there was no difference in the incidence of acute graft-versus-host disease (GVHD (42.9% vs 33.3%, p = 0.72 or grade II-IV acute GVHD (14.3% vs 5.6%, p = 0.57, and there was no difference in the cumulative incidence of chronic GVHD (20% vs 33.3%, p = 0.67. No chronic GVHD was noted in any relapsed patients (BMT, 5; PBSCT, 3, and no patients with chronic GVHD during follow-up had a relapse. Relapse was the most frequent cause of death in both groups (BMT, 5/9, 55.6%; PBSCT, 3/4, 75%; p = 0.25; all relapses occurred within 1 year after transplantation. Overall survival was significantly better in the PBSCT group (35.7% vs 77.8%, p = 0.029, but this difference was lost if only hematologic malignancies were analyzed (30.8% vs 63.6%, p = 0.20. Our results are similar to those reported previously, with faster neutrophil and platelet engraftment and less severe acute GVHD and extensive chronic GVHD with PBSCT. Allogeneic PBSCT is a feasible and beneficial alternative to allogeneic BMT in adult hematologic disease.

[Skin biopsy in diagnosis of chronic graft-versus-host disease in patients after allogeneic haematopoietic stem cell transplantation: pathologist's point of view on quantitative scoring system].

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Grzanka, Dariusz; Styczyński, Jan; Debski, Robert; Krenska, Anna; Pacholska, Małgorzata; Prokurat, Andrzej I; Wysocki, Mariusz; Marszałek, Andrzej

2008-01-01

Pathology diagnosis of chronic graft-versus-host-disease (GVHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an important issue in clinical follow-up, in spite of frequent difficulties in interpretation., related to dynamic changes occurring in the skin during the disease, as well as to sequelae of basic disease and immunosuppressive therapy. Recently presented Consensus NIH (National Health Institute, Bethesda, USA) of histopathologic (HP) analysis is still complex and intrinsically divergent, thus clinically difficult to implement. Analysis of clinical value of histological evaluation results of skin biopsy in children after allo-HSCT and its correlation with clinical status. Ten skin biopsies were taken from 7 patients (4 boys, 3 girls, age 3-15 years) after allo-HSCT (6 MFD, 1 MMUD) and analyzed after hematoxylin/eosine and immunohistochemical (CD3, CD45T, CD20) staining. Pathology analysis was based on commonly accepted criteria enabling simple and unambiguous interpretation. Results were compared with clinical data and indications for immunosuppressive therapy. It was found that reliable and coherent interpretation can be made when following parameters were taken into account: 1. in epithelium: the presence of apoptosis, archetypical changes and vacuolar degeneration in the basilar layer, presence of CD3/CD45 in the epidermis; 2. in the dermis: the extent of collagenization, presence of melanophages and lymphocyte infiltrations; 3. in the eccrine glands epithelium: eccrine glands atrophy and presence of lymphocytes. A new scoring system of skin biopsy analysis in patients with chronic GVHD based on the modified NIH Consensus was proposed. The preliminary clinical value of histological results was assessed. Skin biopsy evaluation based on limited qualitative and quantitative analysis of lymphocyte infiltrates together with studies on intensity of apoptosis, collagenization and archetypical changes is a valuable diagnostic method

Use of telecobalt-therapy in transfusion-associated graft-versus-host disease; Uso da telecobaltoterapia na prevencao da doenca enxerto-versus-hospedeiro associada a transfusao

Energy Technology Data Exchange (ETDEWEB)

Goes, Evamberto Garcia de

1999-08-01

The transfusion-associated Graft-Versus-Host Disease (TA-GVHD) is prevented through the irradiation of blood components before transfusion. This work started with a diagnostic about blood irradiation practices in Brazil, through the application of a questionnaire to 56 regional blood centers, and showed that the majority of the regional blood centers have no means to irradiate their own blood components. This survey have also shown that 62,5% of the regional blood centers have local facilities to irradiate their own blood components, through the use of telecobalt-therapy services. Assuming the use of telecobalt-therapy equipment as an alternative solution to the Brazilian blood irradiation problem, the development of an appropriate technique allowed a good quality for irradiated blood. A prototype of a thermic box was made in acrylic and foam, and an automated system of data acquisition, kept the temperature of blood components bellow 6 deg C, during irradiation. Phantoms built using polystyrene plastic represented blood volume routinely irradiated by the regional blood centers. The distribution of doses on the phantoms volumes determined with LiF-100 thermoluminescent dosimeters, were represented in terms of isodoses curves. The doses distributions on the phantom with higher dimensions, 30 x 30 x 20 cm, changed from a minimum relative dose of 80% up to a maximum of 106%. An investigation concerning effects of Cobalt-60 gamma radiation on red blood cells, irradiated and stored, showed increase in potassium levels, up to the tenth day, in blood units irradiated at 3,00 cGy. Surveillance of the reduction in the capacity of T-Cells proliferation as a function of dose, using Limiting Dilution Analysis, showed that a minimum of 2,500 cGy is necessary to prevent TA-GVHD. Methodology developed in this work guarantee good quality for blood irradiated with telecobalt-therapy equipment, a valid alternative for Brazilian institutions which have available only this technique

Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study.

Science.gov (United States)

Akpek, Gorgun; Lee, Stephanie J; Flowers, Mary E; Pavletic, Steven Z; Arora, Mukta; Lee, Shing; Piantadosi, Steven; Guthrie, Katherine A; Lynch, James C; Takatu, Alessandra; Horowitz, Mary M; Antin, Joseph H; Weisdorf, Daniel J; Martin, Paul J; Vogelsang, Georgia B

2003-08-01

We recently reported 3 risk factors (RFs) at diagnosis of chronic graft-versus-host disease (cGVHD) that were significantly associated with increased nonrelapse mortality. These included extensive skin involvement (ESI), thrombocytopenia (TP), and progressive type of onset (PTO). The hazard ratio (HR) for mortality of the patients with prognostic score (PS) between 0 and 2 (intermediate-risk; 1 RF) compared to those with PS 0 (favorable-risk; 0 RF) was 3.7 (95% CI, 1.4, 9.3); the HR for patients with PS equal to or more than 2 (high-risk; > 1 RF) compared with intermediate-risk group was 6.9 (3.8, 12.4). A rare presentation of TP and PTO without ESI yielded a PS of 1.8 (intermediate-risk). This paper reports the performance of the prognostic model and the individual RFs using data from an additional 1105 patients from University of Nebraska (n = 60), International Bone Marrow Transplantation Registry (n = 708), Fred Hutchinson Cancer Research Center (n = 188), and University of Minnesota (n = 149). The extent of skin involvement was quantified in 3 cohorts using the available data collected in different formats before the analysis. Although the HR for mortality of the patients in the intermediate-risk group versus those in the favorable-risk group ranged from 2.3 to 8.9 across the centers, it was between 1.6 to 6.9 for patients in the high-risk group versus those in the intermediate-risk group. Although TP itself was uniformly associated with increased risk of mortality across all test samples, ESI and PTO showed statistically significant associations with mortality in 1 and 2 cohorts, respectively. In conclusion, the model was predictive of cGVHD-specific survival, but the mortality hazard associated with ESI was lower in each of these test samples compared with the learning sample. Although the new clinical grading based on the model is promising because of its utility across multiple independent data sets, prospective validation is needed.

Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

OpenAIRE

Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R.; Sauer, Martin G.

2009-01-01

Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cel...

GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

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... Disease): A guide for patients and families after stem cell transplant The immune system is the body's tool ... and attacking them. When you receive a donor's stem cells (the “graft”), the stem cells recreate the donor's ...

Immunothérapie adoptive pour le traitement des infections à Adénovirus réfractaires après allogreffes de Cellules Souches Hématopoïétiques : de la recherche fondamentale à la recherche clinique

OpenAIRE

Qian , Chongsheng

2017-01-01

Hematopoietic stem cell transplantation (HSCT) is one of the only curative treatments for benign or malignant hematological diseases and primary immune deficiencies. However, viral infections and graft-versus-host disease (GVHD) are among the most frequent complications after HSCT associated with high morbidity and mortality. Viral infections often occur in the absence of specific immune reconstitution in the context of immunosuppression related to GVHD itself or to the prophylaxis or treatme...

Prevention of transfusion-associated graft-versus-host disease by irradiation: technical aspect of a new ferrous sulphate dosimetric system.

Directory of Open Access Journals (Sweden)

Lucas Sacchini Del Lama

Full Text Available Irradiation of whole blood and blood components before transfusion is currently the only accepted method to prevent Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD. However, choosing the appropriate technique to determine the dosimetric parameters associated with blood irradiation remains an issue. We propose a dosimetric system based on the standard Fricke Xylenol Gel (FXG dosimeter and an appropriate phantom. The modified dosimeter was previously calibrated using a (60Co teletherapy unit and its validation was accomplished with a (137Cs blood irradiator. An ionization chamber, standard FXG, radiochromic film and thermoluminescent dosimeters (TLDs were used as reference dosimeters to determine the dose response and dose rate of the (60Co unit. The dose distributions in a blood irradiator were determined with the modified FXG, the radiochromic film, and measurements by TLD dosimeters. A linear response for absorbed doses up to 54 Gy was obtained with our system. Additionally, the dose rate uncertainties carried out with gel dosimetry were lower than 5% and differences lower than 4% were noted when the absorbed dose responses were compared with ionization chamber, film and TLDs.

Prevention of Transfusion-Associated Graft-versus-Host Disease by Irradiation: Technical Aspect of a New Ferrous Sulphate Dosimetric System

Science.gov (United States)

Del Lama, Lucas Sacchini; de Góes, Evamberto Garcia; Petchevist, Paulo César Dias; Moretto, Edson Lara; Borges, José Carlos; Covas, Dimas Tadeu; de Almeida, Adelaide

2013-01-01

Irradiation of whole blood and blood components before transfusion is currently the only accepted method to prevent Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD). However, choosing the appropriate technique to determine the dosimetric parameters associated with blood irradiation remains an issue. We propose a dosimetric system based on the standard Fricke Xylenol Gel (FXG) dosimeter and an appropriate phantom. The modified dosimeter was previously calibrated using a 60Co teletherapy unit and its validation was accomplished with a 137Cs blood irradiator. An ionization chamber, standard FXG, radiochromic film and thermoluminescent dosimeters (TLDs) were used as reference dosimeters to determine the dose response and dose rate of the 60Co unit. The dose distributions in a blood irradiator were determined with the modified FXG, the radiochromic film, and measurements by TLD dosimeters. A linear response for absorbed doses up to 54 Gy was obtained with our system. Additionally, the dose rate uncertainties carried out with gel dosimetry were lower than 5% and differences lower than 4% were noted when the absorbed dose responses were compared with ionization chamber, film and TLDs. PMID:23762345

Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease

KAUST Repository

Kim, YongHwan; Jin, Hye Jin; Heo, Jinbeom; Ju, Hyein; Lee, Hye-Yeon; Kim, Sujin; Lee, Seungun; Lim, Jisun; Jeong, Sang Young; Kwon, JiHye; Kim, Miyeon; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Hwang, Hyun Ho; Yu, Hwan Yeul; Ryu, Chae-Min; Jeon, Hong Bae; Shin, Dong-Myung

2018-01-01

mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical

Fulminant transfusion-associated graft-versus-host disease in a premature infant

International Nuclear Information System (INIS)

Berger, R.S.; Dixon, S.L.

1989-01-01

A fatal case of transfusion-associated graft-versus-host disease developed in a premature infant after receiving several blood products, including nonirradiated white blood cells. Transfusion-associated graft-versus-host disease can be prevented. Irradiation of blood products is the least controversial and most effective method. Treatment was unsuccessful in most reported cases of transfusion-associated graft-versus-host disease. Therefore irradiation of blood products before transfusing to patients susceptible to transfusion-associated graft-versus-host disease is strongly recommended

Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial.

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Locatelli, Franco; Bernardo, Maria Ester; Bertaina, Alice; Rognoni, Carla; Comoli, Patrizia; Rovelli, Attilio; Pession, Andrea; Fagioli, Franca; Favre, Claudio; Lanino, Edoardo; Giorgiani, Giovanna; Merli, Pietro; Pagliara, Daria; Prete, Arcangelo; Zecca, Marco

2017-08-01

Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD). We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557. Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1

Suppressor cells in transplantation tolerance. III. The role of antigen in the maintenance of transplantation tolerance

International Nuclear Information System (INIS)

Tutschka, P.J.; Hess, A.D.; Beschorner, W.E.; Santos, G.W.

1982-01-01

Suppressor cells, which in an alloantigen-specific manner inhibit proliferation of donor cells to host antigens in a mixed lymphocyte culture and adoptively transfer the suppression of graft-versus-host disease (GVHD), undergo a gradual clonal reduction in long-term, allogeneic, histoincompatible rat radiation chimeras until they can no longer be measured in an in vitro suppressor cell assay. When lymphohematopoietic cells from these chimeras are transferred into lethally irradiated secondary recipients of original donor strain, the suppressor cells, now in a target antigen-free environment, undergo a further clonal reduction. After parking for 120 days, the chimeric cells are specifically tolerant to original host antigens, but cannot adoptively transfer suppression of GVHD. When chimeric cells, parked for 120 days in secondary recipients of original donor strain, are stimulated with original host-type antigen repeatedly during or once at the end of the parking period, the suppressor cell clone is expanded, suppressor cells can be identified in vitro, and suppression of GVHD can adoptively be transferred to tertiary recipients

Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras.

Science.gov (United States)

Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R; Sauer, Martin G

2009-04-30

Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease.

Science.gov (United States)

Fulton, LeShara M; Taylor, Nicholas A; Coghill, James M; West, Michelle L; Föger, Niko; Bear, James E; Baldwin, Albert S; Panoskaltsis-Mortari, Angela; Serody, Jonathan S

2014-06-01

Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD. Here, we show that T cells from mice lacking Coronin 1A (Coro 1A(-/-)), an actin-associated protein shown to be important for thymocyte egress, do not mediate acute GvHD. The attenuation of aGvHD was associated with decreased expression of the critical trafficking proteins C-C chemokines receptor type 7 (CCR7) and sphingosine 1 phosphate receptor on donor T cells. This was mediated in part by impaired activation of the canonical NF-κB pathway in the absence of Coro 1A. As a result of these alterations, donor T cells from Coro 1A(-/-) mice were not able to initially traffic to SLT or exit SLT after BM transplantation. However, this alteration did not abrogate the graft-versus-leukemia response. Our data suggest that blocking T-cell migration into and out of SLT is a valid approach to prevent aGvHD. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A randomized study of the prevention of acute graft-versus-host disease

International Nuclear Information System (INIS)

Ramsay, N.K.C.; Kersey, J.H.; Robison, L.L.; McGlave, P.B.; Woods, W.G.; Krivit, W.; Kim, T.H.; Goldman, A.I.; Nesbit, M.E. Jr.

1982-01-01

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 percent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants

Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations*

Science.gov (United States)

Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; de Souza, Mair Pedro; Orti-Raduan, Érica Sinara Lenharo; Salvio, Ana Gabriela

2014-01-01

The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease. PMID:25054751

Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations.

Science.gov (United States)

Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; Souza, Mair Pedro de; Orti-Raduan, Erica Sinara Lenharo; Salvio, Ana Gabriela

2014-01-01

The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease.

Host susceptibility hypothesis for shell disease in American lobsters.

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Tlusty, Michael F; Smolowitz, Roxanna M; Halvorson, Harlyn O; DeVito, Simone E

2007-12-01

Epizootic shell disease (ESD) in American lobsters Homarus americanus is the bacterial degradation of the carapace resulting in extensive irregular, deep erosions. The disease is having a major impact on the health and mortality of some American lobster populations, and its effects are being transferred to the economics of the fishery. While the onset and progression of ESD in American lobsters is undoubtedly multifactorial, there is little understanding of the direct causality of this disease. The host susceptibility hypothesis developed here states that although numerous environmental and pathological factors may vary around a lobster, it is eventually the lobster's internal state that is permissive to or shields it from the final onset of the diseased state. To support the host susceptibility hypothesis, we conceptualized a model of shell disease onset and severity to allow further research on shell disease to progress from a structured model. The model states that shell disease onset will occur when the net cuticle degradation (bacterial degradation, decrease of host immune response to bacteria, natural wear, and resorption) is greater than the net deposition (growth, maintenance, and inflammatory response) of the shell. Furthermore, lesion severity depends on the extent to which cuticle degradation exceeds deposition. This model is consistent with natural observations of shell disease in American lobster.

The impact of chronic GVHD on survival of Patients with acute myeloid leukemia after non-T-cell depleted HLA-identical sibling peripheral blood stem cells transplantation

Directory of Open Access Journals (Sweden)

farhad Shahsavar

2012-06-01

Conclusion: These data indicate that the occurrence of cGVHD is an important predictor of outcome of non-T-cell depleted HLA-identical sibling allogeneic PBSCT, in those AML patients who develope cGVHD have a high chance of survival.

Marek’s disease herpesvirus vaccines integrate into chicken host chromosomes yet lack a virus-host phenotype associated with oncogenic transformation

Science.gov (United States)

Marek's disease (MD) is a lymphotrophic and oncogenic disease of chickens that can lead to death in susceptible and unimmunized host birds. The causative pathogen, Marek's disease virus (MDV), a highly oncogenic alphaherpesvirus, integrates into host genome near the telomeres during viral latency an...

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

Science.gov (United States)

Güngör, Tayfun; Teira, Pierre; Slatter, Mary; Stussi, Georg; Stepensky, Polina; Moshous, Despina; Vermont, Clementien; Ahmad, Imran; Shaw, Peter J; Telles da Cunha, José Marcos; Schlegel, Paul G; Hough, Rachel; Fasth, Anders; Kentouche, Karim; Gruhn, Bernd; Fernandes, Juliana F; Lachance, Silvy; Bredius, Robbert; Resnick, Igor B; Belohradsky, Bernd H; Gennery, Andrew; Fischer, Alain; Gaspar, H Bobby; Schanz, Urs; Seger, Reinhard; Rentsch, Katharina; Veys, Paul; Haddad, Elie; Albert, Michael H; Hassan, Moustapha

2014-02-01

In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid

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.

Ibrutinib Effective against Graft-Versus-Host Disease

Science.gov (United States)

A Cancer Currents blog post on results from a small clinical trial showing that ibrutinib can effectively treat graft-versus-host-disease, a common and serious complication of allogeneic stem cell transplants.

Cytogenetic studies in dogs after total body irradiation and allogeneic transfusion with cryopreserved blood mononuclear cells: observations in long-term chimeras

International Nuclear Information System (INIS)

Carbonell, F.; Calvo, W.; Fliedner, T.M.; Kratt, E.; Gerhartz, H.; Koerbling, M.; Nothdurft, W.; Ross, W.M.

1984-01-01

Cytogenetic studies were performed on two dog groups after total body irradiation and allogeneic transfusion with cryopreserved blood mononuclear cells. The first group of dogs was transfused with unseparated leukocytes and suffered from graft-versus-host disease (GvHD). Cytogenetic studies demonstrated only cells of donor origin in all dogs of this group. The second group of animals was transfused with fraction 2 of a discontinuous albumin gradient. The dogs of this group did not develop GvHD, and the cytogenetic studies showed the presence of a mosaic of cells from donor and recipient origin in all of them. These results suggest that the GvHD may suppress autochthonous regeneration

Ecosystem screening approach for pathogen-associated microorganisms affecting host disease.

Science.gov (United States)

Galiana, Eric; Marais, Antoine; Mura, Catherine; Industri, Benoît; Arbiol, Gilles; Ponchet, Michel

2011-09-01

The microbial community in which a pathogen evolves is fundamental to disease outcome. Species interacting with a pathogen on the host surface shape the distribution, density, and genetic diversity of the inoculum, but the role of these species is rarely determined. The screening method developed here can be used to characterize pathogen-associated species affecting disease. This strategy involves three steps: (i) constitution of the microbial community, using the pathogen as a trap; (ii) community selection, using extracts from the pathogen as the sole nutrient source; and (iii) molecular identification and the screening of isolates focusing on their effects on the growth of the pathogen in vitro and host disease. This approach was applied to a soilborne plant pathogen, Phytophthora parasitica, structured in a biofilm, for screening the microbial community from the rhizosphere of Nicotiana tabacum (the host). Two of the characterized eukaryotes interfered with the oomycete cycle and may affect the host disease. A Vorticella species acted through a mutualistic interaction with P. parasitica, disseminating pathogenic material by leaving the biofilm. A Phoma species established an amensal interaction with P. parasitica, strongly suppressing disease by inhibiting P. parasitica germination. This screening method is appropriate for all nonobligate pathogens. It allows the definition of microbial species as promoters or suppressors of a disease for a given biotope. It should also help to identify important microbial relationships for ecology and evolution of pathogens.

Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning.

Science.gov (United States)

Raj, Kavita; Pagliuca, Antonio; Bradstock, Kenneth; Noriega, Victor; Potter, Victoria; Streetly, Matthew; McLornan, Donal; Kazmi, Majid; Marsh, Judith; Kwan, John; Huang, Gillian; Getzendaner, Lisa; Lee, Stephanie; Guthrie, Katherine A; Mufti, Ghulam J; O'Donnell, Paul

2014-06-01

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Bone marrow transplantation for acute myelogenous leukemia: factors associated with early mortality

International Nuclear Information System (INIS)

Bortin, M.M.; Gale, R.P.; Kay, H.E.; Rimm, A.A.

1983-01-01

Comprehensive data were reported to the International Bone Marrow Transplant Registry, Milwaukee, regarding 156 patients with acute myelogenous leukemia who were treated with allogeneic bone marrow transplantation between 1978 and 1980. The minimum observation period was 15 months after transplant and most deaths occurred within the first six months. Prognostic factors were evaluated for associations with early mortality or life-threatening complications. Most early deaths were due to infections, interstitial pneumonitis, and graft-v-host disease (GVHD). Multivariate analyses disclosed five factors with significant associations with early death or a major cause of early death: (1) disease status; (2) dose-rate of irradiation; (3) drug used to prevent GVHD; (4) severity of GVHD; and (5) dose of marrow cells.It is emphasized that several of the important prognostic factors are within the control of the referring physician or the transplant team

Reservoir-host amplification of disease impact in an endangered amphibian.

Science.gov (United States)

Scheele, Ben C; Hunter, David A; Brannelly, Laura A; Skerratt, Lee F; Driscoll, Don A

2017-06-01

Emerging wildlife pathogens are an increasing threat to biodiversity. One of the most serious wildlife diseases is chytridiomycosis, caused by the fungal pathogen, Batrachochytrium dendrobatidis (Bd), which has been documented in over 500 amphibian species. Amphibians vary greatly in their susceptibility to Bd; some species tolerate infection, whereas others experience rapid mortality. Reservoir hosts-species that carry infection while maintaining high abundance but are rarely killed by disease-can increase extinction risk in highly susceptible, sympatric species. However, whether reservoir hosts amplify Bd in declining amphibian species has not been examined. We investigated the role of reservoir hosts in the decline of the threatened northern corroboree frog (Pseudophryne pengilleyi) in an amphibian community in southeastern Australia. In the laboratory, we characterized the response of a potential reservoir host, the (nondeclining) common eastern froglet (Crinia signifera), to Bd infection. In the field, we conducted frog abundance surveys and Bd sampling for both P. pengilleyi and C. signifera. We built multinomial logistic regression models to test whether Crinia signifera and environmental factors were associated with P. pengilleyi decline. C. signifera was a reservoir host for Bd. In the laboratory, many individuals maintained intense infections (>1000 zoospore equivalents) over 12 weeks without mortality, and 79% of individuals sampled in the wild also carried infections. The presence of C. signifera at a site was strongly associated with increased Bd prevalence in sympatric P. pengilleyi. Consistent with disease amplification by a reservoir host, P. pengilleyi declined at sites with high C. signifera abundance. Our results suggest that when reservoir hosts are present, population declines of susceptible species may continue long after the initial emergence of Bd, highlighting an urgent need to assess extinction risk in remnant populations of other declined

Bone marrow transplantation

International Nuclear Information System (INIS)

Storb, R.; Santos, G.W.

1979-01-01

Bone marrow transplantation has been increasingly used to treat patients with severe combined immunodeficiency diseases, severe aplastic anemia, and malignant hematologic diseases, especially leukemia. At the Workshop a number of problems were discussed, e.g., conditioning regimens aimed at overcoming the problem of marrow graft rejection and reducing the incidence of recurrent leukemia, prevention of graft-versus-host disease (GVHD), possible mechanisms involved in stable graft-host tolerance, graft-versus-leukemia effect in mice, and finally, the possible use of autologous marrow transplantation

Search for alternate hosts of the coconut Cape Saint Paul Wilt Disease pathogen

Directory of Open Access Journals (Sweden)

Yankey Egya Ndede

2009-03-01

Full Text Available Lethal Yellowing disease locally called Cape Saint Paul wilt disease (CSPWD is the bane of the coconut industry in Ghana and is caused by a phytoplasma. In Ghana, there are areas where the disease has re-infected re-plantings long after decimating all the palms in the area. This brings to the fore the possibility of alternate hosts in the spread of the disease because the pathogen is an obligate parasite. In this work, a number of plants were screened for their host status to the CSPWD pathogen. The presence of phytoplasmas in these plants was tested by polymerase chain reaction analysis using universal phytoplasma primers P1/P7 and CSPWD-specific primers G813/GAKSR. Although Desmodium adscendens tested positive to the CSPWD-specific primers, cloning and sequencing did not confirm it as an alternate host. The identification of alternate hosts will help us to evolve sound control strategies against the spread of the disease.

Host genetics of Epstein-Barr virus infection, latency and disease.

Science.gov (United States)

Houldcroft, Charlotte J; Kellam, Paul

2015-03-01

Epstein-Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host-EBV interaction. © 2014 The Authors Reviews in Medical Virology published by John Wiley & Sons Ltd.

Etanercept on steroid-refractary acute graft-versus-host disease

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Silvia González Munguía

2015-02-01

Full Text Available Objetive: To describe etanercept use and effectiveness on steroid- refractary acute graft-versus-host disease after hematopoietic cell transplantation. Method: Patients treated with etanercept as off label use for steroid-refractary acute graft-versus-host disease were selected and each patient’s medical history was reviewed to assess the clinical response. Results: The study included five patients: four presented with digestive manifestations and one presented pulmonary and liver manifestations. 80% of patients showed a clinical response: 60% a partial response and 20% a total response. In four cases etanercept 25mg was administered twice a week with variable duration of treatment, achieving no response in 1 case (3 weeks, partial response in two 2 cases (4 weeks and 8 weeks and a complete response in 1 case (8 week period. Only one case was treated with etanercept 50mg administered twice a week for 5 weeks with a partial treatment response. Conclusions: The clinical response rate is consistent with the previously published data. This updates the scarce bibliographic information about etanecept use in steroid-refractary acute graft-versus-host disease. Due to clinical design limitations and the small patient population, future clinical studies should be conducted to assess the efficacy and security of etanercept in these patients.

Infectious diseases of marine molluscs and host responses as revealed by genomic tools

Science.gov (United States)

Ford, Susan E.

2016-01-01

More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc's defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance. PMID:26880838

Dynamics and Biocontrol: The Indirect Effects of a Predator Population on a Host-Vector Disease Model

Directory of Open Access Journals (Sweden)

Fengyan Zhou

2014-01-01

Full Text Available A model of the interactions among a host population, an insect-vector population, which transmits virus from hosts to hosts, and a vector predator population is proposed based on virus-host, host-vector, and prey (vector-enemy theories. The model is investigated to explore the indirect effect of natural enemies on host-virus dynamics by reducing the vector densities, which shows the basic reproduction numbers R01 (without predators and R02 (with predators that provide threshold conditions on determining the uniform persistence and extinction of the disease in a host population. When the model is absent from predator, the disease is persistent if R01>1; in such a case, by introducing predators of a vector, then the insect-transmitted disease will be controlled if R02<1. From the point of biological control, these results show that an additional predator population of the vector may suppress the spread of vector-borne diseases. In addition, there exist limit cycles with persistence of the disease or without disease in presence of predators. Finally, numerical simulations are conducted to support analytical results.

Degree of Predicted Minor Histocompatibility Antigen Mismatch Correlates with Poorer Clinical Outcomes of Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

DEFF Research Database (Denmark)

Larsen, Malene Erup; Kornblit, B; Larsen, Mette Voldby

2010-01-01

In fully HLA-matched allogeneic hematopoietic cell transplantations (HCT), the main mechanism of the beneficial graft-versus-tumor (GVT) effect and of the detrimental graft-versus-host disease (GVHD) is believed to be caused by donor cytotoxic T cells directed against disparate recipient minor hi...

HLA-DP and bone marrow transplantation: DP-incompatibility and severe acute graft versus host disease

DEFF Research Database (Denmark)

Ødum, Niels; Platz, P; Jakobsen, B K

1987-01-01

Thirteen recipients of HLA-haploidentical, DR compatible bone marrow (BM) and the corresponding BM donors were HLA-DP typed using primed lymphocyte typing (PLT). Severe acute GVHD (greater than or equal to grade 2) developed within 3 months after BM-transplantation in all of eight recipients of DP...... a role as transplantation antigens....

Quality evaluation of blood irradiation process;Avaliacao da qualidade do processo de irradiacao de hemocomponentes

Energy Technology Data Exchange (ETDEWEB)

Goto, R.E.; Medeiros, R.B. [Universidade Federal de Sao Paulo (DDI/UNIFESP), SP (Brazil). Dept. de Diagnostico por Imagem. Coordenadoria de Fisica e Higiene das Radiacoes

2009-07-01

An adverse reaction in blood transfusion is the graft versus host disease (GVHD). This disease affects immunodeficient or immunosuppressed patients where transfused T cells proliferate and initiate a host's immune system reaction. Blood gamma irradiation is the most efficient way to inhibit lymphocyte T blastic transformation and mitotic activity and it is the most effective method to combat this disorder. However, there is no fast and effective system to analyze the dose distribution in the irradiation process and guarantee that the absorbed doses are in agreement with FDA recommendations. This study aims to establish a periodic quality control of the gammacell irradiators using radiochromic films properly calibrated. The quality control is simply and effective to combat GVHD as well as is useful to detect mechanical fails at rotation set system through the dose uniformity analysis. It was possible to verify the uniformity ranged from -72.38% to 106.33% and some blood bag received doses not compatible with recommended international threshold. (author)

Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

Science.gov (United States)

Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

2017-08-01

Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 10 8 /kg and 4.3 × 10 6 /kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases.

Science.gov (United States)

Tucunduva, Luciana; Volt, Fernanda; Cunha, Renato; Locatelli, Franco; Zecca, Marco; Yesilipek, Akif; Caniglia, Maurizio; Güngör, Tayfun; Aksoylar, Serap; Fagioli, Franca; Bertrand, Yves; Addari, Maria Carmen; de la Fuente, Josu; Winiarski, Jacek; Biondi, Andrea; Sengeloev, Henrik; Badell, Isabel; Mellgren, Karin; de Heredia, Cristina Díaz; Sedlacek, Petr; Vora, Ajay; Rocha, Vanderson; Ruggeri, Annalisa; Gluckman, Eliane

2015-04-01

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD. © 2014 John Wiley & Sons Ltd.

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

OpenAIRE

Xu, Jia; Verbrugghe, Adronie; Louren?o, Marta; Janssens, Geert P. J.; Liu, Daisy J. X.; Van de Wiele, Tom; Eeckhaut, Venessa; Van Immerseel, Filip; Van de Maele, Isabel; Niu, Yufeng; Bosch, Guido; Junius, Greet; Wuyts, Brigitte; Hesta, Myriam

2016-01-01

Background Inflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host me...

Linking spring phenology with mechanistic models of host movement to predict disease transmission risk

Science.gov (United States)

Merkle, Jerod A.; Cross, Paul C.; Scurlock, Brandon M.; Cole, Eric K.; Courtemanch, Alyson B.; Dewey, Sarah R.; Kauffman, Matthew J.

2018-01-01

Disease models typically focus on temporal dynamics of infection, while often neglecting environmental processes that determine host movement. In many systems, however, temporal disease dynamics may be slow compared to the scale at which environmental conditions alter host space-use and accelerate disease transmission.Using a mechanistic movement modelling approach, we made space-use predictions of a mobile host (elk [Cervus Canadensis] carrying the bacterial disease brucellosis) under environmental conditions that change daily and annually (e.g., plant phenology, snow depth), and we used these predictions to infer how spring phenology influences the risk of brucellosis transmission from elk (through aborted foetuses) to livestock in the Greater Yellowstone Ecosystem.Using data from 288 female elk monitored with GPS collars, we fit step selection functions (SSFs) during the spring abortion season and then implemented a master equation approach to translate SSFs into predictions of daily elk distribution for five plausible winter weather scenarios (from a heavy snow, to an extreme winter drought year). We predicted abortion events by combining elk distributions with empirical estimates of daily abortion rates, spatially varying elk seroprevelance and elk population counts.Our results reveal strong spatial variation in disease transmission risk at daily and annual scales that is strongly governed by variation in host movement in response to spring phenology. For example, in comparison with an average snow year, years with early snowmelt are predicted to have 64% of the abortions occurring on feedgrounds shift to occurring on mainly public lands, and to a lesser extent on private lands.Synthesis and applications. Linking mechanistic models of host movement with disease dynamics leads to a novel bridge between movement and disease ecology. Our analysis framework offers new avenues for predicting disease spread, while providing managers tools to proactively mitigate

Eye involvement in haematological malignancies

NARCIS (Netherlands)

Riemens, J.A.

2014-01-01

This thesis describes the involvement of the eye in haematological malignancies and focuses on two topics; primary vitreoretinal lymphoma (PVRL) and ocular Graft-versus-Host Disease (GvHD). The aim of this thesis is first: to compare the efficacy of diverse treatment options of PVRL with regard to

Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease.

Directory of Open Access Journals (Sweden)

Alison R Erickson

Full Text Available Crohn's disease (CD is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD or colon (CCD. Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers.

Integrated Metagenomics/Metaproteomics Reveals Human Host-Microbiota Signatures of Crohn's Disease

Science.gov (United States)

Darzi, Youssef; Mongodin, Emmanuel F.; Pan, Chongle; Shah, Manesh; Halfvarson, Jonas; Tysk, Curt; Henrissat, Bernard; Raes, Jeroen; Verberkmoes, Nathan C.; Jansson, Janet K.

2012-01-01

Crohn's disease (CD) is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD) or colon (CCD). Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers. PMID:23209564

Early and late oral features of chronic graft-versus-host disease

Directory of Open Access Journals (Sweden)

Alessandra Oliveira Ferrari Gomes

2014-01-01

Full Text Available Background: Chronic graft-versus-host disease is a serious complication of allogeneic hematopoietic cell transplantation, and the mouth is one of the affected sites. Objective: The aim of this study was to evaluate the oral features of this disease after hematopoietic cell transplantation. Methods: This was a cross-sectional multicenter study that enrolled patients submitted to transplantation. Oral evaluations used the National Institutes of Health criteria, salivary flow rates, and the range of mouth opening. Pain and xerostomia were evaluated through a visual analogue scale. Patients were divided into two groups based on the transplantation time (up to one year and more than one year. Results: Of the 57 evaluated recipients, 44 had chronic graft-versus-host disease: ten (22.72% in the group with less than one year after transplantation, and 34 (77.27% in the group with more than one year after transplantation. Lichenoid/hyperkeratotic plaques, erythematous lesions, xerostomia, and hyposalivation were the most commonly reported oral features. Lichenoid/hyperkeratotic plaques were significantly more common in patients within the first year after the transplant. The labial mucosa was affected more in the first year. No significant changes occurred in the frequency of xerostomia, hyposalivation, and reduced mouth opening regarding time after transplantation. Conclusion: Oral chronic graft-versus-host disease lesions were identified early in the course of the disease. The changes observed in salivary gland function and in the range of mouth opening were not correlated with the time after transplantation.

Emerging fungal diseases: the importance of the host.

Science.gov (United States)

Procop, Gary W; Roberts, Glenn D

2004-09-01

More yeasts and molds are now recognized to cause more human disease than ever before. This development is not due to a change in the virulence of these fungi, but rather to changes in the human host. These changes include immunosuppression secondary to the pandemic of HIV, the use of life-saving advances in chemotherapy and organ transplantation, and the use of corticosteroids and other immunosuppressive agents to treat a variety of diseases. Fungi that were once considered common saprophytes are now recognized as potential pathogens in these patients. This situation necessitates better communication than ever between the clinician, pathologist, and clinical mycologist to ensure the prompt and accurate determination of the cause of fungal diseases.

Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

Science.gov (United States)

Sasazuki, Takehiko; Inoko, Hidetoshi; Morishima, Satoko; Morishima, Yasuo

2016-01-01

The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure. © 2016 Elsevier Inc. All rights reserved.

Host behaviour–parasite feedback: an essential link between animal behaviour and disease ecology

Science.gov (United States)

Archie, Elizabeth A.; Craft, Meggan E.; Hawley, Dana M.; Martin, Lynn B.; Moore, Janice; White, Lauren

2016-01-01

Animal behaviour and the ecology and evolution of parasites are inextricably linked. For this reason, animal behaviourists and disease ecologists have been interested in the intersection of their respective fields for decades. Despite this interest, most research at the behaviour–disease interface focuses either on how host behaviour affects parasites or how parasites affect behaviour, with little overlap between the two. Yet, the majority of interactions between hosts and parasites are probably reciprocal, such that host behaviour feeds back on parasites and vice versa. Explicitly considering these feedbacks is essential for understanding the complex connections between animal behaviour and parasite ecology and evolution. To illustrate this point, we discuss how host behaviour–parasite feedbacks might operate and explore the consequences of feedback for studies of animal behaviour and parasites. For example, ignoring the feedback of host social structure on parasite dynamics can limit the accuracy of predictions about parasite spread. Likewise, considering feedback in studies of parasites and animal personalities may provide unique insight about the maintenance of variation in personality types. Finally, applying the feedback concept to links between host behaviour and beneficial, rather than pathogenic, microbes may shed new light on transitions between mutualism and parasitism. More generally, accounting for host behaviour–parasite feedbacks can help identify critical gaps in our understanding of how key host behaviours and parasite traits evolve and are maintained. PMID:27053751

Host behaviour-parasite feedback: an essential link between animal behaviour and disease ecology.

Science.gov (United States)

Ezenwa, Vanessa O; Archie, Elizabeth A; Craft, Meggan E; Hawley, Dana M; Martin, Lynn B; Moore, Janice; White, Lauren

2016-04-13

Animal behaviour and the ecology and evolution of parasites are inextricably linked. For this reason, animal behaviourists and disease ecologists have been interested in the intersection of their respective fields for decades. Despite this interest, most research at the behaviour-disease interface focuses either on how host behaviour affects parasites or how parasites affect behaviour, with little overlap between the two. Yet, the majority of interactions between hosts and parasites are probably reciprocal, such that host behaviour feeds back on parasites and vice versa. Explicitly considering these feedbacks is essential for understanding the complex connections between animal behaviour and parasite ecology and evolution. To illustrate this point, we discuss how host behaviour-parasite feedbacks might operate and explore the consequences of feedback for studies of animal behaviour and parasites. For example, ignoring the feedback of host social structure on parasite dynamics can limit the accuracy of predictions about parasite spread. Likewise, considering feedback in studies of parasites and animal personalities may provide unique insight about the maintenance of variation in personality types. Finally, applying the feedback concept to links between host behaviour and beneficial, rather than pathogenic, microbes may shed new light on transitions between mutualism and parasitism. More generally, accounting for host behaviour-parasite feedbacks can help identify critical gaps in our understanding of how key host behaviours and parasite traits evolve and are maintained. © 2016 The Author(s).

Treatment of inflammatory diseases with mesenchymal stem cells.

Science.gov (United States)

Newman, Robert E; Yoo, Dana; LeRoux, Michelle A; Danilkovitch-Miagkova, Alla

2009-06-01

Human mesenchymal stem cells (hMSCs) are rare progenitor cells present in adult bone marrow that have the capacity to differentiate into a variety of tissue types, including bone, cartilage, tendon, fat, and muscle. In addition to multilineage differentiation capacity, MSCs regulate immune and inflammatory responses, providing therapeutic potential for treating diseases characterized by the presence of an inflammatory component. The availability of bone marrow and the ability to isolate and expand hMSCs ex vivo make these cells an attractive candidate for drug development. The low immunogenicity of these cells suggests that hMSCs can be transplanted universally without matching between donors and recipients. MSCs universality, along with the ability to manufacture and store these cells long-term, present a unique opportunity to produce an "off-the-shelf" cellular drug ready for treatment of diseases in acute settings. Accumulated animal and human data support MSC therapeutic potential for inflammatory diseases. Several phase III clinical trials for treatment of acute Graft Versus Host Disease (GVHD) and Crohn's disease are currently in progress. The current understanding of cellular and molecular targets underlying the mechanisms of MSCs action in inflammatory settings as well as clinical experience with hMSCs is summarized in this review.

Survival relative to new and ancestral host plants, phytoplasma infection, and genetic constitution in host races of a polyphagous insect disease vector

Science.gov (United States)

Maixner, Michael; Albert, Andreas; Johannesen, Jes

2014-01-01

Dissemination of vectorborne diseases depends strongly on the vector's host range and the pathogen's reservoir range. Because vectors interact with pathogens, the direction and strength of a vector's host shift is vital for understanding epidemiology and is embedded in the framework of ecological specialization. This study investigates survival in host-race evolution of a polyphagous insect disease vector, Hyalesthes obsoletus, whether survival is related to the direction of the host shift (from field bindweed to stinging nettle), the interaction with plant-specific strains of obligate vectored pathogens/symbionts (stolbur phytoplasma), and whether survival is related to genetic differentiation between the host races. We used a twice repeated, identical nested experimental design to study survival of the vector on alternative hosts and relative to infection status. Survival was tested with Kaplan–Meier analyses, while genetic differentiation between vector populations was quantified with microsatellite allele frequencies. We found significant direct effects of host plant (reduced survival on wrong hosts) and sex (males survive longer than females) in both host races and relative effects of host (nettle animals more affected than bindweed animals) and sex (males more affected than females). Survival of bindweed animals was significantly higher on symptomatic than nonsymptomatic field bindweed, but in the second experiment only. Infection potentially had a positive effect on survival in nettle animals but due to low infection rates the results remain suggestive. Genetic differentiation was not related to survival. Greater negative plant-transfer effect but no negative effect of stolbur in the derived host race suggests preadaptation to the new pathogen/symbiont strain before strong diversifying selection during the specialization process. Physiological maladaptation or failure to accept the ancestral plant will have similar consequences, namely positive assortative

Irradiation process of platelets and red blood cells: uncertainty values; Processo de irradiacao de bolsas contendo plaquetas e hemacias: fontes de incertezas

Energy Technology Data Exchange (ETDEWEB)

Pacifico, Leonardo, E-mail: leonardocpacifico@gmail.com [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil); Peixoto, Jose Gullherme P. [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)

2016-07-01

Irradiation of platelets and red blood cells is critical to prevent a disease called transfusion-associated graft versus host disease (TA-GVHD). An irradiator with source of Cesio-137 is used for this. During the irradiation process, input quantities contributing to the expanded uncertainty of the value of absorbed dose shown. The aim of our study was to identify the input quantities in the process. (author)

Eosinophils from hematopoietic stem cell recipients suppress allogeneic T cell proliferation.

Science.gov (United States)

Andersson, Jennie; Cromvik, Julia; Ingelsten, Madeleine; Lingblom, Christine; Andersson, Kerstin; Johansson, Jan-Erik; Wennerås, Christine

2014-12-01

Eosinophilia has been associated with less severe graft-versus-host disease (GVHD), but the underlying mechanism is unknown. We hypothesized that eosinophils diminish allogeneic T cell activation in patients with chronic GVHD. The capacity of eosinophils derived from healthy subjects and hematopoietic stem cell (HSC) transplant recipients, with or without chronic GVHD, to reduce allogeneic T cell proliferation was evaluated using a mixed leukocyte reaction. Eosinophil-mediated inhibition of proliferation was observed for the eosinophils of both healthy subjects and patients who underwent HSC transplantation. Eosinophils from patients with and without chronic GVHD were equally suppressive. Healthy eosinophils required cell-to-cell contact for their suppressive capacity, which was directed against CD4(+) T cells and CD8(+) T cells. Neither eosinophilic cationic protein, eosinophil-derived neurotoxin, indoleamine 2,3-dioxygenase, or increased numbers of regulatory T cells could account for the suppressive effect of healthy eosinophils. Real-time quantitative PCR analysis revealed significantly increased mRNA levels of the immunoregulatory protein galectin-10 in the eosinophils of both chronic GVHD patients and patients without GVHD, as compared with those from healthy subjects. The upregulation of galectin-10 expression in eosinophils from patients suggests a stimulatory effect of HSC transplantation in itself on eosinophilic galectin-10 expression, regardless of chronic GVHD status. To conclude, eosinophils from HSC transplant recipients and healthy subjects have a T cell suppressive capacity. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Dose uniformity estimations in the blood irradiator

International Nuclear Information System (INIS)

George, J.R.

2002-01-01

Use of irradiated blood in transfusions is recognized as the most effective way of preventing Graft Versus Host Disease (GVHD). This paper shows the study carried out in the dose rate variation for various source arrangements for optimising the source-sample chamber geometry, during the development of the Blood Irradiator, Bl-2000

Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response.

Science.gov (United States)

Rodríguez Pulido, Miguel; Sáiz, Margarita

2017-01-01

Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic, and wild animals worldwide. The aim of the host interferon (IFN) response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co-evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections.

Tolerance and chimerism.

Science.gov (United States)

Kolb, Hans-Jochem; Guenther, Wolfgang; Gyurkocza, Boglarka; Hoetzl, Florian; Simoes, Belinda; Falk, Christine; Schleuning, Michael; Ledderose, Georg

2003-05-15

Stem-cell transplantation from human leukocyte antigen (HLA)-haploidentical family members carries a high risk of rejection and graft-versus-host disease (GVHD) if donor and recipient differ by more than one HLA antigen. The authors have developed treatment protocols from studies in dog leukocyte antigen-haploidentical dogs that prevent rejection and modify GVHD to the extent that patients with aggressive hematologic neoplasia can be treated with success. Principal improvements have been achieved in the use of cyclophosphamide and total-body irradiation for conditioning and T-cell depletion for prevention of GVHD. More recently, the combination of marrow and CD6-depleted mobilized donor blood cells (MDBC) has been introduced for HLA-haploidentical transplantation on the basis that CD6-depleted MDBC contain immunoregulatory cells besides stem cells and natural killer cells. Clinical results are reported on 36 patients with high-risk hematologic neoplasia. The results encourage the use of HLA-haploidentical stem-cell transplantation at an earlier stage of the disease. This method could also be of use for tolerance induction in organ transplantation.

Deletion of Fanca or Fancd2 dysregulates Treg in mice

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Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

2014-01-01

Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

Deletion of Fanca or Fancd2 dysregulates Treg in mice.

Science.gov (United States)

Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C; Steinbrecher, Kris A; Davies, Stella M; Pang, Qishen

2014-03-20

Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.

Prevention of lethal graft-versus-host disease in mice by monoclonal antibodies directed against T cells or their subsets.I.Evidence for the induction of a state of tolerance based on suppression

NARCIS (Netherlands)

Knulst, A.C.; Tibbe, G.J.M.; Noort, W.A.; Bril-Bazuin, C.; Benner, R.; Savelkoul, H.F.J.

1994-01-01

Lethal GVHD in the fully allogeneic BALB/c (donor)-(C57BL x CBA)F1 (recipient) mouse strain combination could be prevented by a single dose of IgG2b monoclonal antibodies (moAb) directed to T cells. The influence of the time of administration of this moAb after GVHD induction and the effect of

Rituximab administration within 6 months of T cell-depleted allogeneic SCT is associated with prolonged life-threatening cytopenias.

Science.gov (United States)

McIver, Zachariah; Stephens, Nicole; Grim, Andrew; Barrett, A John

2010-11-01

The monoclonal anti-CD20 antibody Rituximab (RTX) is increasingly used in allogeneic stem cell transplantation (SCT) to treat lymphoproliferative disorders and chronic graft-versus-host disease (GVHD). RTX administration can be complicated by delayed and prolonged neutropenia, but the mechanism is unclear. We report the occurrence of profound cytopenias following RTX given in the conditioning regimen or early after T cell-deplete SCT to treat B cell lymphoproliferative disorders or chronic GVHD (cGVHD). Between 2006 and 2009, 102 patients (median age: 43 years, range: 13-68 years), received a myeloablative matched-sibling T cell-deplete SCT for lymphoid or myeloid hematologic disorders. Neutropenia occurring within 4 weeks of treatment developed in 16 of 17 patients given RTX within the first 190 days after SCT. Fourteen patients developed severe neutropenia (count SCT compared to patients with cGVHD not treated with early RTX (P SCT experienced only moderate neutropenia 3 to 5 months after treatment lasting 10 to 20 days while maintaining absolute neutrophil count (ANC) >1.0 × 10⁹/L. Although RTX rapidly controlled cGVHD, we conclude that its administration early after T cell-deplete SCT is associated with prolonged profound and life-threatening cytopenias, and should be avoided. Published by Elsevier Inc.

MODELING HOST-PATHOGEN INTERACTIONS: COMPUTATIONAL BIOLOGY AND BIOINFORMATICS FOR INFECTIOUS DISEASE RESEARCH (Session introduction)

Energy Technology Data Exchange (ETDEWEB)

McDermott, Jason E.; Braun, Pascal; Bonneau, Richard A.; Hyduke, Daniel R.

2011-12-01

Pathogenic infections are a major cause of both human disease and loss of crop yields and animal stocks and thus cause immense damage to the worldwide economy. The significance of infectious diseases is expected to increase in an ever more connected warming world, in which new viral, bacterial and fungal pathogens can find novel hosts and ecologic niches. At the same time, the complex and sophisticated mechanisms by which diverse pathogenic agents evade defense mechanisms and subvert their hosts networks to suit their lifestyle needs is still very incompletely understood especially from a systems perspective [1]. Thus, understanding host-pathogen interactions is both an important and a scientifically fascinating topic. Recently, technology has offered the opportunity to investigate host-pathogen interactions on a level of detail and scope that offers immense computational and analytical possibilities. Genome sequencing was pioneered on some of these pathogens, and the number of strains and variants of pathogens sequenced to date vastly outnumbers the number of host genomes available. At the same time, for both plant and human hosts more and more data on population level genomic variation becomes available and offers a rich field for analysis into the genetic interactions between host and pathogen.

Selective elimination of non-lpr lymphoid cells in mice undergoing lpr-mediated graft-vs-host disease

International Nuclear Information System (INIS)

Perkins, D.L.; Michaelson, J.; Glaser, R.M.; Marshak-Rothstein, A.

1987-01-01

The transfer of lpr BM stem cells into lethally irradiated non-lpr recipients (including the congenic MRL/+ differing only at the lpr locus) causes GVHD characterized by a wasting syndrome. In this study we investigated the interaction between the autoimmune (lpr) and normal (A-Thy) B, T, and RBC cell lineages in two types of radiation chimeras: MRL/lpr plus A-Thy----(MRL/lpr X A-Thy)F1 and MRL/+ plus A-Thy----(MRL/lpr X A-Thy)F1. Analysis of B cell repopulation by competitive RIA of serum Igh-1 allotype showed that both the MRL and the A-Thy donor cells initially engrafted. However, by 2 to 4 mo post-transplantation the normal A-Thy allotype was barely detectable (reduced greater than 2 orders of magnitude), whereas the autoimmune MRL/lpr allotype persisted at normal levels. Similarly, investigation of the donor origin of peripheral blood T cells by two-color flow cytometry showed that by 8 mo post-transplantation normal A-Thy T cells had been eliminated and only MRL/lpr T cells were present in the circulation. In contrast, erythrocytes from both the MRL/lpr and A-Thy donor strains successfully engrafted the F1 recipients and persisted until the termination of the study. Control chimeras transplanted with a mixture of MRL/+ plus A-Thy BM were stably engrafted with both donor strains in both the erythroid and lymphoid populations. Additional experiments in which either B6/lpr or MRL/lpr (and B6/+ or MRL/+ control) BM cells were transferred into (MRL/lpr X B6/+)F1 and (MRL/lpr X B6/lpr)F1 recipients demonstrated that the development of GVHD was not simply due to increased alloreactivity by the lpr donor cells. In these chimeras only the recipients heterozygous (but not homozygous) for the lpr gene developed lpr-GVHD, although both types of recipients had identical genotypes except at the lpr locus

Host Phylogeny Determines Viral Persistence and Replication in Novel Hosts

Science.gov (United States)

Longdon, Ben; Hadfield, Jarrod D.; Webster, Claire L.

2011-01-01

Pathogens switching to new hosts can result in the emergence of new infectious diseases, and determining which species are likely to be sources of such host shifts is essential to understanding disease threats to both humans and wildlife. However, the factors that determine whether a pathogen can infect a novel host are poorly understood. We have examined the ability of three host-specific RNA-viruses (Drosophila sigma viruses from the family Rhabdoviridae) to persist and replicate in 51 different species of Drosophilidae. Using a novel analytical approach we found that the host phylogeny could explain most of the variation in viral replication and persistence between different host species. This effect is partly driven by viruses reaching a higher titre in those novel hosts most closely related to the original host. However, there is also a strong effect of host phylogeny that is independent of the distance from the original host, with viral titres being similar in groups of related hosts. Most of this effect could be explained by variation in general susceptibility to all three sigma viruses, as there is a strong phylogenetic correlation in the titres of the three viruses. These results suggest that the source of new emerging diseases may often be predictable from the host phylogeny, but that the effect may be more complex than simply causing most host shifts to occur between closely related hosts. PMID:21966271

Identification of Heme Oxygenase-1 as a Novel Predictor of Hematopoietic Stem Cell Transplantation Outcomes in Acute Leukemia

Directory of Open Access Journals (Sweden)

Yinghao Lu

2016-09-01

Full Text Available Objective: The main aim of this study was to determine the correlation between clinical outcome and heme oxygenase-1 (HO-1 expression before and after hematopoietic stem cell transplantation (HSCT in acute leukemia. Methods: HO-1 mRNA levels in 83 patients were measured using qRT-PCR. In a comparative analysis of HO-1 levels in relation to different post-transplant outcomes, the HO-1 threshold, determined via the receiver operating characteristic (ROC curve, was effectively used to predict clinical relapse and acute graft-versus-host disease (aGVHD. The correlations among clinical relapse, aGVHD and HO-1 expression were analyzed based on this threshold. Results: Leukemia risk stratification and relative expression of HO-1 before pretreatment had significant effects on clinical relapse. Leukemia risk stratification, relative expression of HO-1 after HSCT and the interval from diagnosis to transplantation had a significant influence on aGVHD. Both relapse and aGVHD appeared to be associated with relative HO-1 expression. The relative expression rate of HO-1 was 1.131-1.186 before pretreatment, and strongly associated with post-transplantation relapse. The relative expression rate of HO-1 was 1.102-1.144 after transplantation, and closely related to aGVHD. ROC curve analysis revealed high specificity and sensitivity of HO-1 expression in predicting relapse and aGVHD after allo-HSCT. Conclusions: HO-1 expression can be effectively used as a predictor of relapse as well as a diagnostic factor of aGVHD after transplantation for allo-HSCT patients with acute leukemia.

Angiostrongylus spp. in the Americas: geographical and chronological distribution of definitive hosts versus disease reports.

Science.gov (United States)

Valente, Romina; Robles, Maria Del Rosario; Navone, Graciela T; Diaz, Julia I

2018-03-01

Angiostrongyliasis is an infection caused by nematode worms of the genus Angiostrongylus. The adult worms inhabit the pulmonary arteries, heart, bronchioles of the lung, or mesenteric arteries of the caecum of definitive host. Of a total of 23 species of Angiostrongylus cited worldwide, only nine were registered in the American Continent. Two species, A. cantonensis and A. costaricensis, are considered zoonoses when the larvae accidentally parasitise man. In the present study, geographical and chronological distribution of definitive hosts of Angiostrongylus in the Americas is analysed in order to observe their relationship with disease reports. Moreover, the role of different definitive hosts as sentinels and dispersers of infective stages is discussed. The study area includes the Americas. First records of Angiostrongylus spp. in definitive or accidental hosts were compiled from the literature. Data were included in tables and figures and were matched to geographic information systems (GIS). Most geographical records of Angiostrongylus spp. both for definitive and accidental hosts belong to tropical areas, mainly equatorial zone. In relation to those species of human health importance, as A. cantonensis and A. costaricensis, most disease cases indicate a coincidence between the finding of definitive host and disease record. However, in some geographic site there are gaps between report of definitive host and disease record. In many areas, human populations have invaded natural environments and their socioeconomic conditions do not allow adequate medical care. Consequently, many cases for angiostrongyliasis could have gone unreported or unrecognised throughout history and in the nowadays. Moreover, the population expansion and the climatic changes invite to make broader and more complete range of observation on the species that involve possible epidemiological risks. This paper integrates and shows the current distribution of Angiostrongylus species in America

Angiostrongylus spp. in the Americas: geographical and chronological distribution of definitive hosts versus disease reports

Science.gov (United States)

Valente, Romina; Robles, Maria del Rosario; Navone, Graciela T; Diaz, Julia I

2018-01-01

BACKGROUND Angiostrongyliasis is an infection caused by nematode worms of the genus Angiostrongylus. The adult worms inhabit the pulmonary arteries, heart, bronchioles of the lung, or mesenteric arteries of the caecum of definitive host. Of a total of 23 species of Angiostrongylus cited worldwide, only nine were registered in the American Continent. Two species, A. cantonensis and A. costaricensis, are considered zoonoses when the larvae accidentally parasitise man. OBJECTIVES In the present study, geographical and chronological distribution of definitive hosts of Angiostrongylus in the Americas is analysed in order to observe their relationship with disease reports. Moreover, the role of different definitive hosts as sentinels and dispersers of infective stages is discussed. METHODS The study area includes the Americas. First records of Angiostrongylus spp. in definitive or accidental hosts were compiled from the literature. Data were included in tables and figures and were matched to geographic information systems (GIS). FINDINGS Most geographical records of Angiostrongylus spp. both for definitive and accidental hosts belong to tropical areas, mainly equatorial zone. In relation to those species of human health importance, as A. cantonensis and A. costaricensis, most disease cases indicate a coincidence between the finding of definitive host and disease record. However, in some geographic site there are gaps between report of definitive host and disease record. In many areas, human populations have invaded natural environments and their socioeconomic conditions do not allow adequate medical care. MAIN CONCLUSIONS Consequently, many cases for angiostrongyliasis could have gone unreported or unrecognised throughout history and in the nowadays. Moreover, the population expansion and the climatic changes invite to make broader and more complete range of observation on the species that involve possible epidemiological risks. This paper integrates and shows the

A model to estimate effects of SNPs on host susceptibility and infectivity for an endemic infectious disease.

Science.gov (United States)

Biemans, Floor; de Jong, Mart C M; Bijma, Piter

2017-06-30

Infectious diseases in farm animals affect animal health, decrease animal welfare and can affect human health. Selection and breeding of host individuals with desirable traits regarding infectious diseases can help to fight disease transmission, which is affected by two types of (genetic) traits: host susceptibility and host infectivity. Quantitative genetic studies on infectious diseases generally connect an individual's disease status to its own genotype, and therefore capture genetic effects on susceptibility only. However, they usually ignore variation in exposure to infectious herd mates, which may limit the accuracy of estimates of genetic effects on susceptibility. Moreover, genetic effects on infectivity will exist as well. Thus, to design optimal breeding strategies, it is essential that genetic effects on infectivity are quantified. Given the potential importance of genetic effects on infectivity, we set out to develop a model to estimate the effect of single nucleotide polymorphisms (SNPs) on both host susceptibility and host infectivity. To evaluate the quality of the resulting SNP effect estimates, we simulated an endemic disease in 10 groups of 100 individuals, and recorded time-series data on individual disease status. We quantified bias and precision of the estimates for different sizes of SNP effects, and identified the optimum recording interval when the number of records is limited. We present a generalized linear mixed model to estimate the effect of SNPs on both host susceptibility and host infectivity. SNP effects were on average slightly underestimated, i.e. estimates were conservative. Estimates were less precise for infectivity than for susceptibility. Given our sample size, the power to estimate SNP effects for susceptibility was 100% for differences between genotypes of a factor 1.56 or more, and was higher than 60% for infectivity for differences between genotypes of a factor 4 or more. When disease status was recorded 11 times on each

Host phylogeny determines viral persistence and replication in novel hosts.

Directory of Open Access Journals (Sweden)

Ben Longdon

2011-09-01

Full Text Available Pathogens switching to new hosts can result in the emergence of new infectious diseases, and determining which species are likely to be sources of such host shifts is essential to understanding disease threats to both humans and wildlife. However, the factors that determine whether a pathogen can infect a novel host are poorly understood. We have examined the ability of three host-specific RNA-viruses (Drosophila sigma viruses from the family Rhabdoviridae to persist and replicate in 51 different species of Drosophilidae. Using a novel analytical approach we found that the host phylogeny could explain most of the variation in viral replication and persistence between different host species. This effect is partly driven by viruses reaching a higher titre in those novel hosts most closely related to the original host. However, there is also a strong effect of host phylogeny that is independent of the distance from the original host, with viral titres being similar in groups of related hosts. Most of this effect could be explained by variation in general susceptibility to all three sigma viruses, as there is a strong phylogenetic correlation in the titres of the three viruses. These results suggest that the source of new emerging diseases may often be predictable from the host phylogeny, but that the effect may be more complex than simply causing most host shifts to occur between closely related hosts.

Pathogenic landscapes: Interactions between land, people, disease vectors, and their animal hosts

Science.gov (United States)

2010-01-01

Background Landscape attributes influence spatial variations in disease risk or incidence. We present a review of the key findings from eight case studies that we conducted in Europe and West Africa on the impact of land changes on emerging or re-emerging vector-borne diseases and/or zoonoses. The case studies concern West Nile virus transmission in Senegal, tick-borne encephalitis incidence in Latvia, sandfly abundance in the French Pyrenees, Rift Valley Fever in the Ferlo (Senegal), West Nile Fever and the risk of malaria re-emergence in the Camargue, and rodent-borne Puumala hantavirus and Lyme borreliosis in Belgium. Results We identified general principles governing landscape epidemiology in these diverse disease systems and geographic regions. We formulated ten propositions that are related to landscape attributes, spatial patterns and habitat connectivity, pathways of pathogen transmission between vectors and hosts, scale issues, land use and ownership, and human behaviour associated with transmission cycles. Conclusions A static view of the "pathogenecity" of landscapes overlays maps of the spatial distribution of vectors and their habitats, animal hosts carrying specific pathogens and their habitat, and susceptible human hosts and their land use. A more dynamic view emphasizing the spatial and temporal interactions between these agents at multiple scales is more appropriate. We also highlight the complementarity of the modelling approaches used in our case studies. Integrated analyses at the landscape scale allows a better understanding of interactions between changes in ecosystems and climate, land use and human behaviour, and the ecology of vectors and animal hosts of infectious agents. PMID:20979609

Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases.

Science.gov (United States)

Mahon, Robert N; Hafner, Richard

2017-01-01

To meet the challenges of increasing antimicrobial resistance, the infectious disease community needs innovative therapeutics. Precision medicine and immunotherapies are transforming cancer therapeutics by targeting the regulatory signaling pathways that are involved not only in malignancies but also in the metabolic and immunologic function of the tumor microenvironment. Infectious diseases target many of the same regulatory pathways as they modulate host metabolic functions for their own nutritional requirements and to impede host immunity. These similarities and the advances made in precision medicine and immuno-oncology that are relevant for the current development of host-directed therapies (HDTs) to treat infectious diseases are discussed. To harness this potential, improvements in drug screening methods and development of assays that utilize the research tools including high throughput multiplexes already developed by oncology are essential. A multidisciplinary approach that brings together immunologists, infectious disease specialists, and oncologists will be necessary to fully develop the potential of HDTs.

Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

Science.gov (United States)

Nieto, Yago; Patton, Nigel; Hawkins, Timothy; Spearing, Ruth; Bearman, Scott I; Jones, Roy B; Shpall, Elizabeth J; Rabinovitch, Rachel; Zeng, Chan; Barón, Anna; McSweeney, Peter A

2006-02-01

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Modelling within-host spatiotemporal dynamics of invasive bacterial disease.

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Andrew J Grant

2008-04-01

Full Text Available Mechanistic determinants of bacterial growth, death, and spread within mammalian hosts cannot be fully resolved studying a single bacterial population. They are also currently poorly understood. Here, we report on the application of sophisticated experimental approaches to map spatiotemporal population dynamics of bacteria during an infection. We analyzed heterogeneous traits of simultaneous infections with tagged Salmonella enterica populations (wild-type isogenic tagged strains [WITS] in wild-type and gene-targeted mice. WITS are phenotypically identical but can be distinguished and enumerated by quantitative PCR, making it possible, using probabilistic models, to estimate bacterial death rate based on the disappearance of strains through time. This multidisciplinary approach allowed us to establish the timing, relative occurrence, and immune control of key infection parameters in a true host-pathogen combination. Our analyses support a model in which shortly after infection, concomitant death and rapid bacterial replication lead to the establishment of independent bacterial subpopulations in different organs, a process controlled by host antimicrobial mechanisms. Later, decreased microbial mortality leads to an exponential increase in the number of bacteria that spread locally, with subsequent mixing of bacteria between organs via bacteraemia and further stochastic selection. This approach provides us with an unprecedented outlook on the pathogenesis of S. enterica infections, illustrating the complex spatial and stochastic effects that drive an infectious disease. The application of the novel method that we present in appropriate and diverse host-pathogen combinations, together with modelling of the data that result, will facilitate a comprehensive view of the spatial and stochastic nature of within-host dynamics.

Autoimmune Demyelinating Polyneuropathy as a Manifestation of Chronic Graft-versus-Host Disease after Adult Cord Blood Transplantation in a Patient with Chronic Lymphocytic Leukemia

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Fredrick Hogan

2014-01-01

Full Text Available Immune mediated demyelinating disease after allogeneic stem cell transplantation is a rare entity with unclear etiology. Acute inflammatory demyelinating polyneuropathy (AIDP has been reported after related and adult unrelated allogeneic stem cell transplantation but no such case has been reported after unrelated cord blood transplantation. We hereby present the first case of AIDP after double umbilical cord blood transplantation (DUCBT. A 55-year-old man with chronic lymphocytic leukemia (CLL received a cord blood transplant for relapsed refractory disease with high risk cytogenetics. On day 221, patient presented with skin rash, tingling in both lower extremites, and ascending paralysis that progressed rapidly over the course of 2 days. The workup resulted in a diagnosis of AIDP and administration of intravenous immunoglobulins plus steroids was initiated. Motor and sensory powers were fully recovered and his chronic GVHD was managed for several months with single agent sirolimus.

Optimal control issues in plant disease with host demographic factor and botanical fungicides

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Anggriani, N.; Mardiyah, M.; Istifadah, N.; Supriatna, A. K.

2018-03-01

In this paper, we discuss a mathematical model of plant disease with the effect of fungicide. We assume that the fungicide is given as a preventive treatment to infectious plants. The model is constructed based on the development of the disease in which the monomolecular is monocyclic. We show the value of the Basic Reproduction Number (BRN) ℛ0 of the plant disease transmission. The BRN is computed from the largest eigenvalue of the next generation matrix of the model. The result shows that in the region where ℛ0 greater than one there is a single stable endemic equilibrium. However, in the region where ℛ0 less than one this endemic equilibrium becomes unstable. The dynamics of the model is highly sensitive to changes in contact rate and infectious period. We also discuss the optimal control of the infected plant host by considering a preventive treatment aimed at reducing the infected host plant. The obtaining optimal control shows that it can reduce the number of infected hosts compared to that without control. Some numerical simulations are also given to illustrate our analytical results.

Disease ecology across soil boundaries: effects of below-ground fungi on above-ground host-parasite interactions.

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Tao, Leiling; Gowler, Camden D; Ahmad, Aamina; Hunter, Mark D; de Roode, Jacobus C

2015-10-22

Host-parasite interactions are subject to strong trait-mediated indirect effects from other species. However, it remains unexplored whether such indirect effects may occur across soil boundaries and connect spatially isolated organisms. Here, we demonstrate that, by changing plant (milkweed Asclepias sp.) traits, arbuscular mycorrhizal fungi (AMF) significantly affect interactions between a herbivore (the monarch butterfly Danaus plexippus) and its protozoan parasite (Ophryocystis elektroscirrha), which represents an interaction across four biological kingdoms. In our experiment, AMF affected parasite virulence, host resistance and host tolerance to the parasite. These effects were dependent on both the density of AMF and the identity of milkweed species: AMF indirectly increased disease in monarchs reared on some species, while alleviating disease in monarchs reared on other species. The species-specificity was driven largely by the effects of AMF on both plant primary (phosphorus) and secondary (cardenolides; toxins in milkweeds) traits. Our study demonstrates that trait-mediated indirect effects in disease ecology are extensive, such that below-ground interactions between AMF and plant roots can alter host-parasite interactions above ground. In general, soil biota may play an underappreciated role in the ecology of many terrestrial host-parasite systems. © 2015 The Author(s).

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells.

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Hechinger, Anne-Kathrin; Maas, Kristina; Dürr, Christoph; Leonhardt, Franziska; Prinz, Gabriele; Marks, Reinhard; Gerlach, Ulrike; Hofmann, Maike; Fisch, Paul; Finke, Jürgen; Pircher, Hanspeter; Zeiser, Robert

2013-01-01

Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without

Microbiome Profiles in Periodontitis in Relation to Host and Disease Characteristics

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Hong, Bo-Young; Furtado Araujo, Michel V.; Strausbaugh, Linda D.; Terzi, Evimaria; Ioannidou, Effie; Diaz, Patricia I.

2015-01-01

Periodontitis is an inflammatory condition that affects the supporting tissues surrounding teeth. The occurrence of periodontitis is associated with shifts in the structure of the communities that inhabit the gingival sulcus. Although great inter-subject variability in the subgingival microbiome has been observed in subjects with periodontitis, it is unclear whether distinct community types exist and if differences in microbial signatures correlate with host characteristics or with the variable clinical presentations of periodontitis. Therefore, in this study we explored the existence of different community types in periodontitis and their relationship with host demographic, medical and disease-related clinical characteristics. Clustering analyses of microbial abundance profiles suggested two types of communities (A and B) existed in the 34 subjects with periodontitis evaluated. Type B communities harbored greater proportions of certain periodontitis-associated taxa, including species historically associated with the disease, such as Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola, and taxa recently linked to periodontitis. In contrast, subjects with type A communities had increased proportions of different periodontitis-associated species, and were also enriched for health-associated species and core taxa (those equally prevalent in health and periodontitis). Periodontitis subgingival clusters were not associated with demographic, medical or disease-specific clinical parameters other than periodontitis extent (proportion of sites affected), which positively correlated with the total proportion of cluster B signature taxa. In conclusion, two types of microbial communities were detected in subjects with periodontitis. Host demographics and underlying medical conditions did not correlate with these profiles, which instead appeared to be related to periodontitis extent, with type B communities present in more widespread disease cases. The two

Defibrotide in the prevention and treatment of veno-occlusive disease in autologous and allogeneic stem cell transplantation in children.

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Qureshi, Amrana; Marshall, Lynley; Lancaster, Donna

2008-04-01

Hepatic veno-occlusive disease (VOD) is a common (10-50%) and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We carried out a study to assess whether the use of prophylactic defibrotide in paediatric patients undergoing HSCT results in a lower frequency or severity of hepatic VOD. Forty-seven successive patients who underwent transplantation between April 2004 and December 2005 were given defibrotide prophylaxis and were compared with 56 historical controls transplanted between November 2001 and April 2004. No serious side effects were reported. High risk patients in the control group received ursodeoxycholic acid and tinzaparin as VOD prophylaxis. The groups were matched for sex, age, type of transplant and risk. In the defibrotide group, four patients developed clinical VOD (Seattle criteria) although two had liver biopsies which showed graft versus host disease (GvHD). Defibrotide dose was increased and symptoms resolved within 14 days. Of the control group four patients had VOD. Two of these patients had reversed hepatic vein flow and died 30 days post-transplant, partly due to VOD. VOD was associated with busulfan conditioning (P = 0.001) and not with age, sex, type of transplant, GvHD, abnormal liver function prior to transplant or type of antifungal prophylaxis. VOD incidence and severity was reduced in the defibrotide group which suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting. (c) 2008 Wiley-Liss, Inc.

Host persistence or extinction from emerging infectious disease: insights from white-nose syndrome in endemic and invading regions.

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Hoyt, Joseph R; Langwig, Kate E; Sun, Keping; Lu, Guanjun; Parise, Katy L; Jiang, Tinglei; Frick, Winifred F; Foster, Jeffrey T; Feng, Jiang; Kilpatrick, A Marm

2016-03-16

Predicting species' fates following the introduction of a novel pathogen is a significant and growing problem in conservation. Comparing disease dynamics between introduced and endemic regions can offer insight into which naive hosts will persist or go extinct, with disease acting as a filter on host communities. We examined four hypothesized mechanisms for host-pathogen persistence by comparing host infection patterns and environmental reservoirs for Pseudogymnoascus destructans (the causative agent of white-nose syndrome) in Asia, an endemic region, and North America, where the pathogen has recently invaded. Although colony sizes of bats and hibernacula temperatures were very similar, both infection prevalence and fungal loads were much lower on bats and in the environment in Asia than North America. These results indicate that transmission intensity and pathogen growth are lower in Asia, likely due to higher host resistance to pathogen growth in this endemic region, and not due to host tolerance, lower transmission due to smaller populations, or lower environmentally driven pathogen growth rate. Disease filtering also appears to be favouring initially resistant species in North America. More broadly, determining the mechanisms allowing species persistence in endemic regions can help identify species at greater risk of extinction in introduced regions, and determine the consequences for disease dynamics and host-pathogen coevolution. © 2016 The Author(s).

Molecular mechanisms of Porphyromonas gingivalis-host cell interaction on periodontal diseases

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Masaaki Nakayama

2017-11-01

Full Text Available Porphyromonas gingivalis (P. gingivalis is a major oral pathogen and associated with periodontal diseases including periodontitis and alveolar bone loss. In this review, we indicate that two virulence factors, which are hemoglobin receptor protein (HbR and cysteine proteases “gingipains”, expressed by P. gingivalis have novel functions on the pathogenicity of P. gingivalis. P. gingivalis produces three types of gingipains and concomitantly several adhesin domains. Among the adhesin domains, hemoglobin receptor protein (HbR, also called HGP15, has the function of induction of interleukin-8 (IL-8 expression in human gingival epithelial cells, indicating the possibility that HbR is associated with P. gingivalis-induced periodontal inflammation. On bacteria-host cells contact, P. gingivalis induces cellular signaling alteration in host cells. Phosphatidylinositol 3-kinase (PI3K and Akt are well known to play a pivotal role in various cellular physiological functions including cell survival and glucose metabolism in mammalian cells. Recently, we demonstrated that gingipains attenuate the activity of PI3K and Akt, which might have a causal influence on periodontal diseases by chronic infection to the host cells from the speculation of molecular analysis. In this review, we discuss new molecular and biological characterization of the virulence factors from P. gingivalis.

[Treatment of Gaucher disease with allogeneic hematopoietic stem cell transplantation: report of three cases and review of literatures].

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Tang, Xiangfeng; Luan, Zuo; Wu, Nanhai; Zhang, Bo; Jing, Yuanfang; Du, Hong; Lu, Wei; Xu, Shixia

2015-11-01

To explore the efficacy of unrelated umbilical cord blood transplantation (UCBT) in the treatment of Gaucher disease. The clinical characteristics of three children with Gaucher disease underwent UCBT in our hospital between April 2013 and September 2014 were retrospectively analyzed. Literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of Gaucher disease was searched at Wanfang and Pubmed databases between 1983 and 2015 and was reviewed and summaried. Three children with Gaucher disease, all were female, received UCBT. These patients' age at receiving transplantation was 3.8 years, 7.1 years and 2.6 years, respectively. The second case received the second transplantation. The first and third case received splenectomy before UCBT. The pretreatment regimen was busulfan (Bu)/fludarabine (Flu)/cyclophosphamide (CTX)/antithymocyte globulin (ATG), and for the patient received the second transplantation melphalan was added to the myeloablative conditioning regimen of Bu/Flu/CTX/ATG. Cyclosporine and mycophenolate mofetil (MMF) wee used for prophylaxis of acute graft versus host disease (aGVHD). The dose of cord blood stem cell nucleated cell counts was 9.7 × 10⁷ /kg,11.9 × 10⁷ /kg and 7.6 × 10⁷/kg respectively. The dose of cord blood stem cell CD34⁺ cell counts was 5.4 × 10⁵/kg , 3.5 × 10⁵/kg and 3.2 × 10⁵/kg respectively. The day of granulocytes exceeding 0.5 × 10⁹/L was day 11, 12 and 19 after transplantation, respectively. The day of platelets exceeding 20 × 10⁹/L was day 14, 33 and 74 after transplantation, respectively. At one month after transplantation the rate of chimerism was over 95% and all patients got donor complete chimerism. The level of β-glucocerebrosidase recovered to normal at one month after transplantation. During transplantation, all patients developed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia. In case 1 immune thrombocytopenia occurred at five month after

The PDL1-PD1 Axis Converts Human Th1 Cells Into Regulatory T Cells

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Amarnath, Shoba; Mangus, Courtney W.; Wang, James C.M.; Wei, Fang; He, Alice; Kapoor, Veena; Foley, Jason E.; Massey, Paul R.; Felizardo, Tania C.; Riley, James L.; Levine, Bruce L.; June, Carl H.; Medin, Jeffrey A.; Fowler, Daniel H.

2011-01-01

Immune surveillance by T helper type 1 (Th1) cells is critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GvHD) after transplantation. The inhibitory molecule programmed death ligand-1 (PDL1) has been shown to anergize human Th1 cells, but other mechanisms of PDL1-mediated Th1 inhibition such as the conversion of Th1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause Th1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET+ Th1 cells into FOXP3+ regulatory T cells (TREGS) in vivo, thereby preventing human-into-mouse xenogeneic GvHD (xGvHD). Either blocking PD1 expression on Th1 cells by siRNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized Th1 cell differentiation during PDL1 challenge and restored the capacity of Th1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human Th1 cells to manifest in vivo plasticity, resulting in a TREG phenotype that severely impairs cell-mediated immunity. Converting human Th1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GvHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection. PMID:22133721

Corals hosting symbiotic hydrozoans are less susceptible to predation and disease

KAUST Repository

Montano, Simone

2017-12-20

In spite of growing evidence that climate change may dramatically affect networks of interacting species, whether-and to what extent-ecological interactions can mediate species\\' responses to disturbances is an open question. Here we show how a largely overseen association such as that between hydrozoans and scleractinian corals could be possibly associated with a reduction in coral susceptibility to ever-increasing predator and disease outbreaks. We examined 2455 scleractinian colonies (from both Maldivian and the Saudi Arabian coral reefs) searching for non-random patterns in the occurrence of hydrozoans on corals showing signs of different health conditions (i.e. bleaching, algal overgrowth, corallivory and different coral diseases). We show that, after accounting for geographical, ecological and co-evolutionary factors, signs of disease and corallivory are significantly lower in coral colonies hosting hydrozoans than in hydrozoan-free ones. This finding has important implications for our understanding of the ecology of coral reefs, and for their conservation in the current scenario of global change, because it suggests that symbiotic hydrozoans may play an active role in protecting their scleractinian hosts from stresses induced by warming water temperatures.

Emerging prion disease drives host selection in a wildlife population

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Robinson, Stacie J.; Samuel, Michael D.; Johnson, Chad J.; Adams, Marie; McKenzie, Debbie I.

2012-01-01

Infectious diseases are increasingly recognized as an important force driving population dynamics, conservation biology, and natural selection in wildlife populations. Infectious agents have been implicated in the decline of small or endangered populations and may act to constrain population size, distribution, growth rates, or migration patterns. Further, diseases may provide selective pressures that shape the genetic diversity of populations or species. Thus, understanding disease dynamics and selective pressures from pathogens is crucial to understanding population processes, managing wildlife diseases, and conserving biological diversity. There is ample evidence that variation in the prion protein gene (PRNP) impacts host susceptibility to prion diseases. Still, little is known about how genetic differences might influence natural selection within wildlife populations. Here we link genetic variation with differential susceptibility of white-tailed deer to chronic wasting disease (CWD), with implications for fitness and disease-driven genetic selection. We developed a single nucleotide polymorphism (SNP) assay to efficiently genotype deer at the locus of interest (in the 96th codon of the PRNP gene). Then, using a Bayesian modeling approach, we found that the more susceptible genotype had over four times greater risk of CWD infection; and, once infected, deer with the resistant genotype survived 49% longer (8.25 more months). We used these epidemiological parameters in a multi-stage population matrix model to evaluate relative fitness based on genotype-specific population growth rates. The differences in disease infection and mortality rates allowed genetically resistant deer to achieve higher population growth and obtain a long-term fitness advantage, which translated into a selection coefficient of over 1% favoring the CWD-resistant genotype. This selective pressure suggests that the resistant allele could become dominant in the population within an

Implications of host genetic variation on the risk and prevalence of infectious diseases transmitted through the environment.

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Doeschl-Wilson, Andrea B; Davidson, R; Conington, J; Roughsedge, T; Hutchings, M R; Villanueva, B

2011-07-01

Previous studies have shown that host genetic heterogeneity in the response to infectious challenge can affect the emergence risk and the severity of diseases transmitted through direct contact between individuals. However, there is substantial uncertainty about the degree and direction of influence owing to different definitions of genetic variation, most of which are not in line with the current understanding of the genetic architecture of disease traits. Also, the relevance of previous results for diseases transmitted through environmental sources is unclear. In this article a compartmental genetic-epidemiological model was developed to quantify the impact of host genetic diversity on epidemiological characteristics of diseases transmitted through a contaminated environment. The model was parameterized for footrot in sheep. Genetic variation was defined through continuous distributions with varying shape and degree of dispersion for different disease traits. The model predicts a strong impact of genetic heterogeneity on the disease risk and its progression and severity, as well as on observable host phenotypes, when dispersion in key epidemiological parameters is high. The impact of host variation depends on the disease trait for which variation occurs and on environmental conditions affecting pathogen survival. In particular, compared to homogeneous populations with the same average susceptibility, disease risk and severity are substantially higher in populations containing a large proportion of highly susceptible individuals, and the differences are strongest when environmental contamination is low. The implications of our results for the recording and analysis of disease data and for predicting response to selection are discussed.

Contentious host-microbiota relationship in inflammatory bowel disease--can foes become friends again?

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Satokari, Reetta

2015-01-01

Inflammatory bowel diseases (IBDs) are chronic debilitating disorders of unknown etiology, consisting of two main conditions, ulcerative colitis and Crohn's disease. Major advances have recently taken place in human genetic studies of IBD and over 160 risk loci for these two diseases have been uncovered. These genetic data highlight a key role for genes that code for immunological and epithelial barrier functions. Environmental factors also make substantial contributions to the pathogenesis of IBD and account for the growing incidence of the diseases around the world. Intestinal microbiota creates resistance to infection, provides nutrients, and educates the immune system and in many ways has a significant impact on human health. Aberrant microbiota composition and decreased diversity (dysbiotic microbiota) are key etiopathological events in IBD. Dysbiotic microbiota can lead to loss of normal, regulatory immune effects in the gut mucosa. This may play a central role in the development and perpetuation of chronic inflammation. Further, the expression of specific innate immune receptors that recognize microbes is altered in the IBD epithelium. Therefore, the combination of host side epithelial barrier functions and the presence of dysbiotic microbiota in the gut together promote inflammation. New therapeutic options targeting microbiota are currently considered for IBD and they may, in the future, provide means to reverse the pathogenic host-microbiota relationship into a symbiotic one. In this review, the focus is on the intestinal microbiota and host-microbe interactions in IBD.

Host-seeking behavior and dispersal of Triatoma infestans, a vector of Chagas disease, under semi-field conditions.

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Ricardo Castillo-Neyra

2015-01-01

Full Text Available Chagas disease affects millions of people in Latin America. The control of this vector-borne disease focuses on halting transmission by reducing or eliminating insect vector populations. Most transmission of Trypanosoma cruzi, the causative agent of Chagas disease, involves insects living within or very close to households and feeding mostly on domestic animals. As animal hosts can be intermittently present it is important to understand how host availability can modify transmission risk to humans and to characterize the host-seeking dispersal of triatomine vectors on a very fine scale. We used a semi-field system with motion-detection cameras to characterize the dispersal of Triatoma infestans, and compare the behavior of vector populations in the constant presence of hosts (guinea pigs, and after the removal of the hosts. The emigration rate - net insect population decline in original refuge - following host removal was on average 19.7% of insects per 10 days compared to 10.2% in constant host populations (p = 0.029. However, dispersal of T. infestans occurred in both directions, towards and away from the initial location of the hosts. The majority of insects that moved towards the original location of guinea pigs remained there for 4 weeks. Oviposition and mortality were observed and analyzed in the context of insect dispersal, but only mortality was higher in the group where animal hosts were removed (p-value <0.01. We discuss different survival strategies associated with the observed behavior and its implications for vector control. Removing domestic animals in infested areas increases vector dispersal from the first day of host removal. The implications of these patterns of vector dispersal in a field setting are not yet known but could result in movement towards human rooms.

Fototerapia na doença enxerto contra hospedeiro Phototherapy in the graft versus host disease

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Ida Duarte

2008-10-01

Full Text Available FUNDAMENTOS: A doença enxerto contra hospedeiro é um dos obstáculos ao sucesso do transplante de medula óssea, e o envolvimento cutâneo é freqüente. A fototerapia é utilizada devido à intensa atividade imunomoduladora local, sendo opção terapêutica adjuvante para as lesões cutâneas resistentes à terapia convencional. OBJETIVO: Realizar análise descritiva do tratamento da doença enxerto contra hospedeiro com fototerapia (Puva ou UVB de faixa estreita. MÉTODOS: Foram atendidos nove pacientes com manifestação cutânea da doença enxerto contra hospedeiro aguda ou crônica. Seis foram tratados com Puva, terapia de primeira escolha, e três com UVB de faixa estreita. As sessões foram realizadas três vezes por semana, e a resposta terapêutica avaliada após 12 sessões. RESULTADOS: Todos os pacientes com doença enxerto contra hospedeiro aguda mostraram melhora, com desaparecimento do eritema e do edema. Naqueles com doença crônica, observaram-se involução das lesões liquenóides e melhora da mobilidade daqueles com a forma esclerodermiforme. Dois pacientes apresentaram doença de evolução grave e foram a óbito. CONCLUSÃO: A fototerapia mostrou-se efetiva no tratamento das manifestações cutâneas da doença enxerto contra hospedeiro aguda e crônica. A Puva permite o controle da doença, podendo a UVB de faixa estreita ser opção para pacientes impossibilitados de usar medicação sistêmica.BACKGROUND: Graft versus host disease is one of the obstacles to successful bone marrow transplantation. It often affects the skin. Phototherapy has been used because of its strong local immunomodulatory activity and it is an option for adjuvant therapy for skin lesions of graft versus host disease resistant to conventional therapy. OBJECTIVE: To make a descriptive analysis of treating graft versus host disease with phototherapy (PUVA or narrowband UVB. Methods - Nine patients with cutaneous manifestation of acute or chronic

National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen.

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Saillard, Colombe; Crocchiolo, Roberto; Furst, Sabine; El-Cheikh, Jean; Castagna, Luca; Signori, Alessio; Oudin, Claire; Faucher, Catherine; Lemarie, Claude; Chabannon, Christian; Granata, Angela; Blaise, Didier

2014-05-01

Abstract In 2005, the National Institutes of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of chronic graft-versus-host disease (cGvHD) severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-hematopoietic stem cell transplant (HSCT) with a fludarabine-busulfan-antithymocyte globulin (ATG) conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. The follow up range was effectively 2-120 months. Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms, respectively, and 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49-61), and cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14-23) and 19% (14-24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (hazard ratio [HR] = 3.28, 95% confidence interval [CI]: 1.38-7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05-8.78, p = 0.04) but comparable relapse risk (p = NS). In conclusion, the NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe.

HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse.

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Martelli, Massimo F; Di Ianni, Mauro; Ruggeri, Loredana; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Pierini, Antonio; Massei, Maria Speranza; Amico, Lucia; Urbani, Elena; Del Papa, Beatrice; Zei, Tiziana; Iacucci Ostini, Roberta; Cecchini, Debora; Tognellini, Rita; Reisner, Yair; Aversa, Franco; Falini, Brunangelo; Velardi, Andrea

2014-07-24

Posttransplant relapse is still the major cause of treatment failure in high-risk acute leukemia. Attempts to manipulate alloreactive T cells to spare normal cells while killing leukemic cells have been unsuccessful. In HLA-haploidentical transplantation, we reported that donor-derived T regulatory cells (Tregs), coinfused with conventional T cells (Tcons), protected recipients against graft-versus-host disease (GVHD). The present phase 2 study investigated whether Treg-Tcon adoptive immunotherapy prevents posttransplant leukemia relapse. Forty-three adults with high-risk acute leukemia (acute myeloid leukemia 33; acute lymphoblastic leukemia 10) were conditioned with a total body irradiation-based regimen. Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg). No posttransplant immunosuppression was given. Ninety-five percent of patients achieved full-donor type engraftment and 15% developed ≥grade 2 acute GVHD. The probability of disease-free survival was 0.56 at a median follow-up of 46 months. The very low cumulative incidence of relapse (0.05) was significantly better than in historical controls. These results demonstrate the immunosuppressive potential of Tregs can be used to suppress GVHD without loss of the benefits of graft-versus-leukemia (GVL) activity. Humanized murine models provided insights into the mechanisms underlying separation of GVL from GVHD, suggesting the GVL effect is due to largely unopposed Tcon alloantigen recognition in bone marrow. © 2014 by The American Society of Hematology.

T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.

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How, Joan; Slade, Michael; Vu, Khoan; DiPersio, John F; Westervelt, Peter; Uy, Geoffrey L; Abboud, Camille N; Vij, Ravi; Schroeder, Mark A; Fehniger, Todd A; Romee, Rizwan

2017-04-01

Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome

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Kathryn P. Haley

2016-01-01

Full Text Available Helicobacter pylori colonizes the stomachs of greater than 50% of the world’s human population making it arguably one of the most successful bacterial pathogens. Chronic H. pylori colonization results in gastritis in nearly all patients; however in a subset of people, persistent infection with H. pylori is associated with an increased risk for more severe disease outcomes including B-cell lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma and invasive adenocarcinoma. Research aimed at elucidating determinants that mediate disease progression has revealed genetic differences in both humans and H. pylori which increase the risk for developing gastric cancer. Furthermore, host diet and nutrition status have been shown to influence H. pylori-associated disease outcomes. In this review we will discuss how H. pylori is able to create a replicative niche within the hostile host environment by subverting and modifying the host-generated immune response as well as successfully competing for limited nutrients such as transition metals by deploying an arsenal of metal acquisition proteins and virulence factors. Lastly, we will discuss how micronutrient availability or alterations in the gastric microbiome may exacerbate negative disease outcomes associated with H. pylori colonization.

Disseminated Nocardia cyriacigeorgia causing pancreatitis in a haploidentical stem cell transplant recipient

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Jason Chen

2017-01-01

Full Text Available We report the first published case of acute pancreatitis secondary to disseminated nocardiosis in a hematopoietic stem cell transplant (HSCT recipient on chronic immunosuppression for graft-versus-host disease (GVHD. Nocardiosis in the HSCT population is relatively rare, and has not yet been described in haploidentical HSCT recipients. Our patient is a 28-year-old male with a history of haploidentical HSCT and GVHD of the skin and lung who was admitted to the hospital with acute pancreatitis. The workup for the etiology of his pancreatitis was initially unrevealing. He subsequently developed worsening sepsis and respiratory failure despite broad spectrum antimicrobials. After multiple bronchoscopies and pancreatic fluid sampling, he was found to have disseminated nocardiosis with Nocardia cyriacigeorgia.

Host-bacterial interplay in periodontal disease

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Rudrakshi Chickanna

2015-01-01

Full Text Available A literature search was performed using MEDLINE (PubMed and other electronic basis from 1991 to 2014. Search included books and journals based on the systematic and critical reviews, in vitro and in vivo clinical studies on molecular basis of host microbial interactions. Clearly, an understanding of the host susceptibility factor in addition to microbial factors by elucidating the molecular basis offers opportunity for therapeutic manipulation of advancing periodontal destruction. One of the hallmarks of pathogenesis is the ability of pathogenic organisms to invade surrounding tissues and to evade the host defence. This paper focuses the general overview of molecular mechanisms involved in the microbiota and host response to bacterial inimical behavior in periodontics.

Allogeneic peripheral blood stem cell transplantation in patients with haematological malignancies

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Shamsi, T.S.; Irfan, M.; Ansari, S.H.; Farzana, T.; Kahlid, M.Z.; Panwani, V.K.; Baig, M.I.; Shakoor, N.

2004-01-01

Objective: To report the initial data on allogeneic peripheral blood stem cell transplantation for haematogical malignancies in Pakistan. Patients and Methods: Patients with haematological malignancies were included who had received allogeneic PBSC transplantation of Filgrastim (rhG-CSF) mobilized peripheral blood stem cells from HLA-identical siblings (except one 5/6 antigen sibling) with Busulphan and Cyclophosphamide standard conditioning therapy in all patients. No patient received antibiotics for gut decontamination. Empirical antibiotics included Ceftriaxone and Amikacin for febrile neutropenia, oral Itraconazole for antifungal prophylaxis while oral acyclovir was used for antiviral prophylaxis. All donors and recipients were CMV IgG positive Cyclosporin A / Methotrexate were given for graft versus host disease (GvHD) prophylaxis. Stem cells were harvested using Haemonetics MCS+ cell separator. All patients received G-CSF starting from day +4 until their neutrophil count rose to normal. Results: There were 21 patients with age range of 8-38 years and male to female ratio of 2:1. Engraftment was achieved in all patients; median time to absolute neutrophil count of > 0.5 x 10/sup 9/I was 10 days (range 8 -12 days) and platelet count of > 20 x 10/sup 9/1 was 14 days (12-17 days). Acute graft versus host disease (aGvHD) was seen in 7 patients; one patient had grade IV skin and hepatic GvHD; another patient had grade III gut GvHD, grade II GvHD was seen in 3 patients while grade I skin aGvHD was seen in 2 patients. Median hospital stay was 34 days. Treatment related mortality was seen in 3 patients (18%). Chronic GvHD was seen in 5 patients. Four more patients died during the follow-up period. Malaria was seen in 2 while tuberculosis developed in one case. Relapse was seen in 2 patients. The estimated probability of survival at one hundred day, at one year and five years was 82, 47 and 40 percent respectively. Conclusion: Haematopoietic stem cell transplant

Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury?

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Yuan, Lijuan; Shen, Jianliang

2016-01-01

Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic. PMID:27652837

Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease

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LeBoit, P.E.

1989-01-01

The histopathologic changes of radiation dermatitis have been classified either as early effects (necrotic keratinocytes, fibrin thrombi, and hemorrhage) or as late effects (vacuolar changes at the dermal-epidermal junction, atypical radiation fibroblasts, and fibrosis). Two patients, one exposed to radiation therapeutically and one accidentally, are described. Skin biopsy specimens showed an interface dermatitis characterized by numerous dyskeratotic epidermal cells with lymphocytes in close apposition (satellite cell necrosis); that is, the epidermal changes were similar to those in acute graft-versus-host disease. Because recipients of bone marrow transplants frequently receive total body irradiation as part of their preparatory regimen, the ability of radiation to cause persistent epidermal changes similar to those in acute graft-versus-host disease could complicate the interpretation of posttransplant skin biopsy specimens

Salivary mucins in host defense and disease prevention

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Erica Shapiro Frenkel

2015-12-01

Full Text Available Mucus forms a protective coating on wet epithelial surfaces throughout the body that houses the microbiota and plays a key role in host defense. Mucins, the primary structural components of mucus that creates its viscoelastic properties, are critical components of the gel layer that protect against invading pathogens. Altered mucin production has been implicated in diseases such as ulcerative colitis, asthma, and cystic fibrosis, which highlights the importance of mucins in maintaining homeostasis. Different types of mucins exist throughout the body in various locations such as the gastrointestinal tract, lungs, and female genital tract, but this review will focus on mucins in the oral cavity. Salivary mucin structure, localization within the oral cavity, and defense mechanisms will be discussed. These concepts will then be applied to present what is known about the protective function of mucins in oral diseases such as HIV/AIDS, oral candidiasis, and dental caries.

PRGF exerts more potent proliferative and anti-inflammatory effects than autologous serum on a cell culture inflammatory model.

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Anitua, E; Muruzabal, F; de la Fuente, M; Riestra, A; Merayo-Lloves, J; Orive, G

2016-10-01

Ocular graft versus host disease (oGVHD) is part of a systemic inflammatory disease that usually affects ocular surface tissues manifesting as a dry eye syndrome. Current treatments provide unsatisfactory results. Blood-derived products, like plasma rich in growth factors (PRGF) emerge as a potential therapy for this disease. The purpose of this study was to evaluate the tissue regeneration and anti-inflammatory capability of PRGF, an autologous platelet enriched plasma eye-drop, compared to autologous serum (AS) obtained from oGVHD patients on ocular surface cells cultured in a pro-inflammatory environment. PRGF and AS were obtained from four GVHD patients. Cell proliferation and inflammation markers, intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2), were measured in corneal and conjunctival fibroblastic cells cultured under pro-inflammatory conditions and after treatment with PRGF or AS eye drops. Moreover, cell proliferation increased after treatment with PRGF and AS, though this enhancement in the case of keratocytes was significantly higher with PRGF. PRGF eye drops showed a significant reduction of both inflammatory markers with respect to the initial inflammatory situation and to the AS treatment. Our results concluded that PRGF exerts more potent regenerative and anti-inflammatory effects than autologous serum on ocular surface fibroblasts treated with pro-inflammatory IL-1β and TNFα. Copyright © 2016 Elsevier Ltd. All rights reserved.

Personalized Prognostic Risk Score for Long-Term Survival for Children with Acute Leukemia after Allogeneic Transplantation.

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Bitan, Menachem; Ahn, Kwang Woo; Millard, Heather R; Pulsipher, Michael A; Abdel-Azim, Hisham; Auletta, Jeffery J; Brown, Valerie; Chan, Ka Wah; Diaz, Miguel Angel; Dietz, Andrew; Vincent, Marta González; Guilcher, Gregory; Hale, Gregory A; Hayashi, Robert J; Keating, Amy; Mehta, Parinda; Myers, Kasiani; Page, Kristin; Prestidge, Tim; Shah, Nirali N; Smith, Angela R; Woolfrey, Ann; Thiel, Elizabeth; Davies, Stella M; Eapen, Mary

2017-09-01

We studied leukemia-free (LFS) and overall survival (OS) in children with acute myeloid (AML, n = 790) and acute lymphoblastic leukemia (ALL, n = 1096) who underwent transplantation between 2000 and 2010 and who survived for at least 1 year in remission after related or unrelated donor transplantation. Analysis of patient-, disease-, and transplantation characteristics and acute and chronic graft-versus-host disease (GVHD) was performed to identify factors with adverse effects on LFS and OS. These data were used to develop risk scores for survival. We did not identify any prognostic factors beyond 4 years after transplantation for AML and beyond 3 years for ALL. Risk score for survival for AML includes age, disease status at transplantation, cytogenetic risk group, and chronic GVHD. For ALL, the risk score includes age at transplantation and chronic GVHD. The 10-year probabilities of OS for AML with good (score 0, 1, or 2), intermediate (score 3), and poor risk (score 4, 5, 6, or 7) were 94%, 87%, and 68%, respectively. The 10-year probabilities of OS for ALL were 89% and 80% for good (score 0 or 1) and poor risk (score 2), respectively. Identifying children at risk for late mortality with early intervention may mitigate some excess late mortality. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Host age modulates within-host parasite competition.

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Izhar, Rony; Routtu, Jarkko; Ben-Ami, Frida

2015-05-01

In many host populations, one of the most striking differences among hosts is their age. While parasite prevalence differences in relation to host age are well known, little is known on how host age impacts ecological and evolutionary dynamics of diseases. Using two clones of the water flea Daphnia magna and two clones of its bacterial parasite Pasteuria ramosa, we examined how host age at exposure influences within-host parasite competition and virulence. We found that multiply-exposed hosts were more susceptible to infection and suffered higher mortality than singly-exposed hosts. Hosts oldest at exposure were least often infected and vice versa. Furthermore, we found that in young multiply-exposed hosts competition was weak, allowing coexistence and transmission of both parasite clones, whereas in older multiply-exposed hosts competitive exclusion was observed. Thus, age-dependent parasite exposure and host demography (age structure) could together play an important role in mediating parasite evolution. At the individual level, our results demonstrate a previously unnoticed interaction of the host's immune system with host age, suggesting that the specificity of immune function changes as hosts mature. Therefore, evolutionary models of parasite virulence might benefit from incorporating age-dependent epidemiological parameters. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Understanding the Effects of Host Evolution and Skin Bacteria Composition on Disease Vector Choices

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2016-04-14

Distribution Unlimited UU UU UU UU 14-04-2016 1-Sep-2014 31-Dec-2015 Final Report: Understanding the effects of host evolution and skin bacteria ...S) AND ADDRESS (ES) U.S. Army Research Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 mosquito, skin, bacteria , primate REPORT...reviewed journals: Final Report: Understanding the effects of host evolution and skin bacteria composition on disease vector choices Report Title Here

Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission.

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Page, Kristin M; Labopin, Myriam; Ruggeri, Annalisa; Michel, Gerard; Diaz de Heredia, Cristina; O'Brien, Tracey; Picardi, Alessandra; Ayas, Mouhab; Bittencourt, Henrique; Vora, Ajay J; Troy, Jesse; Bonfim, Carmen; Volt, Fernanda; Gluckman, Eliane; Bader, Peter; Kurtzberg, Joanne; Rocha, Vanderson

2017-08-01

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Immunoglobulin levels in dogs after total-body irradiation and bone marrow transplantation

International Nuclear Information System (INIS)

Vriesendorp, H.M.; Halliwell, R.E.; Johnson, P.M.; Fey, T.A.; McDonough, C.M.

1985-01-01

The influence of total-body irradiation (TBI) and autologous or allogeneic bone marrow transplantation on serum immunoglobulin subclasses was determined in a dog model. Only IgG1 levels decreased after low-dose (+/- 4.5 Gy) TBI, but levels of all immunoglobulin classes fell after high-dose TBI (8.5 GyX1 or 2X6.0 Gy). After autologous bone marrow transplantation IgM levels were the first and IgE levels were the last to return to normal. After successful allogeneic bone marrow transplantation prolonged low IgM and IgE levels were found but IgA levels increased rapidly to over 150% of pretreatment values. A comparison of dogs with or without clinical signs or graft-versus-host disease (GVHD), revealed no differences in IgM levels. Dogs with GVHD had higher IgA but lower IgE levels. Dogs that rejected their allogeneic bone marrow cells showed significant early rises in IgE and IgA levels in comparison with dogs with GVHD. These results differ from the observations made on Ig levels in human bone marrow transplant patients. No significant differences in phytohemagglutinin stimulation tests were found between dogs with or without GVHD or dogs receiving an autologous transplant for the first four months after TBI and transplantation. An early primary or secondary involvement of humoral immunity in GVHD and graft rejection in dogs is postulated

Infection history of the blood-meal host dictates pathogenic potential of the Lyme disease spirochete within the feeding tick vector.

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Bharti Bhatia

2018-04-01

Full Text Available Lyme disease in humans is caused by several genospecies of the Borrelia burgdorferi sensu lato (s.l. complex of spirochetal bacteria, including B. burgdorferi, B. afzelii and B. garinii. These bacteria exist in nature as obligate parasites in an enzootic cycle between small vertebrate hosts and Ixodid tick vectors, with humans representing incidental hosts. During the natural enzootic cycle, infected ticks in endemic areas feed not only upon naïve hosts, but also upon seropositive infected hosts. In the current study, we considered this environmental parameter and assessed the impact of the immune status of the blood-meal host on the phenotype of the Lyme disease spirochete within the tick vector. We found that blood from a seropositive host profoundly attenuates the infectivity (>104 fold of homologous spirochetes within the tick vector without killing them. This dramatic neutralization of vector-borne spirochetes was not observed, however, when ticks and blood-meal hosts carried heterologous B. burgdorferi s.l. strains, or when mice lacking humoral immunity replaced wild-type mice as blood-meal hosts in similar experiments. Mechanistically, serum-mediated neutralization does not block induction of host-adapted OspC+ spirochetes during tick feeding, nor require tick midgut components. Significantly, this study demonstrates that strain-specific antibodies elicited by B. burgdorferi s.l. infection neutralize homologous bacteria within feeding ticks, before the Lyme disease spirochetes enter a host. The blood meal ingested from an infected host thereby prevents super-infection by homologous spirochetes, while facilitating transmission of heterologous B. burgdorferi s.l. strains. This finding suggests that Lyme disease spirochete diversity is stably maintained within endemic populations in local geographic regions through frequency-dependent selection of rare alleles of dominant polymorphic surface antigens.

Allogeneic bone marrow transplantation with conditioning regimen to total body irradiation + thiotepa + melphalan for 35 patients with high-risk leukemia

International Nuclear Information System (INIS)

Yumura-Yagi, Keiko; Inoue, Masami; Okamura, Takayuki

1997-01-01

Thirty-five children with high-risk leukemia received an allogeneic bone marrow transplantation (BMT) following a pre-conditioning regimen consisting of total body irradiation, thiotepa and melphalan. Twenty-one patients had acute lymphocytic leukemia, 6 acute nonlymphocytic leukemia, 2 acute undifferentiated leukemia, 2 acute mixed lineage leukemia, 2 myelodysplastic syndrome and 2 juvenile chronic myeloid leukemia. Sixteen patients received BMT while in complete remission (CR), but 19 were not in CR. Eighteen patients received transplants from HLA-matched related donors, 15 from unrelated donors and 2 from HLA-mismatched related donors. Cyclosporin±methotrexate was used for graft-versus-host disease (GVHD) prophylaxis in the BMTs from related donors and tacrolimus±prednisolone in the BMTs from unrelated donors. Transplant-related death occurred in 12 patients; 5 acute GVHD, 4 infections (3 fungal infections, 1 Cytomegalovirus pneumonia), 1 intracranial haemorrhage and 2 chronic GVHD. Relapses were observed in 6 patients (69, 168, 175, 222, 275 and 609 days post BMT). Event-free survival rate at 2 years is 38.1% in CR patients and 36.9% in nonCR patients. (author)

Menstrual patterns, fertility and main pregnancy outcomes after allogeneic haematopoietic stem cell transplantation.

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Chiodi, Sandra; Spinelli, Simonetta; Bruzzi, Paolo; Anserini, Paola; Di Grazia, Carmen; Bacigalupo, Andrea

2016-08-01

Two-hundred and sixty-nine females aged ≤42 and undergoing an allogeneic stem cell transplant were retrospectively studied to assess the effect of age, conditioning regimen and chronic graft-versus-host disease (cGVHD) on resumption of stable menstrual cyclicity. Overall, a stable menstrual cyclicity was observed in 22% of cases. The cumulative probability of menses resumption was significantly age and conditioning regimen related. A statistically significant inverse correlation between cGVHD severity and menses resumption was observed only in univariate analysis. In patients with residual ovarian function, infertility was found in 43% and early menopause in 45%. An increased incidence of prematurity and low birth weight (LBW) was observed among the single spontaneous pregnancies. Follicle-stimulating hormone (FSH) and 17 beta-oestradiol levels were found to be inadequate to detect both early signs of menses resumption and menstrual stability. Our study confirms the crucial role of full dose total body irradiation (TBI) and age on menses recovery and fertility after haematopoietic stem cell transplantation (HSCT). The impact of severe cGVHD remains unclear.

Detection and Host Range Study of Virus Associated with Pepper Yellow Leaf Curl Disease

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SRI SULANDARI

2006-03-01

Full Text Available High incidence of Pepper yellow leaf curl virus (PepYLCV was observed in Indonesia since early 2000. Disease incidence in Yogyakarta, Central and West Java reached 100% on Capsicum frutescens, but only 10-35% on C. annuum. As an exception, the disease incidence on C. annuum cv. TM 999 was in the range of 70-100%. The causal agent of the disease, PepYLCV, was detected by polymerase chain reaction. Viral specific DNA fragment of the size ~1600 bp and ~550 bp was amplified from infected plants using two pairs of geminivirus universal primers pAL1v1978/pAL1c715, and pAv494/pAc1048, respectively. The PepYLCV has an intermediate host range including plants belonging to the family of Solanaceae, Leguminosae, and Compositae. The species belonging to the families of Cucurbitaceae, Malvaceae, Chenopodiaceae, and Amaranthaceae were resistant to the virus. Physalis floridana, is very prospective as a propagation host for the geminivirus infecting pepper. Nicotiana spp., cucumber, watermelon, cotton, and Sida sp. could be used as a differential host. Besides, Capsicum frutescens cv. Cakra, tomato, N. benthamiana, N. glutinosa, and Ageratum conyzoides could be used as indicator plants for the geminivirus infecting pepper.

GVHD suppression by incubation of bone marrow grafts with anti-t-cell globulin: effect in the canine model and application to clinical bone marrow transplantation

International Nuclear Information System (INIS)

Rodt, H.; Kolb, H.J.; Netzel, B.; Rieder, I.; Janka, G.; Belohradsky, B.; Haas, R.J.; Thierfelder, S.

1979-01-01

The present studies were performed in order to establish the anti-GVHD effect of an incubation treatment in the dog, which is regarded as a model of particular relevance for clinical bone marrow transplantation. Application of this principle to a case of human marrow transplantation will be reported

Molecules at the interface of Cryptococcus and the host that determine disease susceptibility.

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Wozniak, Karen L; Olszewski, Michal A; Wormley, Floyd L

2015-05-01

Cryptococcus neoformans and Cryptococcus gattii, the predominant etiological agents of cryptococcosis, are fungal pathogens that cause disease ranging from a mild pneumonia to life-threatening infections of the central nervous system (CNS). Resolution or exacerbation of Cryptococcus infection is determined following complex interactions of several host and pathogen derived factors. Alternatively, interactions between the host and pathogen may end in an impasse resulting in the establishment of a sub-clinical Cryptococcus infection. The current review addresses the delicate interaction between the host and Cryptococcus-derived molecules that determine resistance or susceptibility to infection. An emphasis will be placed on data highlighted at the recent 9th International Conference on Cryptococcus and Cryptococcosis (ICCC). Copyright © 2015. Published by Elsevier Inc.

Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases.

Science.gov (United States)

Laskowska, Katarzyna; Burzyńska-Makuch, Małgorzata; Krenska, Anna; Kołtan, Sylwia; Chrupek, Małgorzata; Nawrocka, Elżbieta; Lasek, Władysław; Serafin, Zbigniew

2012-04-01

Pneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease. A 5-year-old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy. Pneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation.

Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases

International Nuclear Information System (INIS)

Laskowska, Katarzyna; Burzyńska-Makuch, Małgorzata; Krenska, Anna; Kołtan, Sylwia; Chrupek, Małgorzata; Nawrocka, Elżbieta; Lasek, Władysław; Serafin, Zbigniew

2012-01-01

Pneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease. A 5-year-old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy. Pneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation

A Systems Biology Approach to Infectious Disease Research: Innovating the Pathogen-Host Research Paradigm

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Aderem, Alan; Adkins, Joshua N.; Ansong, Charles; Galagan, James; Kaiser, Shari; Korth, Marcus J.; Law, G. L.; McDermott, Jason E.; Proll, Sean; Rosenberger, Carrie; Schoolnik, Gary; Katze, Michael G.

2011-02-01

The 20th century was marked by extraordinary advances in our understanding of microbes and infectious disease, but pandemics remain, food and water borne illnesses are frequent, multi-drug resistant microbes are on the rise, and the needed drugs and vaccines have not been developed. The scientific approaches of the past—including the intense focus on individual genes and proteins typical of molecular biology—have not been sufficient to address these challenges. The first decade of the 21st century has seen remarkable innovations in technology and computational methods. These new tools provide nearly comprehensive views of complex biological systems and can provide a correspondingly deeper understanding of pathogen-host interactions. To take full advantage of these innovations, the National Institute of Allergy and Infectious Diseases recently initiated the Systems Biology Program for Infectious Disease Research. As participants of the Systems Biology Program we think that the time is at hand to redefine the pathogen-host research paradigm.

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

Science.gov (United States)

Cox, Jonathan A.; Hiscox, Julian A.; Solomon, Tom; Ooi, Mong-How; Ng, Lisa F. P.

2017-01-01

Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. Infection can cause severe neurological, cardiac, and respiratory problems in children under the age of 5. Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host–viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions. PMID:29238324

The Influence of Host and Bacterial Genotype on the Development of Disseminated Disease with Mycobacterium tuberculosis

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Caws, Maxine; Thwaites, Guy; Dunstan, Sarah; Hawn, Thomas R.; Thi Ngoc Lan, Nguyen; Thuong, Nguyen Thuy Thuong; Stepniewska, Kasia; Huyen, Mai Nguyet Thu; Bang, Nguyen Duc; Huu Loc, Tran; Gagneux, Sebastien; van Soolingen, Dick; Kremer, Kristin; van der Sande, Marianne; Small, Peter; Thi Hoang Anh, Phan; Chinh, Nguyen Tran; Thi Quy, Hoang; Thi Hong Duyen, Nguyen; Quang Tho, Dau; Hieu, Nguyen T.; Torok, Estee; Hien, Tran Tinh; Dung, Nguyen Huy; Thi Quynh Nhu, Nguyen; Duy, Phan Minh; van Vinh Chau, Nguyen; Farrar, Jeremy

2008-01-01

The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193–0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15–2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis. PMID:18369480

The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis.

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Maxine Caws

2008-03-01

Full Text Available The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP and Toll-like receptor-2 (TLR-2. We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR for causing TBM 0.395, 95% confidence intervals (C.I. 0.193-0.806, P = 0.009, suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15-2.15] than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis.

The impact of Fusarium mycotoxins on human and animal host susceptibility to infectious diseases.

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Antonissen, Gunther; Martel, An; Pasmans, Frank; Ducatelle, Richard; Verbrugghe, Elin; Vandenbroucke, Virginie; Li, Shaoji; Haesebrouck, Freddy; Van Immerseel, Filip; Croubels, Siska

2014-01-28

Contamination of food and feed with mycotoxins is a worldwide problem. At present, acute mycotoxicosis caused by high doses is rare in humans and animals. Ingestion of low to moderate amounts of Fusarium mycotoxins is common and generally does not result in obvious intoxication. However, these low amounts may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host pathogen interactions and thus a different outcome of infection. This review summarizes the current state of knowledge about the impact of Fusarium mycotoxin exposure on human and animal host susceptibility to infectious diseases. On the one hand, exposure to deoxynivalenol and other Fusarium mycotoxins generally exacerbates infections with parasites, bacteria and viruses across a wide range of animal host species. Well-known examples include coccidiosis in poultry, salmonellosis in pigs and mice, colibacillosis in pigs, necrotic enteritis in poultry, enteric septicemia of catfish, swine respiratory disease, aspergillosis in poultry and rabbits, reovirus infection in mice and Porcine Reproductive and Respiratory Syndrome Virus infection in pigs. However, on the other hand, T-2 toxin has been shown to markedly decrease the colonization capacity of Salmonella in the pig intestine. Although the impact of the exposure of humans to Fusarium toxins on infectious diseases is less well known, extrapolation from animal models suggests possible exacerbation of, for instance, colibacillosis and salmonellosis in humans, as well.

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/− Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

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Séverine Bézie

2018-01-01

Full Text Available Both CD4+ and CD8+ Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClow/− Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8+CD45RClow/− Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8+ Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8+CD45RClow/− Tregs are equivalent to canonical CD4+CD25highCD127low/− Tregs for suppression of allogeneic immune responses in vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.

Infectious Bursal Disease Virus-Host Interactions: Multifunctional Viral Proteins that Perform Multiple and Differing Jobs

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Yao Qin

2017-01-01

Full Text Available Infectious bursal disease (IBD is an acute, highly contagious and immunosuppressive poultry disease caused by IBD virus (IBDV. The consequent immunosuppression increases susceptibility to other infectious diseases and the risk of subsequent vaccination failure as well. Since the genome of IBDV is relatively small, it has a limited number of proteins inhibiting the cellular antiviral responses and acting as destroyers to the host defense system. Thus, these virulence factors must be multifunctional in order to complete the viral replication cycle in a host cell. Insights into the roles of these viral proteins along with their multiple cellular targets in different pathways will give rise to a rational design for safer and effective vaccines. Here we summarize the recent findings that focus on the virus–cell interactions during IBDV infection at the protein level.

Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis

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Brouwer, Matthijs C.; Read, Robert C.; van de Beek, Diederik

2010-01-01

Various genes regulate the intensity of the inflammatory and coagulation response to infection and therefore might determine the severity and outcome of meningococcal disease. We systematically reviewed the published work for case control studies on the influence of host genetics on severity and

A model to estimate effects of SNPs on host susceptibility and infectivity for an endemic infectious disease

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Biemans, Floor; Jong, de Mart C.M.; Bijma, Piter

2017-01-01

Background: Infectious diseases in farm animals affect animal health, decrease animal welfare and can affect human health. Selection and breeding of host individuals with desirable traits regarding infectious diseases can help to fight disease transmission, which is affected by two types of

Gut Microbiota and Host Reaction in Liver Diseases

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Hiroshi Fukui

2015-10-01

Full Text Available Although alcohol feeding produces evident intestinal microbial changes in animals, only some alcoholics show evident intestinal dysbiosis, a decrease in Bacteroidetes and an increase in Proteobacteria. Gut dysbiosis is related to intestinal hyperpermeability and endotoxemia in alcoholic patients. Alcoholics further exhibit reduced numbers of the beneficial Lactobacillus and Bifidobacterium. Large amounts of endotoxins translocated from the gut strongly activate Toll-like receptor 4 in the liver and play an important role in the progression of alcoholic liver disease (ALD, especially in severe alcoholic liver injury. Gut microbiota and bacterial endotoxins are further involved in some of the mechanisms of nonalcoholic fatty liver disease (NAFLD and its progression to nonalcoholic steatohepatitis (NASH. There is experimental evidence that a high-fat diet causes characteristic dysbiosis of NAFLD, with a decrease in Bacteroidetes and increases in Firmicutes and Proteobacteria, and gut dysbiosis itself can induce hepatic steatosis and metabolic syndrome. Clinical data support the above dysbiosis, but the details are variable. Intestinal dysbiosis and endotoxemia greatly affect the cirrhotics in relation to major complications and prognosis. Metagenomic approaches to dysbiosis may be promising for the analysis of deranged host metabolism in NASH and cirrhosis. Management of dysbiosis may become a cornerstone for the future treatment of liver diseases.

Host Factors and Biomarkers Associated with Poor Outcomes in Adults with Invasive Pneumococcal Disease.

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Shigeo Hanada

Full Text Available Invasive pneumococcal disease (IPD causes considerable morbidity and mortality. We aimed to identify host factors and biomarkers associated with poor outcomes in adult patients with IPD in Japan, which has a rapidly-aging population.In a large-scale surveillance study of 506 Japanese adults with IPD, we investigated the role of host factors, disease severity, biomarkers based on clinical laboratory data, treatment regimens, and bacterial factors on 28-day mortality.Overall mortality was 24.1%, and the mortality rate increased from 10.0% in patients aged ˂50 years to 33.1% in patients aged ≥80 years. Disease severity also increased 28-day mortality, from 12.5% among patients with bacteraemia without sepsis to 35.0% in patients with severe sepsis and 56.9% with septic shock. The death rate within 48 hours after admission was high at 54.9%. Risk factors for mortality identified by multivariate analysis were as follows: white blood cell (WBC count <4000 cells/μL (odds ratio [OR], 6.9; 95% confidence interval [CI], 3.7-12.8, p < .001; age ≥80 years (OR, 6.5; 95% CI, 2.0-21.6, p = .002; serum creatinine ≥2.0 mg/dL (OR, 4.5; 95% CI, 2.5-8.1, p < .001; underlying liver disease (OR, 3.5; 95% CI, 1.6-7.8, p = .002; mechanical ventilation (OR, 3.0; 95% CI, 1.7-5.6, p < .001; and lactate dehydrogenase ≥300 IU/L (OR, 2.4; 95% CI, 1.4-4.0, p = .001. Pneumococcal serotype and drug resistance were not associated with poor outcomes.Host factors, disease severity, and biomarkers, especially WBC counts and serum creatinine, were more important determinants of mortality than bacterial factors.

Long-Term Intravenous Ketamine for Analgesia in a Child with Severe Chronic Intestinal Graft versus Host Disease

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Jennifer Busse

2015-01-01

Full Text Available Ketamine is reported to be an effective adjuvant to opioids in the treatment of refractory cancer pain; however, the use of high doses of ketamine for extended periods in pediatric patients has not been described. We present a five-year-old male with grade IV intestinal GVHD whose abdominal pain required both hydromorphone and ketamine for a period of over four months. There was no evidence of hepatotoxicity, hemorrhagic cystitis, or other adverse effects. Possible withdrawal symptoms were mild and were readily mitigated by gradually weaning ketamine.

Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease.

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Cardona, Diana M; Detweiler, Claire J; Shealy, Michael J; Sung, Anthony D; Wild, Daniel M; Poleski, Martin H; Balmadrid, Bryan L; Cirrincione, Constance T; Howell, David N; Sullivan, Keith M

2018-04-26

- Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical record from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

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Bryant, A; Nivison-Smith, I; Pillai, E S; Kennedy, G; Kalff, A; Ritchie, D; George, B; Hertzberg, M; Patil, S; Spencer, A; Fay, K; Cannell, P; Berkahn, L; Doocey, R; Spearing, R; Moore, J

2014-01-01

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Pathogen reduction by ultraviolet C light effectively inactivates human white blood cells in platelet products.

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Pohler, Petra; Müller, Meike; Winkler, Carla; Schaudien, Dirk; Sewald, Katherina; Müller, Thomas H; Seltsam, Axel

2015-02-01

Residual white blood cells (WBCs) in cellular blood components induce a variety of adverse immune events, including nonhemolytic febrile transfusion reactions, alloimmunization to HLA antigens, and transfusion-associated graft-versus-host disease (TA-GVHD). Pathogen reduction (PR) methods such as the ultraviolet C (UVC) light-based THERAFLEX UV-Platelets system were developed to reduce the risk of transfusion-transmitted infection. As UVC light targets nucleic acids, it interferes with the replication of both pathogens and WBCs. This preclinical study aimed to evaluate the ability of UVC light to inactivate contaminating WBCs in platelet concentrates (PCs). The in vitro and in vivo function of WBCs from UVC-treated PCs was compared to that of WBCs from gamma-irradiated and untreated PCs by measuring cell viability, proliferation, cytokine secretion, antigen presentation in vitro, and xenogeneic GVHD responses in a humanized mouse model. UVC light was at least as effective as gamma irradiation in preventing GVHD in the mouse model. It was more effective in suppressing T-cell proliferation (>5-log reduction in the limiting dilution assay), cytokine secretion, and antigen presentation than gamma irradiation. The THERAFLEX UV-Platelets (MacoPharma) PR system can substitute gamma irradiation for TA-GVHD prophylaxis in platelet (PLT) transfusion. Moreover, UVC treatment achieves suppression of antigen presentation and inhibition of cytokine accumulation during storage of PCs, which has potential benefits for transfusion recipients. © 2014 AABB.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation.

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Doki, Noriko; Suyama, Masahiro; Sasajima, Satoshi; Ota, Junko; Igarashi, Aiko; Mimura, Iyo; Morita, Hidetoshi; Fujioka, Yuki; Sugiyama, Daisuke; Nishikawa, Hiroyoshi; Shimazu, Yutaka; Suda, Wataru; Takeshita, Kozue; Atarashi, Koji; Hattori, Masahira; Sato, Eiichi; Watakabe-Inamoto, Kyoko; Yoshioka, Kosuke; Najima, Yuho; Kobayashi, Takeshi; Kakihana, Kazuhiko; Takahashi, Naoto; Sakamaki, Hisashi; Honda, Kenya; Ohashi, Kazuteru

2017-09-01

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p strategy to prevent aGVHD.

Host genetics affect microbial ecosystems via host immunity.

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El Kafsi, Hela; Gorochov, Guy; Larsen, Martin

2016-10-01

Genetic evolution of multicellular organisms has occurred in response to environmental challenges, including competition for nutrients, climate change, physical and chemical stressors, and pathogens. However, fitness of an organism is dependent not only on defense efficacy, but also on the ability to take advantage of symbiotic organisms. Indeed, microbes not only encompass pathogenicity, but also enable efficient nutrient uptake from diets nondegradable by the host itself. Moreover, microbes play important roles in the development of host immunity. Here we review associations between specific host genes and variance in microbiota composition and compare with interactions between microbes and host immunity. Recent genome-wide association studies reveal that symbiosis between host and microbiota is the exquisite result of genetic coevolution. Moreover, a subset of microbes from human and mouse microbiota have been identified to interact with humoral and cellular immunity. Interestingly, microbes associated with both host genetics and host immunity are taxonomically related. Most involved are Bifidobacterium, Lactobacillus, and Akkermansia, which are dually associated with both host immunity and host genetics. We conclude that future therapeutics targeting microbiota in the context of chronic inflammatory diseases need to consider both immune and genetic host features associated with microbiota homeostasis.

Animal salmonelloses: a brief review of “host adaptation and host specificity” of Salmonella spp.

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Grammato Evangelopoulou

2013-07-01

Full Text Available Salmonella enterica, the most pathogenic species of the genusSalmonella, includes more than 2,500 serovars, many of which are of great veterinary and medical significance. The emergence of food-borne pathogens, such as Salmonella spp., has increased knowledge about the mechanisms helping microorganisms to persist and spread within new host populations. It has also increased information about the properties they acquire for adapting in the biological environment of a new host. Thedifferences observed between serovars in their host preference and clinical manifestations are referred to as “serovar-host specificity” or “serovar-host adaptation”. The genus Salmonella, highly adaptive to vertebrate hosts, has many pathogenic serovars showing host specificity. Serovar Salmonella Typhi, causing disease to man and higher primates, is a good example of host specificity. Thus, understanding the mechanisms that Salmonella serovars use to overcome animal species' barriers or adapt to new hosts is also important for understanding the origins of any other infectious diseases or the emergence of new pathogens. In addition, molecular methods used to study the virulence determinants of Salmonella serovars, could also be used to model ways of studying the virulence determinants used by bacteria in general, when causing disease to a specific animal species

Prevalence, care-seeking, and health service utilization for non-communicable diseases among Syrian refugees and host communities in Lebanon.

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Doocy, Shannon; Lyles, Emily; Hanquart, Baptiste; Woodman, Michael

2016-01-01

Given the large burden of non-communicable diseases (NCDs) among both Syrian refugees and the host communities within which they are settled, humanitarian actors and the government of Lebanon face immense challenges in addressing health needs. This study assessed health status, unmet needs, and utilization of health services among Syrian refugees and host communities in Lebanon. A cross-sectional survey of Syrian refugees and host communities in Lebanon was conducted using a two-stage cluster survey design with probability proportional to size sampling. To obtain information on chronic NCDs, respondents were asked a series of questions about hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and arthritis. Differences in household characteristics by care-seeking for these conditions were examined using chi-square, t-test, and adjusted logistic regression methods. Over half (50.4 %) of refugee and host community households (60.2 %) reported a member with one of the five NCDs. Host community prevalence rates were significantly higher than refugees for all conditions except chronic respiratory diseases ( p  = 0.08). Care-seeking for NCDs among refugees and host community households was high across all conditions with 82.9 and 97.8 %, respectively, having sought care in Lebanon for their condition. Refugees utilized primary health care centers (PHCC) (57.7 %) most often while host communities sought care most in private clinics (62.4 %). Overall, 69.7 % of refugees and 82.7 % of host community members reported an out-of-pocket consultation payment ( p  = 0.041) with an average payment of US$15 among refugees and US$42 for the host community ( p Syrian crisis and the burden on the Lebanese health system, implications for both individuals with NCDs and Lebanon's health system are immense. The burden of out of pocket expenses on persons with NCDs are also substantial, especially given the tenuous economic status of many refugees

How host regulation of Helicobacter pylori-induced gastritis protects against peptic ulcer disease and gastric cancer.

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Dhar, Poshmaal; Ng, Garrett Z; Sutton, Philip

2016-09-01

The bacterial pathogen Helicobacter pylori is the etiological agent of a range of gastrointestinal pathologies including peptic ulcer disease and the major killer, gastric adenocarcinoma. Infection with this bacterium induces a chronic inflammatory response in the gastric mucosa (gastritis). It is this gastritis that, over decades, eventually drives the development of H. pylori-associated disease in some individuals. The majority of studies investigating H. pylori pathogenesis have focused on factors that promote disease development in infected individuals. However, an estimated 85% of those infected with H. pylori remain completely asymptomatic, despite the presence of pathogenic bacteria that drive a chronic gastritis that lasts many decades. This indicates the presence of highly effective regulatory processes in the host that, in most cases, keeps a check on inflammation and protect against disease. In this minireview we discuss such known host factors and how they prevent the development of H. pylori-associated pathologies. Copyright © 2016 the American Physiological Society.

Echinococcus multilocularis and Its Intermediate Host: A Model of Parasite-Host Interplay

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Dominique Angèle Vuitton

2010-01-01

Full Text Available Host-parasite interactions in the E. multilocularis-intermediate host model depend on a subtle balance between cellular immunity, which is responsible for host's resistance towards the metacestode, the larval stage of the parasite, and tolerance induction and maintenance. The pathological features of alveolar echinococcosis. the disease caused by E. multilocularis, are related both to parasitic growth and to host's immune response, leading to fibrosis and necrosis, The disease spectrum is clearly dependent on the genetic background of the host as well as on acquired disturbances of Th1-related immunity. The laminated layer of the metacestode, and especially its carbohydrate components, plays a major role in tolerance induction. Th2-type and anti-inflammatory cytokines, IL-10 and TGF-β, as well as nitric oxide, are involved in the maintenance of tolerance and partial inhibition of cytotoxic mechanisms. Results of studies in the experimental mouse model and in patients suggest that immune modulation with cytokines, such as interferon-α, or with specific antigens could be used in the future to treat patients with alveolar echinococcosis and/or to prevent this very severe parasitic disease.

The role of Ixodes scapularis, Borrelia burgdorferi and wildlife hosts in Lyme disease prevalence: A quantitative review.

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Halsey, Samniqueka J; Allan, Brian F; Miller, James R

2018-04-16

Due to the ongoing expansion of Ixodes scapularis (blacklegged tick) throughout the northeastern and midwestern United States, there is need to identify the role wildlife hosts play in the establishment and maintenance of tick populations. To quantify and synthesize the patterns of I. scapularis and Borrelia burgdorferi sensu stricto and sensu lato prevalence relative to wildlife hosts, we reviewed the findings of independent studies conducted throughout the United States. We performed a comprehensive literature search from 1970 to 2017 using the ISS Web of Science Core Collection and the keywords "Ixodes scapularis," "Ixodes dammini" and "Borrelia burgdorferi." We identified 116 studies for inclusion in our meta-analysis, with 187,414 individual wildlife hosts captured and examined for I. scapularis and either the host or ticks collected subsequently tested for B. burgdorferi. We found that only 13% of the wildlife mammals sampled comprised species other than Odocoileus virginianus (white-tailed deer) and Peromyscus leucopus (white-footed mouse). To examine whether there were regional differences between the Northeast, Midwest and the Southeast U.S. in I. scapularis infestation rates on wildlife hosts, we used general linear models (glm), with post hoc pairwise comparisons. In most cases, detection of I. scapularis and B. burgdorferi was significantly higher in the Northeast than the Midwest. Using data on host-specific I. scapularis infestation prevalence, B. burgdorferi prevalence in feeding larvae, and host permissiveness, we developed an epizootiological model to determine the relative contributions of individual hosts to B. burgdorferi-infected nymphs. Our model provides additional evidence that wildlife hosts other than P. leucopus may contribute more to Lyme disease risk than commonly thought. To aid in understanding the ecology of Lyme disease, we propose that additional studies sample non-Peromyscus spp. hosts to obtain more detailed tick and pathogen

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

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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.

Successful treatment of dry eye in two patients with chronic graft-versus-host disease with systemic administration of FK506 and corticosteroids.

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Ogawa, Y; Okamoto, S; Kuwana, M; Mori, T; Watanabe, R; Nakajima, T; Yamada, M; Mashima, Y; Tsubota, K; Oguchi, Y

2001-05-01

We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids. A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time. Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

Research Strategies to Reduce Tick Densities and the Risk of Tick-borne Disease Transmission through Host-Targeted Control

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While white-tailed deer are not reservoir hosts for the Lyme disease agent, Borrelia burgdorferi, they are the keystone host animal on which adult female blacklegged ticks engorge on blood that is essential to production of tick eggs and completion of the life cycle. This session explores current re...

Predators indirectly control vector-borne disease: linking predator-prey and host-pathogen models.

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Moore, Sean M; Borer, Elizabeth T; Hosseini, Parviez R

2010-01-06

Pathogens transmitted by arthropod vectors are common in human populations, agricultural systems and natural communities. Transmission of these vector-borne pathogens depends on the population dynamics of the vector species as well as its interactions with other species within the community. In particular, predation may be sufficient to control pathogen prevalence indirectly via the vector. To examine the indirect effect of predators on vectored-pathogen dynamics, we developed a theoretical model that integrates predator-prey and host-pathogen theory. We used this model to determine whether predation can prevent pathogen persistence or alter the stability of host-pathogen dynamics. We found that, in the absence of predation, pathogen prevalence in the host increases with vector fecundity, whereas predation on the vector causes pathogen prevalence to decline, or even become extinct, with increasing vector fecundity. We also found that predation on a vector may drastically slow the initial spread of a pathogen. The predator can increase host abundance indirectly by reducing or eliminating infection in the host population. These results highlight the importance of studying interactions that, within the greater community, may alter our predictions when studying disease dynamics. From an applied perspective, these results also suggest situations where an introduced predator or the natural enemies of a vector may slow the rate of spread of an emerging vector-borne pathogen.

Scheduled transplantation of bone marrow cells preincubated with acidic fibroblast growth factor (aFGF)

International Nuclear Information System (INIS)

Xiang Yingsong; Yang Rujun; Cai Jianming; Li Bailong

1999-01-01

Objective: To develop a new method of bone marrow scheduled transplantation (BMST) by making use of the effects of acidic fibroblast growth factor (aFGF) on improving hematopoiesis. Methods: The scheduled transplantation of bone marrow cells preincubated with aFGF (aFGF-BMST) was carried out to study the effects of aFGF on hematopoietic reconstitution and reducing acute graft versus host disease (GVHD) in acute radiation disease model of Kunming mice. Results: The survival rate of the group of aFGF-BMST mice with 4 x 10 6 BMXs was 40%, which was higher than the survival of the group of BMT with 1 x 10 7 BMCs alone (30%), but was lower than the survival of the group of BMST with 4 x 10 6 BMCs. On the other hand, the recovery rates in numbers of leucocytes, nucleated cells and CFU-E, CFU-GM, CFU-S were faster than those in the group of BMT with 1 x 10 7 BMCs alone and in the group of BMST with 4 x 10 6 BMCs. In addition, the severity of GVHD in the group of aFGF-BMST mice with 4 x 10 6 BMCs was lower than that in the group of BMT with 1 x 10 7 BMCs alone but was higher than that in the group of BMST with 4 x 10 6 BMCs. Conclusion: Although aFGF can activate heterogeneous T cells to cause GVHD, there is prospect of making full use of the effects of aFGF on improving hematopoiesis and reducing the side effects of aFGF leading to GVHD through scheduled transplantation of bone marrow cells preincubated with aFGF

The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation

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Ke Zhao

2016-05-01

Full Text Available Abstract Mesenchymal stromal cells (MSCs are multipotent stem cells well known for repairing tissue, supporting hematopoiesis, and modulating immune and inflammation response. These outstanding properties make MSCs as an attractive candidate for cellular therapy in immune-based disorders, especially hematopoietic stem cell transplantation (HSCT. In this review, we outline the progress of MSCs in preventing and treating engraftment failure (EF, graft-versus-host disease (GVHD following HSCT and critically discuss unsolved issues in clinical applications.

INFUSION OF THIRD-PARTY MESENCHYMAL STEM CELLS (MSC) AFTER KIDNEY AND LIVER TRANSPLANTATION: A PHASE I-II, OPEN-LABEL, CLINICAL STUDY (EudraCT 2011-001822-81 & NCT01429038)

OpenAIRE

DETRY, Olivier; DELBOUILLE, Marie-Hélène; LECHANTEUR, Chantal; SOMJA, Joan; DE ROOVER, Arnaud; WEEKERS, Laurent; SQUIFFLET, Jean-Paul; Honoré, Pierre; DELVENNE, Philippe; MEURISSE, Michel; BAUDOUX, Etienne; BEGUIN, Yves

2013-01-01

MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC infusion after cadaveric kidney and liver transplantation in a prospective phase I-II study, taking advantage of our centre expertise and experience in MSC use in graft-versus-host disease (GVHD) after bone marrow transplantation and using an already functioning GMP-compliant laboratory producing...

Sequence typing of human adenoviruses isolated from Polish patients subjected to allogeneic hematopoietic stem cell transplantation - a single center experience.

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Przybylski, Maciej; Rynans, Sylwia; Waszczuk-Gajda, Anna; Bilinski, Jarosław; Basak, Grzegorz W; Jędrzejczak, Wiesław W; Wróblewska, Marta; Młynarczyk, Grażyna; Dzieciątkowski, Tomasz

2018-03-28

Human adenoviruses (HAdV) from species A, B and C are commonly recognized as pathogens causing severe morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. The purpose of the present study was to determine HAdV types responsible for viremia in HSCT recipients at a large tertiary hospital in Poland. Analysis of partial nucleotide sequences of HAdV hexon gene was used to type 40 clinical isolates of HAdV obtained from 40 HSCT recipients. We identified six different HAdV serotypes belonging to species B, C and E. We demonstrated high variability in sequences of detected HAdV types, and patients infected with the same HAdV types were not hospitalized at the same time, which suggests the low possibility of cross-infection. In almost all patients, anti-HAdV antibodies in IgG class were detected, which indicates a history of HAdV infection in the past. Clinical symptoms accompanying HAdV viremia were in 89%, and in 61.5% of individuals, HAdV was a sole pathogen detected. There were no cases with high-level HAdV viremia and severe systemic or organ infections. Graft-versus-host disease (GvHD) was present in patients infected with species B and C, but grade II of GvHD was observed only in patients infected with HAdV-B. The predominance of HAdV-C and common presence of anti-HAdV antibodies in IgG class may strongly suggest that most infections in the present study were reactivations of HAdV persisting into the patient's mucosa-associated lymphoid tissues. Variability of HAdV sequences suggests that cross-infections between patients were very rare. GvHD: graft-versus-host disease; HAdV: human adenoviruses; HSCT: hematopoietic stem cell transplantation.

Comparative genetic diversity of Lyme disease bacteria in Northern Californian ticks and their vertebrate hosts.

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Swei, Andrea; Bowie, Verna C; Bowie, Rauri C K

2015-04-01

Vector-borne pathogens are transmitted between vertebrate hosts and arthropod vectors, two immensely different environments for the pathogen. There is further differentiation among vertebrate hosts that often have complex, species-specific immunological responses to the pathogen. All this presents a heterogeneous environmental and immunological landscape with possible consequences on the population genetic structure of the pathogen. We evaluated the differential genetic diversity of the Lyme disease pathogen, Borrelia burgdorferi, in its vector, the western black-legged tick (Ixodes pacificus), and in its mammal host community using the 5S-23S rRNA intergenic spacer region. We found differences in haplotype distribution of B. burgdorferi in tick populations from two counties in California as well as between a sympatric tick and vertebrate host community. In addition, we found that three closely related haplotypes consistently occurred in high frequency in all sample types. Lastly, our study found lower species diversity of the B. burgdorferi species complex, known as B. burgdorferi sensu lato, in small mammal hosts versus the tick populations in a sympatric study area. Copyright © 2015 Elsevier GmbH. All rights reserved.

The interplay between intestinal bacteria and host metabolism in health and disease: lessons from Drosophila melanogaster

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Adam C. N. Wong

2016-03-01

Full Text Available All higher organisms negotiate a truce with their commensal microbes and battle pathogenic microbes on a daily basis. Much attention has been given to the role of the innate immune system in controlling intestinal microbes and to the strategies used by intestinal microbes to overcome the host immune response. However, it is becoming increasingly clear that the metabolisms of intestinal microbes and their hosts are linked and that this interaction is equally important for host health and well-being. For instance, an individual's array of commensal microbes can influence their predisposition to chronic metabolic diseases such as diabetes and obesity. A better understanding of host–microbe metabolic interactions is important in defining the molecular bases of these disorders and could potentially lead to new therapeutic avenues. Key advances in this area have been made using Drosophila melanogaster. Here, we review studies that have explored the impact of both commensal and pathogenic intestinal microbes on Drosophila carbohydrate and lipid metabolism. These studies have helped to elucidate the metabolites produced by intestinal microbes, the intestinal receptors that sense these metabolites, and the signaling pathways through which these metabolites manipulate host metabolism. Furthermore, they suggest that targeting microbial metabolism could represent an effective therapeutic strategy for human metabolic diseases and intestinal infection.

Genetic stability of foot-and-mouth disease virus during long-term infections in natural hosts.

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Ramirez-Carvajal, Lisbeth; Pauszek, Steven J; Ahmed, Zaheer; Farooq, Umer; Naeem, Khalid; Shabman, Reed S; Stockwell, Timothy B; Rodriguez, Luis L

2018-01-01

Foot-and-mouth disease (FMD) is a severe infection caused by a picornavirus that affects livestock and wildlife. Persistence in ruminants is a well-documented feature of Foot-and-mouth disease virus (FMDV) pathogenesis and a major concern for disease control. Persistently infected animals harbor virus for extended periods, providing a unique opportunity to study within-host virus evolution. This study investigated the genetic dynamics of FMDV during persistent infections of naturally infected Asian buffalo. Using next-generation sequencing (NGS) we obtained 21 near complete FMDV genome sequences from 12 sub-clinically infected buffalo over a period of one year. Four animals yielded only one virus isolate and one yielded two isolates of different serotype suggesting a serial infection. Seven persistently infected animals yielded more than one virus of the same serotype showing a long-term intra-host viral genetic divergence at the consensus level of less than 2.5%. Quasi-species analysis showed few nucleotide variants and non-synonymous substitutions of progeny virus despite intra-host persistence of up to 152 days. Phylogenetic analyses of serotype Asia-1 VP1 sequences clustered all viruses from persistent animals with Group VII viruses circulating in Pakistan in 2011, but distinct from those circulating on 2008-2009. Furthermore, signature amino acid (aa) substitutions were found in the antigenically relevant VP1 of persistent viruses compared with viruses from 2008-2009. Intra-host purifying selective pressure was observed, with few codons in structural proteins undergoing positive selection. However, FMD persistent viruses did not show a clear pattern of antigenic selection. Our findings provide insight into the evolutionary dynamics of FMDV populations within naturally occurring subclinical and persistent infections that may have implications to vaccination strategies in the region.

Genetic stability of foot-and-mouth disease virus during long-term infections in natural hosts.

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Lisbeth Ramirez-Carvajal

Full Text Available Foot-and-mouth disease (FMD is a severe infection caused by a picornavirus that affects livestock and wildlife. Persistence in ruminants is a well-documented feature of Foot-and-mouth disease virus (FMDV pathogenesis and a major concern for disease control. Persistently infected animals harbor virus for extended periods, providing a unique opportunity to study within-host virus evolution. This study investigated the genetic dynamics of FMDV during persistent infections of naturally infected Asian buffalo. Using next-generation sequencing (NGS we obtained 21 near complete FMDV genome sequences from 12 sub-clinically infected buffalo over a period of one year. Four animals yielded only one virus isolate and one yielded two isolates of different serotype suggesting a serial infection. Seven persistently infected animals yielded more than one virus of the same serotype showing a long-term intra-host viral genetic divergence at the consensus level of less than 2.5%. Quasi-species analysis showed few nucleotide variants and non-synonymous substitutions of progeny virus despite intra-host persistence of up to 152 days. Phylogenetic analyses of serotype Asia-1 VP1 sequences clustered all viruses from persistent animals with Group VII viruses circulating in Pakistan in 2011, but distinct from those circulating on 2008-2009. Furthermore, signature amino acid (aa substitutions were found in the antigenically relevant VP1 of persistent viruses compared with viruses from 2008-2009. Intra-host purifying selective pressure was observed, with few codons in structural proteins undergoing positive selection. However, FMD persistent viruses did not show a clear pattern of antigenic selection. Our findings provide insight into the evolutionary dynamics of FMDV populations within naturally occurring subclinical and persistent infections that may have implications to vaccination strategies in the region.

Estimating Coextinction Risks from Epidemic Tree Death: Affiliate Lichen Communities among Diseased Host Tree Populations of Fraxinus excelsior

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Jönsson, Mari T.; Thor, Göran

2012-01-01

At least 10% of the world’s tree species are threatened with extinction and pathogens are increasingly implicated in tree threats. Coextinction and threats to affiliates as a consequence of the loss or decline of their host trees is a poorly understood phenomenon. Ash dieback is an emerging infectious disease causing severe dieback of common ash Fraxinus excelsior throughout Europe. We utilized available empirical data on affiliate epiphytic lichen diversity (174 species and 17,800 observations) among 20 ash dieback infected host tree populations of F. excelsior on the island Gotland in the Baltic Sea, Sweden. From this, we used structured scenario projections scaled with empirical data of ash dieback disease to generate probabilistic models for estimating local and regional lichen coextinction risks. Average coextinction probabilities (Ā) were 0.38 (95% CI ±0.09) for lichens occurring on F. excelsior and 0.14 (95% CI ±0.03) when considering lichen persistence on all tree species. Ā was strongly linked to local disease incidence levels and generally increasing with lichen host specificity to F. excelsior and decreasing population size. Coextinctions reduced affiliate community viability, with significant local reductions in species richness and shifts in lichen species composition. Affiliates were projected to become locally extirpated before their hosts, illuminating the need to also consider host tree declines. Traditionally managed open wooded meadows had the highest incidence of ash dieback disease and significantly higher proportions of affiliate species projected to go extinct, compared with unmanaged closed forests and semi-open grazed sites. Most cothreatened species were not previously red-listed, which suggest that tree epidemics cause many unforeseen threats to species. Our analysis shows that epidemic tree deaths represent an insidious, mostly overlooked, threat to sessile affiliate communities in forested environments. Current conservation and

Relevance of genetically determined host factors to the prognosis of meningococcal disease.

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Domingo, P; Muñiz-Diaz, E; Baraldès, M A; Arilla, M; Barquet, N; Pericas, R; Juárez, C; Madoz, P; Vázquez, G

2004-08-01

To assess the relevance of genetically determined host factors for the prognosis of meningococcal disease, Fc gamma receptor IIA (FcgammaRIIA), the tumor necrosis factor alpha (TNF-alpha) gene promoter region, and plasminogen-activator-inhibitor-1 (PAI-1) gene polymorphisms were studied in 145 patients with meningococcal disease and in 290 healthy controls matched by sex. Distribution of FcgammaRIIA, TNF-alpha, and PAI-1 alleles was not significantly different between patients and controls. Patients with the FcgammaRIIA-R/R 131 allotype scored > or =1 point in the Barcelona prognostic system more frequently than patients with other allotypes (odds ratio, 18.6; 95% confidence interval, 7.1-49.0, PFc gamma receptor IIA polymorphism was associated with markers of disease severity, but TNF-alpha and PAI-1 polymorphisms were not.

Suppressor cells in transplantation tolerance II. Maturation of suppressor cells in the bone marrow chimera

International Nuclear Information System (INIS)

Tutschka, P.J.; Ki, P.F.; Beschorner, W.E.; Hess, A.D.; Santos, G.W.

1981-01-01

Histoincompatible bone marrow allografts were established in lethally irradiated rats. At various times after transplantation, the spleen cells were harvested, subjected to mixed lymphocyte cultures, and assayed for suppressor cells in vitro and in vivo by adoptive transfer studies. Alloantigen-nonspecific suppressor cells appeared in the chimera at 40 days after grafting, coinciding with the resolution of graft-versus-host disease (GVHD). At 250 days the nonspecific suppressor cells were replaced by suppressor cells specifically suppressing donor-versus-host alloantigen responses. At 720 days suppressor cells could no longer be identified by in vitro methods but were identified by in vivo adoptive transfer of transplantation tolerance. After injection of host-type antigen into chimeras, the suppressor cells could be again demonstrated by in vitro methods

Suppressor cells in transplantation tolerance. II. maturation of suppressor cells in the bone marrow chimera

International Nuclear Information System (INIS)

Tutschka, P.J.; Ki, P.F.; Beschorner, W.E.; Hess, A.D.; Santos, G.W.

1981-01-01

Histoincompatible bone marrow allografts were established in lethally irradiated rats. At various times after transplantation, the spleen cells were harvested, subjected to mixed lymphocyte cultures, and assayed for suppressor cells in vitro and in vivo by adoptive transfer studies. Alloantigen-nonspecific suppressor cells appeared in the chimera at 40 days after grafting, coinciding with the resolution of graft-versus-host disease (GVHD). At 250 days the nonspecific suppressor cells were replaced by suppressor cells specifically suppressing donor-versus-host alloantigen responses. At 720 days suppressor cells could no longer be identified by in vitro methods but were identified by in vivo adoptive transfer of transplantation tolerance. After injection of host-type antigen into chimeras, the suppressor cells could be again demonstrated by in vitro methods

Aqueous two-phase system patterning of detection antibody solutions for cross-reaction-free multiplex ELISA

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Frampton, John P.; White, Joshua B.; Simon, Arlyne B.; Tsuei, Michael; Paczesny, Sophie; Takayama, Shuichi

2014-05-01

Accurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross-reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co-localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings.

IMMUNITY TO INFECTIONS AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION

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Franco Aversa

2016-10-01

Full Text Available The advantage of using a Human Leukocyte Antigen (HLA-mismatched related donor is that almost every patient who does not have a HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT has at least one family member with whom shares one haplotype (haploidentical and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD. Advances in graft processing and in pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor. Indeed, the haplo-HSCT  has spread to centers worldwide even though some centers have preferred an approach based on T cell depletion of G-CSF-mobilized peripheral blood progenitor cells (PBPCs, others have focused on new strategies for GvHD prevention, such as G-CSF priming of bone marrow and robust post-transplant immune suppression or post-transplant cyclophosphamide (PTCY. Today, the graft can be a megadose of T-cell depleted PBPCs or standard dose of unmanipulated bone marrow and/or PBPCs.  Although haplo-HSCT modalities are based mainly on high intensity conditioning regimens, recently introduced reduced intensity regimens (RIC   showed promise in decreasing early transplant-related mortality (TRM, and extending the opportunity of HSCT to an elderly population with more comorbidities. Infections are still mostly responsible for toxicity and non-relapse mortality due to prolonged immunosuppression related, or not, to GVHD. Future challenges lie in determining the safest preparative conditioning regimen, minimizing GvHD and promoting rapid and more robust immune reconstitution.

Experimental study on therapy of acute radiation sickness with transplantation of allogeneic peripheral blood hemopoietic stem cells

International Nuclear Information System (INIS)

Ma Enpu; Bi Jianjin; Zhan Aiqin

1995-01-01

In the study, 10 beagles were used. All the dogs were irradiated with 6.5 Gy of γ-rays from a 60 Co source (dose rate, 95.6-107.9 R/min) and divided into three groups. All the three dogs in the control group died, having survived 7.5 days on the average after irradiation. In the second group, four dogs were transplanted with allogeneic peripheral blood hemopoietic stem cells (PBHSC) without removing T lymphocytes. The results of sex chromosome tests after irradiation and transplantation showed that the cells were of donor type. All the four dogs died of severe graft versus-host disease (GVHD) and survived 41.6 days on the average after irradiation. In the third group, three dogs received transplantation of allogeneic PBHSC without T lymphocytes. Two of them died, and the third developed mild GVHD and survived over 4 years

Recent Developments in Cellular Immunotherapy for HSCT-associated Complications

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Monica Reis

2016-11-01

Full Text Available Allogeneic HSCT is associated with serious complications and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, post-transplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft versus host disease (GvHD, infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application. Establishing an appropriate manufacturing process, to guarantee safe and effective therapeutics with simultaneous consideration of economic requirements is one of the most critical hurdles. In this review we will discuss the recent scientific findings, clinical experiences, and technological advances for cell processing, towards the application of MSC as a therapy for treatment of severe GvHD, virus-specific T cells for targeting life-threating infections, and of CAR-engineered T cells to treat relapsed leukemia.

Bone marrow transplantation in aplastic anaemia using cyclophosphamide and total lymphoid irradiation

International Nuclear Information System (INIS)

Jansen, J.; Zwaan, F.E.; Noordijk, E.M.

1980-01-01

Six patients with severe aplastic anaemia received a bone-marrow graft after conditioning with cyclophosphamide and total lymphoid irradiation (TLI). No rejections occurred. Acute graft-versus-host disease developed in 3 patients and was fatal in one. Another patient died from systemic aspergillus infection. Chronic GVHD of the skin developed in a patient who was grafted with bone marrow from her HLA-phenotypically identical father. These data suggest that conditioning with cyclophosphamide and TLI is a promising regimen. (orig.) [de

Host response mechanisms in periodontal diseases

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Nora SILVA

2015-06-01

Full Text Available Periodontal diseases usually refer to common inflammatory disorders known as gingivitis and periodontitis, which are caused by a pathogenic microbiota in the subgingival biofilm, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola that trigger innate, inflammatory, and adaptive immune responses. These processes result in the destruction of the tissues surrounding and supporting the teeth, and eventually in tissue, bone and finally, tooth loss. The innate immune response constitutes a homeostatic system, which is the first line of defense, and is able to recognize invading microorganisms as non-self, triggering immune responses to eliminate them. In addition to the innate immunity, adaptive immunity cells and characteristic cytokines have been described as important players in the periodontal disease pathogenesis scenario, with a special attention to CD4+ T-cells (T-helper cells. Interestingly, the T cell-mediated adaptive immunity development is highly dependent on innate immunity-associated antigen presenting cells, which after antigen capture undergo into a maturation process and migrate towards the lymph nodes, where they produce distinct patterns of cytokines that will contribute to the subsequent polarization and activation of specific T CD4+ lymphocytes. Skeletal homeostasis depends on a dynamic balance between the activities of the bone-forming osteoblasts (OBLs and bone-resorbing osteoclasts (OCLs. This balance is tightly controlled by various regulatory systems, such as the endocrine system, and is influenced by the immune system, an osteoimmunological regulation depending on lymphocyte- and macrophage-derived cytokines. All these cytokines and inflammatory mediators are capable of acting alone or in concert, to stimulate periodontal breakdown and collagen destruction via tissue-derived matrix metalloproteinases, a characterization of the progression of periodontitis as

Host response mechanisms in periodontal diseases

Science.gov (United States)

SILVA, Nora; ABUSLEME, Loreto; BRAVO, Denisse; DUTZAN, Nicolás; GARCIA-SESNICH, Jocelyn; VERNAL, Rolando; HERNÁNDEZ, Marcela; GAMONAL, Jorge

2015-01-01

Periodontal diseases usually refer to common inflammatory disorders known as gingivitis and periodontitis, which are caused by a pathogenic microbiota in the subgingival biofilm, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola that trigger innate, inflammatory, and adaptive immune responses. These processes result in the destruction of the tissues surrounding and supporting the teeth, and eventually in tissue, bone and finally, tooth loss. The innate immune response constitutes a homeostatic system, which is the first line of defense, and is able to recognize invading microorganisms as non-self, triggering immune responses to eliminate them. In addition to the innate immunity, adaptive immunity cells and characteristic cytokines have been described as important players in the periodontal disease pathogenesis scenario, with a special attention to CD4+ T-cells (T-helper cells). Interestingly, the T cell-mediated adaptive immunity development is highly dependent on innate immunity-associated antigen presenting cells, which after antigen capture undergo into a maturation process and migrate towards the lymph nodes, where they produce distinct patterns of cytokines that will contribute to the subsequent polarization and activation of specific T CD4+ lymphocytes. Skeletal homeostasis depends on a dynamic balance between the activities of the bone-forming osteoblasts (OBLs) and bone-resorbing osteoclasts (OCLs). This balance is tightly controlled by various regulatory systems, such as the endocrine system, and is influenced by the immune system, an osteoimmunological regulation depending on lymphocyte- and macrophage-derived cytokines. All these cytokines and inflammatory mediators are capable of acting alone or in concert, to stimulate periodontal breakdown and collagen destruction via tissue-derived matrix metalloproteinases, a characterization of the progression of periodontitis as a stage that

Does canine inflammatory bowel disease influence gut microbial profile and host metabolism?

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Xu, Jia; Verbrugghe, Adronie; Lourenço, Marta; Janssens, Geert P J; Liu, Daisy J X; Van de Wiele, Tom; Eeckhaut, Venessa; Van Immerseel, Filip; Van de Maele, Isabel; Niu, Yufeng; Bosch, Guido; Junius, Greet; Wuyts, Brigitte; Hesta, Myriam

2016-06-16

Inflammatory bowel disease (IBD) refers to a diverse group of chronic gastrointestinal diseases, and gut microbial dysbiosis has been proposed as a modulating factor in its pathogenesis. Several studies have investigated the gut microbial ecology of dogs with IBD but it is yet unclear if this microbial profile can alter the nutrient metabolism of the host. The aim of the present study was to characterize the faecal bacterial profile and functionality as well as to determine host metabolic changes in IBD dogs. Twenty-three dogs diagnosed with IBD and ten healthy control dogs were included. Dogs with IBD were given a clinical score using the canine chronic enteropathy clinical activity index (CCECAI). Faecal short-chain fatty acids (SCFA) and ammonia concentrations were measured and quantitative PCR was performed. The concentration of plasma amino acids, acylcarnitines, serum folate, cobalamin, and indoxyl sulfate was determined. No significant differences in the abundance of a selection of bacterial groups and fermentation metabolites were observed between the IBD and control groups. However, significant negative correlations were found between CCECAI and the faecal proportion of Lactobacillus as well as between CCECAI and total SCFA concentration. Serum folate and plasma citrulline were decreased and plasma valine was increased in IBD compared to control dogs. Increased plasma free carnitine and total acylcarnitines were observed in IBD compared with control dogs, whereas short-chain acylcarnitines (butyrylcarnitine + isobutyrylcarnitine and, methylmalonylcarnitine) to free carnitine ratios decreased. Dogs with IBD had a higher 3-hydroxyisovalerylcarnitine + isovalerylcarnitine to leucine ratio compared to control dogs. Canine IBD induced a wide range of changes in metabolic profile, especially for the plasma concentrations of short-chain acylcarnitines and amino acids, which could have evolved from tissue damage and alteration in host metabolism. In

Multifunctional roles of leader protein of foot-and-mouth disease viruses in suppressing host antiviral responses.

Science.gov (United States)

Liu, Yingqi; Zhu, Zixiang; Zhang, Miaotao; Zheng, Haixue

2015-10-28

Foot-and-mouth disease virus (FMDV) leader protein (L(pro)) is a papain-like proteinase, which plays an important role in FMDV pathogenesis. L(pro) exists as two forms, Lab and Lb, due to translation being initiated from two different start codons separated by 84 nucleotides. L(pro) self-cleaves from the nascent viral polyprotein precursor as the first mature viral protein. In addition to its role as a viral proteinase, L(pro) also has the ability to antagonize host antiviral effects. To promote FMDV replication, L(pro) can suppress host antiviral responses by three different mechanisms: (1) cleavage of eukaryotic translation initiation factor 4 γ (eIF4G) to shut off host protein synthesis; (2) inhibition of host innate immune responses through restriction of interferon-α/β production; and (3) L(pro) can also act as a deubiquitinase and catalyze deubiquitination of innate immune signaling molecules. In the light of recent functional and biochemical findings regarding L(pro), this review introduces the basic properties of L(pro) and the mechanisms by which it antagonizes host antiviral responses.

Use of lymphokine-activated killer cells to prevent bone marrow graft rejection and lethal graft-vs-host disease

International Nuclear Information System (INIS)

Azuma, E.; Yamamoto, H.; Kaplan, J.

1989-01-01

Prompted by our recent finding that lymphokine-activated killer (LAK) cells mediate both veto and natural suppression, we tested the ability of adoptively transferred LAK cells to block two in vivo alloreactions which complicate bone marrow transplantation: resistance to transplanted allogeneic bone marrow cells, and lethal graft-vs-host disease. Adoptive transfer of either donor type B6D2 or recipient-type B6 lymphokine-activated bone marrow cells, cells found to have strong LAK activity, abrogated or inhibited the resistance of irradiated B6 mice to both B6D2 marrow and third party-unrelated C3H marrow as measured by CFU in spleen on day 7. The ability of lymphokine-activated bone marrow cells to abrogate allogeneic resistance was eliminated by C lysis depletion of cells expressing asialo-GM1, NK1.1, and, to a variable degree, Thy-1, but not by depletion of cells expressing Lyt-2, indicating that the responsible cells had a LAK cell phenotype. Similar findings were obtained by using splenic LAK cells generated by 3 to 7 days of culture with rIL-2. Demonstration that allogeneic resistance could be blocked by a cloned LAK cell line provided direct evidence that LAK cells inhibit allogeneic resistance. In addition to inhibiting allogeneic resistance, adoptively transferred recipient-type LAK cells prevented lethal graft-vs-host disease, and permitted long term engraftment of allogeneic marrow. Irradiation prevented LAK cell inhibition of both allogeneic resistance and lethal graft-vs-host disease. These findings suggest that adoptive immunotherapy with LAK cells may prove useful in preventing graft rejection and graft-versus-host disease in human bone marrow transplant recipients

The Role of Programmed Cell Death Ligand-1 (PD-L1/CD274) in the Development of Graft versus Host Disease

Science.gov (United States)

Al-Chaqmaqchi, Heevy; Sadeghi, Behnam; Abedi-Valugerdi, Manuchehr; Al-Hashmi, Sulaiman; Fares, Mona; Kuiper, Raoul; Lundahl, Joachim

2013-01-01

Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease. PMID:23593203

T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia.

Science.gov (United States)

Jaiswal, Sarita Rani; Bhakuni, Prakash; Zaman, Shamsuz; Bansal, Satish; Bharadwaj, Priyanka; Bhargava, Sneh; Chakrabarti, Suparno

2017-08-01

We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56 bright CD16 - NK cells in the CONTROL group (p=0.004), but similar CD56 dim CD16 + NK cells in both groups at day+30. Tregs (CD4 + CD25 + CD127 dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs. Copyright © 2017 Elsevier B.V. All rights reserved.

The Role of NLR-related Protein 3 Inflammasome in Host Defense and Inflammatory Diseases

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Chul-Su Yang

2012-03-01

Full Text Available Among a number of innate receptors, the nucleotide-binding domain leucine-rich repeat containing (NLR nucleotide oligomerization domain (NOD-like receptor families are involved in the recognition of cytosolic pathogen- or danger-associated molecules. Activation of these specific sets of receptors leads to the assembly of a multiprotein complex, the inflammasome, leading to the activation of caspase-1 and maturation of the cytokines interleukin (IL-1β, IL-18, and IL-33. Among NLRs, NLR-related protein 3 (NLRP3 is one of the best-characterized receptors that activates the inflammasome. There is no doubt that NLRP3 inflammasome activation is important for host defense and effective pathogen clearance against fungal, bacterial, and viral infection. In addition, mounting evidence indicates that the NLRP3 inflammasome plays a role in a variety of inflammatory diseases, including gout, atherosclerosis, and type II diabetes, as well as under conditions of cellular stress or injury. Here, we review recent advances in our understanding of the role of the NLRP3 inflammasome in host defense and various inflammatory diseases.

Scaling up from greenhouse resistance to fitness in the field for a host of an emerging forest disease

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Katherine J. Hayden; Matteo Garbelotto; Richard Dodd; Jessica W. Wright

2013-01-01

Forest systems are increasingly threatened by emergent, exotic diseases, yet management strategies for forest trees may be hindered by long generation times and scant background knowledge. We tested whether nursery disease resistance and growth traits have predictive value for the conservation of Notholithocarpus densiflorus, the host most...

Disease spread across multiple scales in a spatial hierarchy: effect of host spatial structure and of inoculum quantity and distribution.

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Gosme, Marie; Lucas, Philippe

2009-07-01

Spatial patterns of both the host and the disease influence disease spread and crop losses. Therefore, the manipulation of these patterns might help improve control strategies. Considering disease spread across multiple scales in a spatial hierarchy allows one to capture important features of epidemics developing in space without using explicitly spatialized variables. Thus, if the system under study is composed of roots, plants, and planting hills, the effect of host spatial pattern can be studied by varying the number of plants per planting hill. A simulation model based on hierarchy theory was used to simulate the effects of large versus small planting hills, low versus high level of initial infections, and aggregated versus uniform distribution of initial infections. The results showed that aggregating the initially infected plants always resulted in slower epidemics than spreading out the initial infections uniformly. Simulation results also showed that, in most cases, disease epidemics were slower in the case of large host aggregates (100 plants/hill) than with smaller aggregates (25 plants/hill), except when the initially infected plants were both numerous and spread out uniformly. The optimal strategy for disease control depends on several factors, including initial conditions. More importantly, the model offers a framework to account for the interplay between the spatial characteristics of the system, rates of infection, and aggregation of the disease.

MECHANISMS OF MICROBE-HOST-INTERACTION IN CROHN'S DISEASE: DYSBIOSIS VS. PATHOBIONT SELECTION

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Ludovica F. Buttó

2015-11-01

Full Text Available Crohn’s disease (CD is a systemic chronic inflammatory condition mainly characterized by discontinuous transmural pathology of the gastrointestinal tract and frequent extra-intestinal manifestations with intermittent episodes of remission and relapse. Genome-wide association studies identified a number of risk loci that, catalyzed by environmental triggers, result in the loss of tolerance towards commensal bacteria based on dysregulated innate effector functions and anti-microbial defense, leading to exacerbated adaptive immune responses responsible for chronic immune-mediated tissue damage. In this review, we discuss the interrelated role of changes in the intestinal microbiota, epithelial barrier integrity and immune cell functions on the pathogenesis of CD, describing the current approaches available to investigate the molecular mechanisms underlying the disease. Substantial effort has been dedicated to define disease-associated changes in the intestinal microbiota (dysbiosis and to link pathobionts to the aetiology of IBD. A cogent definition of dysbiosis is lacking, as well as an agreement of whether pathobionts or complex shifts in the microbiota trigger inflammation in the host. Among the rarely available animal models, SAMP/Yit and TNFdeltaARE mice are the best known displaying a transmural CD-like phenotype. New hypothesis-driven mouse models e.g. epithelial-specific Caspase8-/-, ATG16L1-/- and XBP-1-/- mice validate pathway-focused function of specific CD-associated risk genes highlighting the role of Paneth cells in antimicrobial defense. To study the causal role of bacteria in initiating inflammation in the host, the use of germfree mouse models is indispensable. Unraveling the interactions of genes, immune cells and microbes constitute a criterion for the development of safe, reliable and effective treatment options for CD.

Effect of Intermediate Hosts on Emerging Zoonoses.

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Cui, Jing-An; Chen, Fangyuan; Fan, Shengjie

2017-08-01

Most emerging zoonotic pathogens originate from animals. They can directly infect humans through natural reservoirs or indirectly through intermediate hosts. As a bridge, an intermediate host plays different roles in the transmission of zoonotic pathogens. In this study, we present three types of pathogen transmission to evaluate the effect of intermediate hosts on emerging zoonotic diseases in human epidemics. These types are identified as follows: TYPE 1, pathogen transmission without an intermediate host for comparison; TYPE 2, pathogen transmission with an intermediate host as an amplifier; and TYPE 3, pathogen transmission with an intermediate host as a vessel for genetic variation. In addition, we established three mathematical models to elucidate the mechanisms underlying zoonotic disease transmission according to these three types. Stability analysis indicated that the existence of intermediate hosts increased the difficulty of controlling zoonotic diseases because of more difficult conditions to satisfy for the disease to die out. The human epidemic would die out under the following conditions: TYPE 1: [Formula: see text] and [Formula: see text]; TYPE 2: [Formula: see text], [Formula: see text], and [Formula: see text]; and TYPE 3: [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] Simulation with similar parameters demonstrated that intermediate hosts could change the peak time and number of infected humans during a human epidemic; intermediate hosts also exerted different effects on controlling the prevalence of a human epidemic with natural reservoirs in different periods, which is important in addressing problems in public health. Monitoring and controlling the number of natural reservoirs and intermediate hosts at the right time would successfully manage and prevent the prevalence of emerging zoonoses in humans.

A mathematical modelling framework for linked within-host and between-host dynamics for infections with free-living pathogens in the environment.

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Garira, Winston; Mathebula, Dephney; Netshikweta, Rendani

2014-10-01

In this study we develop a mathematical modelling framework for linking the within-host and between-host dynamics of infections with free-living pathogens in the environment. The resulting linked models are sometimes called immuno-epidemiological models. However, there is still no generalised framework for linking the within-host and between-host dynamics of infectious diseases. Furthermore, for infections with free-living pathogens in the environment, there is an additional stumbling block in that there is a gap in knowledge on how environmental factors (through water, air, soil, food, fomites, etc.) alter many aspects of such infections including susceptibility to infective dose, persistence of infection, pathogen shedding and severity of the disease. In this work, we link the two subsystems (within-host and between-host models) by identifying the within-host and between-host variables and parameters associated with the environmental dynamics of the pathogen and then design a feedback of the variables and parameters across the within-host and between-host models using human schistosomiasis as a case study. We study the mathematical properties of the linked model and show that the model is epidemiologically well-posed. Using results from the analysis of the endemic equilibrium expression, the disease reproductive number R0, and numerical simulations of the full model, we adequately account for the reciprocal influence of the linked within-host and between-host models. In particular, we illustrate that for human schistosomiasis, the outcome of infection at the individual level determines if, when and how much the individual host will further transmit the infectious agent into the environment, eventually affecting the spread of the infection in the host population. We expect the conceptual modelling framework developed here to be applicable to many infectious disease with free-living pathogens in the environment beyond the specific disease system of human

Host control of human papillomavirus infection and disease.

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Doorbar, John

2018-02-01

Most human papillomaviruses cause inapparent infections, subtly affecting epithelial homeostasis, to ensure genome persistence in the epithelial basal layer. As with conspicuous papillomas, these self-limiting lesions shed viral particles to ensure population level maintenance and depend on a balance between viral gene expression, immune cell stimulation and immune surveillance for persistence. The complex immune evasion strategies, characteristic of high-risk HPV types, also allow the deregulated viral gene expression that underlies neoplasia. Neoplasia occurs at particular epithelial sites where vulnerable cells such as the reserve or cuboidal cells of the cervical transformation zone are found. Beta papillomavirus infection can also predispose an individual with immune deficiencies to the development of cancers. The host control of HPV infections thus involves local interactions between keratinocytes and the adaptive immune response. Effective immune detection and surveillance limits overt disease, leading to HPV persistence as productive microlesions or in a true latent state. Copyright © 2017. Published by Elsevier Ltd.

Associação dos níveis de citocinas no pós-transplante de células-tronco hematopoiéticas com a Doença do Enxerto Contra o Hospedeiro aguda Association of cytokine levels with acute graft versus host disease following full match allogeneic stem cell transplantation

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Jeane E. L. Visentainer

2005-09-01

Full Text Available Este estudo foi realizado para investigar se os níveis séricos de sIL-2R, TNF-alfa, IFN-gama, IL-6, IL-10 e TGF-beta1 estavam associados com o desenvolvimento de DECH (Doença do Enxerto Contra o Hospedeiro aguda. Os níveis de citocinas foram seqüencialmente mensurados por Elisa em 13 pacientes que haviam sido submetidos ao transplante alogênico de células progenitoras hematopoiéticas. Os níveis de sIL-2R e IL-10 da 1ª a 15ª semanas pós-transplante foram significativamente maiores no grupo que desenvolveu DECH aguda que naquele sem a doença. Os níveis de sIL-2R aumentaram em direta correlação com a pega do enxerto e ao tempo do DECH aguda, enquanto os níveis de IL-10 aumentaram transitoriamente pós-transplante. A média da concentração de TNF-alfa nas primeiras semanas após o transplante foi maior no grupo que desenvolveu DECH aguda. Além disso, uma queda dos níveis de TGF-beta1 após a pega esteve significativamente associada à DECH aguda. Nenhuma correlação foi encontrada entre DECH aguda e as outras citocinas investigadas. Estes resultados suportam a idéia de que um balanço entre as citocinas derivadas de linfócitos T auxiliadores do tipo 1 e 2 pode ser importante no desenvolvimento e controle da DECH aguda. Embora os níveis de sIL-2R, TNF-alfa, IL-10 e TGF-beta1 tenham sido correlacionados com a DECH aguda, os níveis de sIL-2R ao tempo da pega podem prover um melhor parâmetro para a detecção precoce de DECH aguda após o transplante alogênico.This study was performed to investigate whether the serum levels of sIL-2R, TNF-alpha, IFN-gamma, IL-6, IL-10, and TGF-beta1 are associated with the development of acute GVHD. Serum cytokine levels were sequentially measured by sandwich Enzyme Linked-Immuno-Sorbent Assay (Elisa in 13 patients who had received full match allogeneic stem cell transplantation. Serum sIL-2R and IL-10 levels from the 1st to the 15th week post transplantation were significantly higher in the

Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

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Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

2015-06-01

The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

Blood irradiation

International Nuclear Information System (INIS)

Chandy, Mammen

1998-01-01

Viable lymphocytes are present in blood and cellular blood components used for transfusion. If the patient who receives a blood transfusion is immunocompetent these lymphocytes are destroyed immediately. However if the patient is immunodefficient or immunosuppressed the transfused lymphocytes survive, recognize the recipient as foreign and react producing a devastating and most often fatal syndrome of transfusion graft versus host disease [T-GVHD]. Even immunocompetent individuals can develop T-GVHD if the donor is a first degree relative since like the Trojan horse the transfused lymphocytes escape detection by the recipient's immune system, multiply and attack recipient tissues. T-GVHD can be prevented by irradiating the blood and different centers use doses ranging from 1.5 to 4.5 Gy. All transfusions where the donor is a first degree relative and transfusions to neonates, immunosuppressed patients and bone marrow transplant recipients need to be irradiated. Commercial irradiators specifically designed for irradiation of blood and cellular blood components are available: however they are expensive. India needs to have blood irradiation facilities available in all large tertiary institutions where immunosuppressed patients are treated. The Atomic Energy Commission of India needs to develop a blood irradiator which meets international standards for use in tertiary medical institutions in the country. (author)

Bone marrow transplantation in patients with Thalassemia

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Ghavamzadeh A

1993-05-01

Full Text Available During April, 1991 and September, 1993, eighteen patients with major thalassemia admitted to Shariati BMT center. Seventeen patients were transplanted were from HLA identical siblings and one from. his HLA identical father. Eleven of the donors were the known cases of minor thalassemia. The range of patients' age was within 3-10 years (with the average of 5 years and 11 months. Among them, seven patients were male and eleven were female. As the other international BMT centers, we classified our patients into three classes. Our criteria for this classification were hepatomegaly, ferretin, and liver fibrous; 60% of our patients were put in class I and 40% in class II. All of our patients revealed a GVHD (severe graft vs. host disease three weeks post-BMT as pruritus, diarrhea, and skin erythema especially in hands and feet. Two of the patients showed severe GVHD. One of the patients had chimerism after BMT. Although one year after BMT has passed, the patients is still depended on blood transfusion. One patient, despite graft rejection, died nine months post-BMT; another one died after +70 due to GVHD. During 2.5 years, the overall graft survival rate was 88% in our center

One-unit versus two-unit cord-blood transplantation for hematologic cancers.

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Wagner, John E; Eapen, Mary; Carter, Shelly; Wang, Yanli; Schultz, Kirk R; Wall, Donna A; Bunin, Nancy; Delaney, Colleen; Haut, Paul; Margolis, David; Peres, Edward; Verneris, Michael R; Walters, Mark; Horowitz, Mary M; Kurtzberg, Joanne

2014-10-30

Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival. Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit. We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the

Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study.

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Berger, Massimo; Lanino, Edoardo; Cesaro, Simone; Zecca, Marco; Vassallo, Elena; Faraci, Maura; De Bortoli, Massimiliano; Barat, Veronica; Prete, Arcangelo; Fagioli, Franca

2016-05-01

Post-transplant high-dose cyclophosphamide (PTCy) is a novel approach to prevent graft-versus-host disease (GVHD) and rejection in patients given haploidentical hematopoietic stem cell transplantation (HSCT). Thirty-three patients with high-risk hematologic malignancies and lacking a match-related or -unrelated donor were treated with PTCy haploidentical HSCT in 5 Italian AIEOP centers. Nineteen patients had a nonmyeloablative preparative regimen (57%), and 14 patients received a full myeloablative conditioning regimen (43%). No patients received serotherapy; GVHD prophylaxis was based on PTCy (50 mg/kg on days +3 and +4) combined with mycophenolate plus tacrolimus or cyclosporine A. Neutrophil and platelet engraftment was achieved on days +17 (range, 14 to 37) and +27 (range, 16 to 71). One patient had autologous reconstitution for anti-HLA antibodies. Acute GVHD grades II to IV and III to IV and chronic GVHD developed in 22% (95% CI, 11 to 42), 3% (95% CI, 0 to 21), and 4% (95% CI, 0 to 27) of cases, respectively. The 1-year overall survival rate was 72% (95% CI, 56 to 88), progression-free survival rate was 61% (95% CI, 43 to 80), cumulative incidence of relapse was 24% (95% CI, 13 to 44), and transplant-related mortality was 9% (95% CI, 3 to 26). The univariate analysis for risk of relapse incidence showed how 3 significant variables, mother as donor (P = .02), donor gender as female (P = .04), and patient gender as female (P = .02), were significantly associated with a lower risk of relapse. Disease progression was the main cause of death. PTCy is a safe procedure also for children and adolescents who have already received several lines of chemotherapy. Among the different diseases, a trend for better 1-year rates of overall survival was obtained for nonacute leukemia patients. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Selection of unrelated donors for bone marrow transplantation studied in rhesus monkeys

International Nuclear Information System (INIS)

Wagemaker, G.; Bekkum, D.W. van

Graft versus Host disease (GvHD) remains to be a severe limitation to a more general application of bone marrow transplantation. Clinically acceptable results are restricted to those potential recipients for which a major histocompatibility complex (MHC) identical sibling donor is available. At an average family size of 2 to 3 siblings, the frequency of such donors is not more than approximately 30%. This pre-clinical study in rhesus monkeys is directed at the selection of donors for recipients which lack an MHC identical sibling. (Auth.)

New mechanisms of disease and parasite-host interactions.

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de Souza, Tiago Alves Jorge; de Carli, Gabriel Jose; Pereira, Tiago Campos

2016-09-01

An unconventional interaction between a patient and parasites was recently reported, in which parasitic cells invaded host's tissues, establishing several tumors. This finding raises various intriguing hypotheses on unpredicted forms of interplay between a patient and infecting parasites. Here we present four unusual hypothetical host-parasite scenarios with intriguing medical consequences. Relatively simple experimental designs are described in order to evaluate such hypotheses. The first one refers to the possibility of metabolic disorders in parasites intoxicating the host. The second one is on possibility of patients with inborn errors of metabolism (IEM) being more resistant to parasites (due to accumulation of toxic compounds in the bloodstream). The third one refers to a mirrored scenario: development of tumors in parasites due to ingestion of host's circulating cancer cells. The last one describes a complex relationship between parasites accumulating a metabolite and supplying it to a patient with an IEM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant.

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Xu, Lan-Ping; Jin, Song; Wang, Shun-Qing; Xia, Ling-Hui; Bai, Hai; Gao, Su-Jun; Liu, Qi-Fa; Wang, Jian-Min; Wang, Xin; Jiang, Ming; Zhang, Xi; Wu, De-Pei; Huang, Xiao-Jun

2017-01-21

Haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) is an alternative treatment method for severe aplastic anemia (SAA) patients lacking suitable identical donors and those who are refractory to immunosuppressive therapy (IST). The current study evaluated the feasibility of upfront haploidentical HSCT in SAA patients. We conducted a multicenter study based on a registry database. One hundred fifty-eight SAA patients who underwent upfront transplantation between June 2012 and September 2015 were enrolled. Eighty-nine patients had haploidentical donors (HIDs), and 69 had matched related donors (MRDs) for HSCT. The median times for myeloid engraftment in the HID and MRD cohorts were 12 (range, 9-20) and 11 (range, 8-19) days, with a cumulative incidence of 97.8 and 97.1% (P = 0.528), respectively. HID recipients had an increased cumulative incidence of grades II-IV acute graft-versus-host disease (aGVHD) (30.3 vs. 1.5%, P < 0.001), grades III-IV aGVHD (10.1 vs. 1.5%, P = 0.026), and chronic GVHD (cGVHD) (30.6 vs. 4.4%, P < 0.001) at 1 year but similar extensive cGVHD (3.4 vs. 0%, P = 0.426). The three-year estimated overall survival (OS) rates were 86.1 and 91.3% (P = 0.358), while the three-year estimated failure-free survival (FFS) rates were 85.0 and 89.8% (P = 0.413) in the HID and MRD cohorts, respectively. In multivariate analysis, survival outcome for the entire population was significantly adversely associated with increased transfusions and poor performance status pre-SCT. We did not observe differences in primary engraftment and survival outcomes by donor type. Haploidentical SCT as upfront therapy was an effective and safe option for SAA patients, with favorable outcomes in experienced centers.

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

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Locatelli, Franco; Merli, Pietro; Pagliara, Daria; Li Pira, Giuseppina; Falco, Michela; Pende, Daniela; Rondelli, Roberto; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Masetti, Riccardo; Milano, Giuseppe Maria; Bertaina, Valentina; Algeri, Mattia; Pinto, Rita Maria; Strocchio, Luisa; Meazza, Raffaella; Grapulin, Lavinia; Handgretinger, Rupert; Moretta, Alessandro; Bertaina, Alice; Moretta, Lorenzo

2017-08-03

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. © 2017 by The American Society of Hematology.

Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

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Luigi F. Agnati

2007-01-01