WorldWideScience

Sample records for allogeneic immune regulatory

  1. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

    2016-01-01

    The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

  2. Cross-immunity among allogeneic tumors in rats immunized with gamma-irradiated ascites tumors

    International Nuclear Information System (INIS)

    Sato, Tatsusuke; Suga, Michio; Kudo, Hajime; Waga, Takashi; Ogasawara, Masamichi

    1980-01-01

    Non-inbred rats of the Gifu strain were intraperitoneally challenged with Hirosaki sarcoma (Tetraploid type, 10 5 cells) after repeated immunization with gamma-irradiated (13,000 rads 60 Co) allogeneic non-viral tumors of ascites type (Tetraploid or diploid type of Hirosaki sarcoma, Usubuchi sarcoma or AH130). In rats immunized not only with the same tumor as the immunizing tumor but also with a different tumor, the growth of the challenge tumor was markedly inhibited as compared with the control in non-immunized rats. It is considered that these tumors retained common antigen(s) by the resistance to irradiation because of their form of ascites tumor. The marked cross-immunity in rats immunized with AH130 may be explained by the fact that gamma-irradiated AH130 cells were alive longer in the peritoneal cavity than other tumors on account of its high resistance to irradiation. (author)

  3. Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients

    Directory of Open Access Journals (Sweden)

    V. Wiegering

    2017-03-01

    Conclusion: Children undergoing a HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and re-vaccinations.

  4. Cross-immunity among allogeneic tumors of rats immunized with solid tumors

    International Nuclear Information System (INIS)

    Ogasawara, Masamichi

    1979-01-01

    Several experiments were done for the study of cross-immunity among allogeneic rat tumors by immunization using gamma-irradiated or non-irradiated solid tumors. Each group of rats which were immunized with gamma-irradiation solid tumor inocula from ascites tumor cell line of tetra-ploid Hirosaki sarcoma, Usubuchi sarcoma or AH 130, showed an apparent resistance against the intraperitoneal challenge with Hirosaki sarcoma. A similar resistance was demonstrated in the case of the challenge with Usubuchi sarcoma into rats immunized with non-irradiated methylcholanthrene (MCA)-induced tumors. In using solid MCA tumors as immunogen and Hirosaki sarcoma as challenge tumor, it was also demonstrated in 2 out of 3 groups immunized with non-irradiated tumors. In the experiment of trying to induce cross-immunity between 2 MCA tumors by immunization with irradiated solid tumor only, the inhibitory effect on the growth was observed in the early stage in the treated groups as compared with the control one. From the above results, it may be considered that the immunization with irradiated solid tumors fromas cites cell lines and non-irradiated solid MCA tumors induced strong cross-immunity in general, but that the immunization with only irradiated solid MCA tumors induced weak cross-immunity commonly. (author)

  5. Regulatory T-cells and immune tolerance in pregnancy : a new target for infertility treatment?

    NARCIS (Netherlands)

    Guerin, Leigh R.; Prins, Jelmer R.; Robertson, Sarah A.

    2009-01-01

    Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are implicated in infertility and reproductive pathologies. T regulatory (Treg) cells are a recently discovered subset of T-lymphocytes with

  6. Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials.

    Science.gov (United States)

    Wang, Raymond M; Johnson, Todd D; He, Jingjin; Rong, Zhili; Wong, Michelle; Nigam, Vishal; Behfar, Atta; Xu, Yang; Christman, Karen L

    2017-06-01

    Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4 + T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses to biomaterials in an in vivo environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Immune transfer studies in canine allogeneic marrow graft donor-recipient pairs

    International Nuclear Information System (INIS)

    Grosse-Wilde, H.; Krumbacher, K.; Schuening, F.D.; Doxiadis, I.; Mahmoud, H.K.; Emde, C.; Schmidt-Weinmar, A.; Schaefer, U.W.

    1986-01-01

    Transfer of immunity occurring with bone marrow grafting was studied using the dog as a preclinical model. Allogeneic bone marrow transplantation (BMT) was performed between DLA-identical beagle litter-mates. The donors were immunized with tetanus toxoid (TT) or sheep red blood cells (SRBC), and their humoral response was monitored by hemagglutination. The recipients of bone marrow from TT-immunized donors showed a marked increase of antibody titer one week posttransplantation, while in the recipients of marrow from SRBC immunized donors the antibody titers were considerably lower. Within the following 60 days the antibody titers in both groups diminished gradually to pregrafting levels. Control experiments in which cell-free plasma from donors immunized with TT and SRBC respectively was transfused indicated that the initial rise of specific antibody titers after marrow grafting is likely to be due to a passive transfer of humoral immunity. A single challenge of these marrow graft recipients with the respective antigen 15-18 weeks posttransplantation led to a secondary type of humoral immune response. It could be demonstrated that transfer of memory against TT or SRBC was independent from the actual antibody titer and the time of vaccination of the donor. One dog was immunized with TT after serving as marrow donor. When the donor had shown an antibody response, a peripheral blood leukocytes (PBL) transfusion was given to his chimera. Subsequent challenge of the latter resulted in a secondary type of specific antibody response. This indicates that specific cellular-bound immunological memory can be transferred after BMT from the donor to his allogeneic bone marrow chimera by transfusion of peripheral blood leukocytes. The data may be of importance in clinical BMT to protect patients during the phase of reduced immune reactivity by transfer of memory cells

  8. Immune responses to an encapsulated allogeneic islet β-cell line in diabetic NOD mice

    International Nuclear Information System (INIS)

    Black, Sasha P.; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J.; Safley, Susan A.

    2006-01-01

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic β-cell line (βTC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of βTC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic β-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes

  9. Regulatory T cells: immune suppression and beyond

    OpenAIRE

    Wan, Yisong Y

    2010-01-01

    Foxp3-expressing regulatory T cells (Tregs) were originally identified as critical in maintaining self-tolerance and immune homeostasis. The immunosuppressive functions of Tregs are widely acknowledged and have been extensively studied. Recent studies have revealed many diverse roles of Tregs in shaping the immune system and the inflammatory response. This review will discuss our efforts as well as the efforts of others towards understanding the multifaceted function of Treg...

  10. Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

    Directory of Open Access Journals (Sweden)

    Paul Lohan

    2017-11-01

    Full Text Available Mesenchymal stromal cells (MSC have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.

  11. Regulatory T cells and immunity to pathogens.

    Science.gov (United States)

    Rouse, Barry T; Suvas, Susmit

    2007-09-01

    Immune responses to pathogens are modulated by one or more types of cells that perform a regulatory function. Some cells with this function, such as CD4+ Foxp3+ natural regulatory T cells (nTreg), pre-exist prior to infections whereas others may be induced as a consequence of infection (adaptive Treg). With pathogens that have a complex pathogenesis, multiple types of regulatory cells could influence the outcome. One major property of Treg is to help minimize collateral tissue damage that can occur during immune reactions to a chronic infection. The consequence is less damage to the host but in such situations the pathogen is likely to establish persistence. In some cases, a fine balance is established between Treg responses, effector components of immunity and the pathogen. Treg responses to pathogens may also act to hamper the efficacy of immune control. This review discusses these issues as well as the likely mechanisms by which various pathogens can signal the participation of Treg during infection.

  12. A tritherapy combination of inactivated allogeneic leukocytes infusion and cell vaccine with cyclophosphamide in a sequential regimen enhances antitumor immunity

    OpenAIRE

    Yishu Tang; Wenbo Ma; Chunxia Zhou; Dongmei Wang; Shuren Zhang

    2018-01-01

    Background: Tumor-induced immunosuppression can impede tumor-specific immune responses and limit the effects of cancer immunotherapy. The aim of this study was to investigate the possible effects of sequential chemoimmunotherapeutic strategies to enhance antitumor immune responses. Methods: Using the E7-expressing tumor TC-1 as the tumor model, the treatment groups were divided into the following groups: (1) inactivated allogeneic leukocyte infusion (ALI), (2) ALI + MMC-inactivated TC-1 cell ...

  13. Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Tadepally Lakshmikanth

    2017-08-01

    Full Text Available Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.

  14. 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

  15. Anti-bacterial immunity to Listeria monocytogenes in allogeneic bone marrow chimera in mice

    International Nuclear Information System (INIS)

    Onoe, K.; Good, R.A.; Yamamoto, K.

    1986-01-01

    Protection and delayed-type hypersensitivity (DTH) to the facultative intracellular bacterium Listeria monocytogenes (L.m.) were studied in allogeneic and syngeneic bone marrow chimeras. Lethally irradiated AKR (H-2k) mice were successfully reconstituted with marrow cells from C57BL/10 (B10) (H-2b), B10 H-2-recombinant strains or syngeneic mice. Irradiated AKR mice reconstituted with marrow cells from H-2-compatible B10.BR mice, [BR----AKR], as well as syngeneic marrow cells, [AKR----AKR], showed a normal level of responsiveness to the challenge stimulation with the listeria antigens when DTH was evaluated by footpad reactions. These mice also showed vigorous activities in acquired resistance to the L.m. By contrast, chimeric mice that had total or partial histoincompatibility at the H-2 determinants between donor and recipient, [B10----AKR], [B10.AQR----AKR], [B10.A(4R)----AKR], or [B10.A(5R)----AKR], were almost completely unresponsive in DTH and antibacterial immunity. However, when [B10----AKR] H-2-incompatible chimeras had been immunized with killed L.m. before challenge with live L.m., these mice manifested considerable DTH and resistance to L.m. These observations suggest that compatibility at the entire MHC between donor and recipient is required for bone marrow chimeras to be able to manifest DTH and protection against L.m. after a short-term immunization schedule. However, this requirement is overcome by a preceding or more prolonged period of immunization with L.m. antigens. These antigens, together with marrow-derived antigen-presenting cells, can then stimulate and expand cell populations that are restricted to the MHC (H-2) products of the donor type

  16. Indicators of allogenic interactions of lymphocytes in spouses as additional diagnostic and prognostic criteria of immune forms of reproductive failures

    Directory of Open Access Journals (Sweden)

    Belenkova O.V.

    2013-12-01

    Full Text Available Research objective: to search new laboratory approaches to the diagnostics of immune forms of reproductive failures. Materials and methods. Retrospective research a case — control of 54 married couples with idiopathic reproductive failures (in the anamnesis — 3 and more spontaneously interrupted pregnancy in the 4-8th weeks and 47 married couples having two and more children has been conducted. Results. It has been revealed that at the immune form of reproductive failures increase of cells of level A- mononuclear cells, expression of HLDR takes place that promotes tolerance cancellation to allogenic germs and to immune interruption of pregnancy. At reproductive failures female au-toserum positively influences activation of T-lymphocyte (CD3 +/HLADR + that may lead to the death of half- allogenic germ. Conclusion. Level of expression of CD3 and HLADR on CD45 + of mixed allogenic mononuclear cells of spouses may serve as a diagnostic significant criterion for revealing immune reasons of reproductive failures.

  17. Cognate CD4 T-cell licensing of dendritic cells heralds anti-CMV CD8 T-cell immunity after human allogeneic umbilical cord blood transplantation

    NARCIS (Netherlands)

    Flinsenberg, T W H; Spel, Lotte; Jansen, M; Koning, D; de Haar, C; Plantinga, M; Scholman, R; van Loenen, M M; Nierkens, S; Boon, L; van Baarle, D; Heemskerk, M H M; Boelens, J J; Boes, M

    2014-01-01

    Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord-blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control requires CD8(+) T-cell-driven immunity. Mouse studies

  18. Major Histocompatibilty Complex-Restricted Adaptive Immune Responses to CT26 Colon Cancer Cell Line in Mixed Allogeneic Chimera.

    Science.gov (United States)

    Lee, K W; Choi, B; Kim, Y M; Cho, C W; Park, H; Moon, J I; Choi, G-S; Park, J B; Kim, S J

    2017-06-01

    Although the induction of mixed allogeneic chimera shows promising clinical tolerance results in organ transplantation, its clinical relevance as an anti-cancer therapy is yet unknown. We introduced a mixed allogenic chimera setting with the use of a murine colon cancer cell line, CT26, by performing double bone marrow transplantation. We analyzed donor- and recipient-restricted anti-cancer T-cell responses, and phenotypes of subpopulations of T cells. The protocol involves challenging 1 × 10 5 cells of CT26 cells intra-hepatically on day 50 after bone marrow transplantation, and, by use of CT26 lysates and an H-2L d -restricted AH1 pentamer, flow cytometric analysis was performed to detect the generation of cancer-specific CD4 + and CD8 + T cells at various time points. We found that immunocompetence against tumors depends heavily on cancer-specific CD8 + T-cell responses in a major histocompatibility complex-restricted manner; the evidence was further supported by the increase of interferon-γ-secreting CD4 + T cells. Moreover, we demonstrated that during the effector immune response to CT26 cancer challenge, there was a presence of central memory cells (CD62L hi CCR7 + ) as well as effector memory cells (CD62L lo CCR7 - ). Moreover, mixed allogeneic chimeras (BALB/c to C56BL/6 or vice versa) showed similar or heightened immune responses to CT26 cells compared with that of wild-type mice. Our results suggest that the responses of primary immunocompetency and of pre-existing memory T cells against allogeneic cancer are sustained and preserved long-term in a mixed allogeneic chimeric environment. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Effects of combined radiation-burn injury on survival rate of allogeneic skin grafts and immune reaction in rats

    International Nuclear Information System (INIS)

    Ran Xinze; Yan Yongtang; Cheng Tianmin; Li Yuan; Wei Shuqing

    1996-01-01

    The effects of combined radiation-burn injury on survival rate of allogeneic skin grafts and immune reaction were studied in rats with combined injury of 3-8 Gy 60 Co γ-ray irradiation plus 15% total body surface area full thickness burn induced by exposure to a 5 kw bromotungsten lamp. The allogeneic skin was transplanted 24 hours after injury. It was found that all the skin grafts failed to survive in 10 days and the immune reaction significantly increased in the early stage of burn injury. But the immune reaction was obviously suppressed by the combined radiation-burn injury. The survival rates of skin grafts were 20% and 30% in the combined injury of burn plus 3 and 4 Gy irradiation respectively. When the radiation doses increased to 5,6 and 8 Gy, the survival rates elevated to 69%, 88% and 100% respectively (in the group of 8 Gy, bone marrow transplantation was conducted before receiving skin graft). At day 30 post-transplantation the survival rates were still 36%, 42% and 100% respectively. Compared with burn group, there was a significant difference in survival rate when the radiation doses were higher than 5 Gy. These results indicate that the survival rate of the allogeneic skin graft increases concurrently with the increase in radiation dose and decreases with the elapse of the post-transplantation time

  20. Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.

    Directory of Open Access Journals (Sweden)

    Noriyuki Kashiyama

    Full Text Available Allogeneic transplantation (Tx of induced pluripotent stem cells (iPSCs is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET imaging targets translocator protein (TSPO, which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714 is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group, or Balb/c mice as an allogeneic model (allogeneic Tx group. 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune

  1. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

    Science.gov (United States)

    Goodyear, Oliver C; Dennis, Mike; Jilani, Nadira Y; Loke, Justin; Siddique, Shamyla; Ryan, Gordon; Nunnick, Jane; Khanum, Rahela; Raghavan, Manoj; Cook, Mark; Snowden, John A; Griffiths, Mike; Russell, Nigel; Yin, John; Crawley, Charles; Cook, Gordon; Vyas, Paresh; Moss, Paul; Malladi, Ram; Craddock, Charles F

    2012-04-05

    Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

  2. Regulatory immune cells and functions in autoimmunity and transplantation immunology.

    Science.gov (United States)

    Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

    2017-05-01

    In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Foetal immune programming: hormones, cytokines, microbes and regulatory T cells.

    Science.gov (United States)

    Hsu, Peter; Nanan, Ralph

    2014-10-01

    In addition to genetic factors, environmental cues play important roles in shaping the immune system. The first environment that the developing foetal immune system encounters is the uterus. Although physically the mother and the foetus are separated by the placental membranes, various factors such as hormones and cytokines may provide "environmental cues" to the foetal immune system. Additionally, increasing evidence suggests that prenatal maternal environmental factors, particularly microbial exposure, might significantly influence the foetal immune system, affecting long-term outcomes, a concept termed foetal immune programming. Here we discuss the potential mediators of foetal immune programming, focusing on the role of pregnancy-related hormones, cytokines and regulatory T cells, which play a critical role in immune tolerance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Natural and adoptive T-cell immunity against herpes family viruses after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Thomas, Simone; Herr, Wolfgang

    2011-06-01

    Reactivated infections with herpes family-related cytomegalovirus, Epstein-Barr virus and varicella zoster virus are serious and sometimes life-threatening complications for patients undergoing allogeneic hematopoietic stem cell transplantation. The pathogenesis of these infections critically involves the slow and inefficient recovery of antiviral T-cell immunity after transplantation. Although efficient drugs to decrease viral load during this vulnerable period have been developed, long-term control of herpes viruses and protection from associated diseases require the sufficient reconstitution of virus-specific memory T cells. To heal the deficiency by immunotherapeutic means, numerous research groups have developed antiviral vaccines and strategies based on the adoptive transfer of virus-specific T cells. This article summarizes the substantial progress made in this field during the past two decades and gives future perspectives about challenges that need to be addressed before antigen-specific immunotherapy against herpes family viruses can be implemented in general clinical practice.

  5. Immune reconstitution in patients with Fanconi anemia after allogeneic bone marrow transplantation.

    Science.gov (United States)

    Perlingeiro Beltrame, Miriam; Malvezzi, Mariester; Bonfim, Carmem; Covas, Dimas Tadeu; Orfao, Alberto; Pasquini, Ricardo

    2014-07-01

    Fanconi anemia is an autosomal recessive or X-linked genetic disorder characterized by bone marrow (BM) failure/aplasia. Failure of hematopoiesis results in depletion of the BM stem cell reservoir, which leads to severe anemia, neutropenia and thrombocytopenia, frequently requiring therapeutic interventions, including hematopoietic stem cell transplantation (HSCT). Successful BM transplantation (BMT) requires reconstitution of normal immunity. In the present study, we performed a detailed analysis of the distribution of peripheral blood subsets of T, B and natural killer (NK) lymphocytes in 23 patients with Fanconi anemia before and after BMT on days +30, +60, +100, +180, +270 and +360. In parallel, we evaluated the effect of related versus unrelated donor marrow as well as the presence of graft-versus-host disease (GVHD). After transplantation, we found different kinetics of recovery for the distinct major subsets of lymphocytes. NK cells were the first to recover, followed by cytotoxic CD8(+) T cells and B cells, and finally CD4(+) helper T cells. Early lymphocyte recovery was at the expense of memory cells, potentially derived from the graft, whereas recent thymic emigrant (CD31(+) CD45RA(+)) and naive CD4(+) or CD8(+) T cells rose only at 6 months after HSCT, in the presence of immunosuppressive GVHD prophylactic agents. Only slight differences were observed in the early recovery of cytotoxic CD8(+) T cells among those cases receiving a graft from a related donor versus an unrelated donor. Patients with GVHD displayed a markedly delayed recovery of NK cells and B cells as well as of regulatory T cells and both early thymic emigrant and total CD4(+) T cells. Our results support the utility of post-transplant monitoring of a peripheral blood lymphocyte subset for improved follow-up of patients with Fanconi anemia undergoing BMT. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. Immune Privilege and Eye-Derived T-Regulatory Cells

    Directory of Open Access Journals (Sweden)

    Hiroshi Keino

    2018-01-01

    Full Text Available Certain cellular components of the eye, such as neural retina, are unable to regenerate and replicate after destructive inflammation. Ocular immune privilege provides the eye with immune protection against intraocular inflammation in order to minimize the risk to vision integrity. The eye and immune system use strategies to maintain the ocular immune privilege by regulating the innate and adaptive immune response, which includes immunological ignorance, peripheral tolerance to eye-derived antigens, and intraocular immunosuppressive microenvironment. In this review, we summarize current knowledge regarding the molecular mechanism responsible for the development and maintenance of ocular immune privilege via regulatory T cells (Tregs, which are generated by the anterior chamber-associated immune deviation (ACAID, and ocular resident cells including corneal endothelial (CE cells, ocular pigment epithelial (PE cells, and aqueous humor. Furthermore, we examined the therapeutic potential of Tregs generated by RPE cells that express transforming growth factor beta (TGF-β, cytotoxic T lymphocyte-associated antigen-2 alpha (CTLA-2α, and retinoic acid for autoimmune uveoretinitis and evaluated a new strategy using human RPE-induced Tregs for clinical application in inflammatory ocular disease. We believe that a better understanding of the ocular immune privilege associated with Tregs might offer a new approach with regard to therapeutic interventions for ocular autoimmunity.

  7. Immune Privilege and Eye-Derived T-Regulatory Cells.

    Science.gov (United States)

    Keino, Hiroshi; Horie, Shintaro; Sugita, Sunao

    2018-01-01

    Certain cellular components of the eye, such as neural retina, are unable to regenerate and replicate after destructive inflammation. Ocular immune privilege provides the eye with immune protection against intraocular inflammation in order to minimize the risk to vision integrity. The eye and immune system use strategies to maintain the ocular immune privilege by regulating the innate and adaptive immune response, which includes immunological ignorance, peripheral tolerance to eye-derived antigens, and intraocular immunosuppressive microenvironment. In this review, we summarize current knowledge regarding the molecular mechanism responsible for the development and maintenance of ocular immune privilege via regulatory T cells (Tregs), which are generated by the anterior chamber-associated immune deviation (ACAID), and ocular resident cells including corneal endothelial (CE) cells, ocular pigment epithelial (PE) cells, and aqueous humor. Furthermore, we examined the therapeutic potential of Tregs generated by RPE cells that express transforming growth factor beta (TGF- β ), cytotoxic T lymphocyte-associated antigen-2 alpha (CTLA-2 α ), and retinoic acid for autoimmune uveoretinitis and evaluated a new strategy using human RPE-induced Tregs for clinical application in inflammatory ocular disease. We believe that a better understanding of the ocular immune privilege associated with Tregs might offer a new approach with regard to therapeutic interventions for ocular autoimmunity.

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

    Science.gov (United States)

    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

  9. The placental barrier in allogenic immune conflict in spontaneous early abortions: immunohistochemical and morphological study.

    Science.gov (United States)

    Gurevich, Pavel; Elhayany, Asher; Milovanov, Andrey P; Halperin, Reuvit; Kaganovsky, Ella; Zusman, Itzhak; Ben-Hur, Herzel

    2007-11-01

    Morphologic changes in the placental barrier in spontaneous early abortions under the maternal-embryonic immune conflict, and the role of maternal immunoglobulins (Igs) in these changes. We examined chorionic villi and other tissues obtained from 54 aborts between weeks 3.5 and 8 of pregnancy. Material was divided into two groups. Group 1 (control) contained 15 medically recommended and spontaneous early aborts with no signs of inflammations or pathologic immune processes. Group 2 contained 39 spontaneous early aborts with acute chorionic villitis. Immunohistochemical and morphometric methods were used to study the Igs, different types of immunocompetent cells, and apoptosis-related components of the placental barrier. Acute villitis was found to be characterized by the destruction of all components of the chorionic villi, thrombovasculitis with apoptosis of the endothelium of capillaries and erythroblasts, mucous swelling of the basal membrane, and coagulation of the blood proteins. Due to destruction of the capillaries, the number of avasculate villi increased, and the average number of capillaries per villus decreased. The extremely high number of phagolysosomes with IgG and IgA in the villous monocytes in the group 2 indicates an increase in the phagocytic activity of monocytes against maternal Igs and may reflect the presence of mother-embryo immune conflict. Apoptosis of monocytes and a high number of promonocytes were seen accompanied by a high concentration of p53 protein. A large disturbance in the trophoblast occurred with disappearance of bcl-2 and the appearance of Fas ligand. Massive destruction of maternal Igs in embryonic monocytes and acute villitis in the placental barrier are manifested during the mother-embryo immune conflict, and this may be one of the reasons of spontaneous early abortions.

  10. Allogeneic tumor cell vaccines

    Science.gov (United States)

    Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

    2014-01-01

    The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies. PMID:24064957

  11. The effect of cyclosporin A on the primary immune response to allogeneic red cells in rabbits.

    Science.gov (United States)

    Smith, G N

    1982-01-01

    Cyclosporin A (CSA) has been used in an attempt to suppress the primary immune response of HgA(A)-negative rabbits to A-positive red cells. The immune response was assessed by measuring the survival of a small intravenous (i.v.) dose of 51Cr-labelled A-positive cells and by testing the serum of the immunized rabbits for anti-A. In one experiment, eight A-negative rabbits were given a first i.v. injection of A-positive red cells, and CSA (25 mg/kg/day) in olive oil was given by mouth for 17-34 days. There was no evidence of impaired alloimmunization compared with the responses in control animals treated with olive oil alone. In a second experiment, eight A-negative rabbits were given a first injection of A-positive muscularly (i.m.), and CSA (25 mg/kg/day) in miglyol was given by im.m. injection for 10 days. Six of these rabbits were rendered unresponsive, and the remaining two, who showed impaired survival of the monitoring red cells, produced only low anit-A titres. Seven out of eight controls given i.m. miglyol without CSA responded with good anti-A production. Rabbits that were unresponsive to A-positive red cells responded normally to sheep red blood cells 15 weeks after CSA treatment. Higher serum levels of CSA were found following i.m. administration of the drug but treatment by this route as associated with severe toxicity in some rabbits. PMID:7056563

  12. Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD.

    Science.gov (United States)

    Lin, Kaifeng Lisa; Fulton, LeShara M; Berginski, Matthew; West, Michelle L; Taylor, Nicholas A; Moran, Timothy P; Coghill, James M; Blazar, Bruce R; Bear, James E; Serody, Jonathan S

    2014-03-06

    Graft-versus-host disease (GVHD) is a systemic inflammatory response due to the recognition of major histocompatibility complex disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T-cell activation is critical to the induction of GVHD, and data from our group and others have shown that regulatory T cells (Tregs) prevent GVHD when given at the time of HSCT. Using multiphoton laser scanning microscopy, we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs postallogeneic transplantation. We found that donor conventional T cells (Tcons) spent very little time screening host DCs. Tcons formed stable contacts with DCs very early after transplantation and only increased velocity in the lymph node at 20 hours after transplant. We also observed that Tregs reduced the interaction time between Tcons and DCs, which was dependent on the generation of interleukin 10 by Tregs. Imaging using inducible Tregs showed similar disruption of Tcon-DC contact. Additionally, we found that donor Tregs induce host DC death and down-regulate surface proteins required for donor T-cell activation. These data indicate that Tregs use multiple mechanisms that affect host DC numbers and function to mitigate acute GVHD.

  13. Genetic Background of Immune Complications after Allogeneic Hematopoietic Stem Cell Transplantation in Children

    Directory of Open Access Journals (Sweden)

    Szymon Skoczen

    2016-01-01

    Full Text Available Immune reactions are among the most serious complications observed after hematopoietic stem cell transplantation (HSCT in children. Microarray technique allows for simultaneous assessment of expression of nearly all human genes. The objective of the study was to compare the whole genome expression in children before and after HSCT. A total of 33 children referred for HSCT were enrolled in the study. In 70% of the patients HSCT was performed for the treatment of neoplasms. Blood samples were obtained before HSCT and six months after the procedure. Subsequently, the whole genome expression was assessed in leukocytes using GeneChip Human Gene 1.0 ST microarray. The analysis of genomic profiles before and after HSCT revealed altered expression of 124 genes. Pathway enrichment analysis revealed upregulation of five pathways after HSCT: allograft rejection, graft-versus-host disease, type I diabetes mellitus, autoimmune thyroid disease, and viral myocarditis. The activation of those pathways seems to be related to immune reactions commonly observed after HSCT. Our results contribute to better understanding of the genomic background of the immunologic complications of HSCT.

  14. Immune reconstitution after allogeneic hematopoietic stem cell transplantation in children: a single institution study of 59 patients

    Directory of Open Access Journals (Sweden)

    Hyun O Kim

    2013-01-01

    Full Text Available <b>Purpose:</b> Lymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT. Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's posttransplant immune reconstitution, and therefore require investigation. <b>Methods:</b> The time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK cell recovery. The impact of preand post-transplant variables, including diagnosis of Epstein-Barr virus (EBV DNAemia posttransplant,on lymphocyte recovery was evaluated. <b>Results:</b> The lymphocyte subsets recovered in the following order: NK cells, cytotoxic T cells, B cells,and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16+/56+ cell recovery. Younger patients showed delayed recovery of both CD3+/CD8+ and CD19+ cells. EBV DNAemia had a deleterious impact on the recovery of both CD3+ and CD3+/CD4+ lymphocytes at 1 year post-transplant. <b>Conclusion:</b> In our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells.

  15. Effects of X-rays and γ-rays on reconstitution of hematopoiesis and immunity after allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Pan Bin; Zeng Lingyu; Cheng Hai; Song Guoliang; Jia Lu; Yan Zhiling; Chen Chong; Xu Kailin

    2011-01-01

    those of the X-ray + transplantation group (t=3.624, 6.695, P<0.05). The chimeric rats of the peripheral lymphocytes 10 and 20 days after transplantation of the γ-ray + transplantation group were both significantly higher than those of the X-ray + transplantation group (t=12.317, 8.295, P<0.05). The homogeneity rate of transplantation of the γ-ray + transplantation group was better than that of the X-ray + transplantation group. Conclusions: As a conditioning regimen in allogeneic hematopoietic stem cell transplantation γ-ray irradiation causes milder injury and accelerated reconstitution of hematopoiesis and immunity, in comparison with X-ray irradiation. (authors)

  16. TLR5 signaling enhances the proliferation of human allogeneic CD40-activated B cell induced CD4hiCD25+ regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Ping-Lung Chan

    Full Text Available Although diverse functions of different toll-like receptors (TLR on human natural regulatory T cells have been demonstrated recently, the role of TLR-related signals on human induced regulatory T cells remain elusive. Previously our group developed an ex vivo high-efficient system in generating human alloantigen-specific CD4(hiCD25(+ regulatory T cells from naïve CD4(+CD25(- T cells using allogeneic CD40-activated B cells as stimulators. In this study, we investigated the role of TLR5-related signals on the generation and function of these novel CD4(hiCD25(+ regulatory T cells. It was found that induced CD4(hiCD25(+ regulatory T cells expressed an up-regulated level of TLR5 compared to their precursors. The blockade of TLR5 using anti-TLR5 antibodies during the co-culture decreased CD4(hiCD25(+ regulatory T cells proliferation by induction of S phase arrest. The S phase arrest was associated with reduced ERK1/2 phosphorylation. However, TLR5 blockade did not decrease the CTLA-4, GITR and FOXP3 expressions, and the suppressive function of CD4(hiCD25(+ regulatory T cells. In conclusion, we discovered a novel function of TLR5-related signaling in enhancing the proliferation of CD4(hiCD25(+ regulatory T cells by promoting S phase progress but not involved in the suppressive function of human CD40-activated B cell-induced CD4(hiCD25(+ regulatory T cells, suggesting a novel role of TLR5-related signals in the generation of induced regulatory T cells.

  17. Regulatory T Cells in Post-stroke Immune Homeostasis.

    Science.gov (United States)

    Liesz, Arthur; Kleinschnitz, Christoph

    2016-08-01

    The secondary neuroinflammatory response has come into focus of experimental stroke research. Immunological mechanisms after acute stroke are being investigated in the hope to identify novel and druggable pathways that contribute to secondary infarct growth after stroke. Among a variety of neuroimmunological events after acute brain ischemia, including microglial activation, brain leukocyte invasion, and secretion of pro-inflammatory factors, lymphocytes have been identified as the key leukocyte subpopulation driving the neuroinflammatory response and contributing to stroke outcome. Several studies have shown that pro-inflammatory lymphocyte subpopulations worsen stroke outcome and that inhibiting their invasion to the injured brain is neuroprotective. In contrast to the effector functions of pro-inflammatory lymphocytes, regulatory T cells (Treg) are critically involved in maintaining immune homeostasis and have been characterized as disease-limiting protective cells in several inflammatory conditions, particularly in primary inflammatory diseases of the central nervous system (CNS). However, due to the complex function of regulatory cells in immune homeostasis and disease, divergent findings have been described for the role of Treg in stroke models. Emerging evidence suggests that this discrepancy arises from potentially differing functions of Treg depending on the predominant site of action within the neurovascular unit and the surrounding inflammatory milieu. This article will provide a comprehensive review of current findings on Treg in brain ischemia models and discuss potential reasons for the observed discrepancies.

  18. Immune competence in /sup 90/Sr-exposed, adult thymectomized and antilymphocyteglobulin-treated CBA mice. Pt. 1. Allogenic skin graft reaction

    Energy Technology Data Exchange (ETDEWEB)

    Bierke, P.

    1989-01-01

    CBA mice subjected to either adult thymectomy, internal exposure to /sup 90/Sr or antilymphocyteglobulin treatment separately, or to combinations of the three were tested for cellular immune competence using their reaction to allogenic skin grafts. Peripheral blood white cell counts did not reveal any obvious correlation between the degree of mononuclear cell depletion and the ability to accept grafts, suggesting that the particular treatments depleted specific fractions of mononuclear cells, differing in their extent of involvement in the rejection process. No single treatment alone induced a significant prolongation in the time elapsed before graft rejection. Adult thymectomy followed by appropriate antilymphocyteglobulin treatment induced severe lymphocytopenia and a profound suppression of the cell-mediate immune system, as evidenced by the acceptance of allogenic skin grafts. When applied to /sup 90/Sr-preexposed mice the same treatment induced lifelong acceptance of grafts, indicating a similar, though weaker immunosuppressive impact of /sup 90/Sr. Hence it was possible to significantly enhance immunosuppression in /sup 90/Sr-exposed mice. This in vivo model should be useful when investigating the role of immunological responsiveness in radiation carcinogenesis. (orig.).

  19. Citoquinas reguladoras de la respuesta al transplante renal alogénico Regulatory cytokines in the response to the allogeneic renal transplant

    Directory of Open Access Journals (Sweden)

    Rita L. Cardoni

    2005-03-01

    monitoring the transplant rejection and the diagnosis of the associated nephropathies, in spite of the invasiveness of the procedure. Thus, it is of great interest to find alternative tools for diagnosis. The evaluation of regulatory cytokines is a simple procedure of low cost that could be useful to increase the sensitivity of the detection of polymorphic differences, to predict the graft acceptance and for the early detection of rejection. Recent studies suggest that the high production of pro-inflammatory mediators, such as Th1 cytokines, could be detrimental, whereas the production of anti-inflammatory regulatory cytokines, such as interleukin (IL-10 and tumor necrosis factor (TGF-b, could be beneficial for graft survival. In the early stages, the cellular cytotoxicity is activated by the Th1 response and the detection of cytotoxic molecules is associated to the acute rejection. Later, the balance between pro and anti-inflammatory mediators and the regulation of their levels could be more important. In this regard, TGF-b is also fibrogenic and a high local production can contribute to kidney damage. On the other hand, the increased production of IL-10 in response to the allogeneic stimuli could be, in most cases, an important marker of long-term acceptance.

  20. SMAD regulatory networks construct a balanced immune system.

    Science.gov (United States)

    Malhotra, Nidhi; Kang, Joonsoo

    2013-05-01

    A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine transforming growth factor-β (TGF-β), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF-β is to regulate the peripheral immune homeostasis, particularly in the microbe-rich and antigen-rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGF-β, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4(+) T cells into inflammatory T helper type 17 cells and suppressive FOXP3(+) T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as the vitamin A metabolite retinoic acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context-dependent functions of TGF-β are achieved by the co-operation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners. © 2013 Blackwell Publishing Ltd.

  1. Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

    Science.gov (United States)

    Hahn, M; Böttcher, S; Dietrich, S; Hegenbart, U; Rieger, M; Stadtherr, P; Bondong, A; Schulz, R; Ritgen, M; Schmitt, T; Tran, T H; Görner, M; Herth, I; Luft, T; Schönland, S; Witzens-Harig, M; Zenz, T; Kneba, M; Ho, A D; Dreger, P

    2015-10-01

    To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

  2. miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

    Directory of Open Access Journals (Sweden)

    William Becker

    2018-04-01

    Full Text Available The promise of inducing immunological tolerance through regulatory T cell (Treg control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4+ T cells in the draining lymph node (dLN of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC after allogeneic transplantation, in CD4+ T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p, targeting transforming growth factor beta 2 (TGF-β2, as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4+ T cells led to a decreased inducible FoxP3+ Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.

  3. Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

    OpenAIRE

    Lohan, Paul; Treacy, Oliver; Griffin, Matthew D.; Ritter, Thomas; Ryan, Aideen E.

    2017-01-01

    Mesenchymal stromal cells (MSC) have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous) MS...

  4. Different faces of regulatory DCs in homeostasis and immunity

    NARCIS (Netherlands)

    Smits, Hermelijn H.; de Jong, Esther C.; Wierenga, Eddy A.; Kapsenberg, Martien L.

    2005-01-01

    Adaptive immunity protects against infection and cancer but is also a potential threat to the host because of the risk of excessive inflammation or the development of autoimmunity and allergy. Therefore, immune responses are subject to negative regulation. An important aspect of negative regulation

  5. An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response

    Directory of Open Access Journals (Sweden)

    Katherine M. Buckley

    2017-10-01

    Full Text Available The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17, are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism.

  6. Interaction between the immune system and acute myeloid leukemia: A model incorporating promotion of regulatory T cell expansion by leukemic cells.

    Science.gov (United States)

    Nishiyama, Yoshiaki; Saikawa, Yutaka; Nishiyama, Nobuaki

    2018-03-01

    Population dynamics of regulatory T cells (Treg) are crucial for the underlying interplay between leukemic and immune cells in progression of acute myeloid leukemia (AML). The goal of this work is to elucidate the dynamics of a model that includes Treg, which can be qualitatively assessed by accumulating clinical findings on the impact of activated immune cell infusion after selective Treg depletion. We constructed an ordinary differential equation model to describe the dynamics of three components in AML: leukemic blast cells, mature regulatory T cells (Treg), and mature effective T cells (Teff), including cytotoxic T lymphocytes. The model includes promotion of Treg expansion by leukemic blast cells, leukemic stem cell and progenitor cell targeting by Teff, and Treg-mediated Teff suppression, and exhibits two coexisting, stable steady states, corresponding to high leukemic cell load at diagnosis or relapse, and to long-term complete remission. Our model is capable of explaining the clinical findings that the survival of patients with AML after allogeneic stem cell transplantation is influenced by the duration of complete remission, and that cut-off minimal residual disease thresholds associated with a 100% relapse rate are identified in AML. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

    Directory of Open Access Journals (Sweden)

    Daniel Benitez-Ribas

    2018-04-01

    Full Text Available Background and objectiveDiffuse intrinsic pontine glioma (DIPG is a lethal brainstem tumor in children. Dendritic cells (DCs have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT clinical trial with the use of autologous dendritic cells (ADCs pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy.MethodsNine patients with newly diagnosed DIPG met enrollment criteria. Autologous dendritic cell vaccines (ADCV were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received three boosts of tumor lysate every 3 months during the maintenance phase.ResultsVaccine fabrication was feasible in all patients included in the study. Non-specific KLH (9/9 patients and specific (8/9 patients antitumor response was identified by immunologic studies in peripheral blood mononuclear cells (PBMC. Immunological responses were also confirmed in the T lymphocytes isolated from the cerebrospinal fluid (CSF of two patients. Vaccine administration resulted safe in all patients treated with this schema.ConclusionThese preliminary results demonstrate that ADCV preparation is feasible, safe, and generate a DIPG-specific immune response detected in PBMC and CSF. This strategy shows a promising backbone for future schemas of combination IT.

  8. Uveitis and Myositis as Immune Complications in Chemorefractory NK/T-Cell Nasal-Type Lymphoma Successfully Treated with Allogeneic Stem-Cell Transplant

    Directory of Open Access Journals (Sweden)

    Maria José Gómez-Crespo

    2016-01-01

    Full Text Available NK/T-cell lymphomas are a group of clonal proliferations of NK- or, rarely, T-cell types and have peculiar clinicopathologic features. Most common site of involvement is the upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, and palate. Association of autoimmune paraneoplastic disorders with NK/T-cell lymphomas is not well studied. Our patient was diagnosed with NK/T-cell lymphoma stage IV with skin involvement and treated frontline with CHOEP regimen. While he was under treatment, two immune complications presented: anterior uveitis of autoimmune origin refractory to steroids and myositis in lower limbs muscles. Autologous transplantation was rejected due to confirmed early relapse after first-line treatment, and the patient received second-line treatment according to the SMILE scheme, reaching complete response after four cycles. The patient underwent allogeneic transplantation and at the time of manuscript preparation is alive despite multiple complications. The disease should be suspected in patients with rhinitis or recurrent sinusitis, and early biopsy is recommended for all patients to avoid a delay in diagnosis. Our patient also presented symptoms of disease progression after first-line treatment, representing a paraneoplastic process, a very rare phenomenon in T-type lymphomas. This case is novel for the appearance of an inflammatory myositis, a histologically verified paraneoplastic phenomenon that responded to treatment for lymphoma.

  9. Network modeling reveals prevalent negative regulatory relationships between signaling sectors in Arabidopsis immune signaling.

    Directory of Open Access Journals (Sweden)

    Masanao Sato

    Full Text Available Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. We studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2. This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles for 571 immune response genes of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with Pto DC3000 AvrRpt2. The mRNA profiles were analyzed as detailed descriptions of changes in the network state resulting from the genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting static network model accurately predicted 23 of 25 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i the components of the network are highly interconnected; and (ii negative regulatory relationships are common between signaling sectors. Complex regulatory relationships, including a novel negative regulatory relationship between the early microbe-associated molecular pattern-triggered signaling sectors and the salicylic acid sector, were further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a "sector

  10. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

    Science.gov (United States)

    Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

    2014-03-07

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.

  11. Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.

    Science.gov (United States)

    Hovingh, Elise S; van den Broek, Bryan; Jongerius, Ilse

    2016-01-01

    The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.

  12. Construction of an integrated gene regulatory network link to stress-related immune system in cattle.

    Science.gov (United States)

    Behdani, Elham; Bakhtiarizadeh, Mohammad Reza

    2017-10-01

    The immune system is an important biological system that is negatively impacted by stress. This study constructed an integrated regulatory network to enhance our understanding of the regulatory gene network used in the stress-related immune system. Module inference was used to construct modules of co-expressed genes with bovine leukocyte RNA-Seq data. Transcription factors (TFs) were then assigned to these modules using Lemon-Tree algorithms. In addition, the TFs assigned to each module were confirmed using the promoter analysis and protein-protein interactions data. Therefore, our integrated method identified three TFs which include one TF that is previously known to be involved in immune response (MYBL2) and two TFs (E2F8 and FOXS1) that had not been recognized previously and were identified for the first time in this study as novel regulatory candidates in immune response. This study provides valuable insights on the regulatory programs of genes involved in the stress-related immune system.

  13. Prolongation of the survival of breast cancer-bearing mice immunized with GM-CSF-secreting syngeneic/allogeneic fibroblasts transfected with a cDNA expression library from breast cancer cells.

    Science.gov (United States)

    Kim, Tae S; Jung, Mi Y; Cho, Daeho; Cohen, Edward P

    2006-10-30

    Breast cancer cells, like other types of neoplastic cells, form weakly immunogenic tumor-associated antigens. The antigenic properties of the tumor-associated antigens can be enhanced if they are expressed by highly immunogenic cells. In this study, a cancer vaccine was prepared by transfer of a cDNA expression library from SB5b breast carcinoma into mouse fibroblast cells of C3H/He mouse origin (H-2(k)), that had been previously modified to secrete GM-CSF and to express allogeneic class I-determinants (H-2(b)). The transfected syngeneic/allogeneic fibroblasts secreting GM-CSF were used as a vaccine in C3H/He mice. Robust cell-mediated immunity toward the breast cancer cells was generated in mice immunized with the cDNA-based vaccine. The immunity, mediated predominantly by CD8(+) T lymphocytes, was directed toward the breast cancer cells, but not against either of two other non-cross-reactive neoplasms of C3H/He mice. The immunity was sufficient to prolong the survival of mice with established breast cancer. Among other advantages, preparation of the vaccine by cDNA-transfer into a fibroblast cell line enabled the recipient cells to be modified in advance of DNA-transfer to augment their immunogenic properties. As the transferred DNA is replicated as the transfected cells divide, the vaccine could be prepared from microgram quantities of tumor tissue.

  14. Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes.

    Science.gov (United States)

    Toor, Amir A; Sabo, Roy T; Roberts, Catherine H; Moore, Bonny L; Salman, Salman R; Scalora, Allison F; Aziz, May T; Shubar Ali, Ali S; Hall, Charles E; Meier, Jeremy; Thorn, Radhika M; Wang, Elaine; Song, Shiyu; Miller, Kristin; Rizzo, Kathryn; Clark, William B; McCarty, John M; Chung, Harold M; Manjili, Masoud H; Neale, Michael C

    2015-07-01

    Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3(+) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3(+) at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  15. Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia.

    Science.gov (United States)

    Janikashvili, Nona; LaCasse, Collin J; Larmonier, Claire; Trad, Malika; Herrell, Amanda; Bustamante, Sara; Bonnotte, Bernard; Har-Noy, Michael; Larmonier, Nicolas; Katsanis, Emmanuel

    2011-02-03

    Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.

  16. Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis; Andersen, Line Sidsel Fisker; Krych, Lukasz

    2014-01-01

    diabetes. In this study, we demonstrate that both C-section and cross-fostering with a genetically distinct strain influence the gut microbiota composition and immune key markers in mice. Gut microbiota profiling by denaturing gradient gel electrophoresis and 454/FLX-based 16S rRNA gene amplicon sequencing...... electrophoresis profiles was evident in adult mice. However, the adult C-section-born mice had lower proportions of Foxp3(+) regulatory T cells, tolerogenic CD103(+) dendritic cells, and less Il10 gene expression in mesenteric lymph nodes and spleens. This demonstrates long-term systemic effect on the regulatory...... and priming of regulatory immune system in mice, and mode of delivery strongly influences this....

  17. Different immune regulatory potential of Lactobacillus plantarum and Lactobacillus sakei isolated from Kimchi.

    Science.gov (United States)

    Hong, Yi-Fan; Kim, Hangeun; Kim, Hye Rim; Gim, Min Geun; Chung, Dae Kyun

    2014-12-28

    It is known that lactic acid bacteria (LAB) have many beneficial health effects, including antioxidative activity and immune regulation. In this study, the immune regulatory effects of Lactobacillus sakei and Lactobacillus plantarum, which are found in different types of kimchi, were evaluated. L. sakei and its lipoteichoic acid (LTA) have greater immune stimulating potential in IL-12, IFN-γ, and TNF-α production as compared with L. plantarum in an in vitro condition. On the other hand, L. plantarum is assumed to repress the Th1 immune response in murine experiments. After being injected with LPS, L. plantarum-fed mice maintained a healthier state, and the level of TNF-α in their blood was lower than in other bacterial strainfed mice and in the LPS-only control mice. Additionally, IL-12 production was significantly decreased and the production of IL-4 was greatly increased in the splenocytes from L. plantarum-fed mice. Further experiments revealed that the pre-injection of purified LTA from L. plantarum (pLTA), L. sakei (sLTA), and S. aureus (aLTA) decreased TNF-α and IL-4 production in LPS-injected mice. Mouse IL-12, however, was significantly increased by aLTA pre-injection. In conclusion, the L. sakei and L. plantarum strains have immune regulation effects, but the effects differ in cytokine production and the regulatory effects of the Th1/Th2 immune response.

  18. Non-traditional CD4+CD25-CD69+ regulatory T cells are correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Zhao, Xiao-su; Wang, Xu-hua; Zhao, Xiang-yu; Chang, Ying-jun; Xu, Lan-ping; Zhang, Xiao-hui; Huang, Xiao-jun

    2014-07-01

    Non-traditional CD4+CD25-CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT). The frequency of CD4+CD25-CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion. The results showed that the frequency of CD4+CD25-CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25-CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion. This study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.

  19. Anti-Inflammatory and Immune Regulatory Actions of Naja naja atra Venom

    Directory of Open Access Journals (Sweden)

    Shu-Zhi Wang

    2018-02-01

    Full Text Available Naja naja atra venom (NNAV is composed of various proteins, peptides, and enzymes with different biological and pharmacological functions. A number of previous studies have reported that NNAV exerts potent analgesic effects on various animal models of pain. The clinical studies using whole venom or active components have confirmed that NNAV is an effective and safe medicine for treatment of chronic pain. Furthermore, recent studies have demonstrated that NNAV has anti-inflammatory and immune regulatory actions in vitro and in vivo. In this review article, we summarize recent studies of NNAV and its components on inflammation and immunity. The main new findings in NNAV research show that it may enhance innate and humoral immune responses while suppressing T lymphocytes-mediated cellular immunity, thus suggesting that NNAV and its active components may have therapeutic values in the treatment of inflammatory and autoimmune diseases.

  20. Small and long regulatory RNAs in the immune system and immune diseases

    NARCIS (Netherlands)

    Stachurska, Anna; Zorro, Maria M.; van der Sijde, Marijke R.; Withoff, Sebo

    2014-01-01

    Cellular differentiation is regulated on the level of gene expression, and it is known that dysregulation of gene expression can lead to deficiencies in differentiation that contribute to a variety of diseases, particularly of the immune system. Until recently, it was thought that the dysregulation

  1. Heterogenous populations of cytotoxic cells in the peritoneal cavity of BALB/c mice immunized with allogeneic EL4 leukemia cells

    International Nuclear Information System (INIS)

    Zighelboim, J.; Bonavida, B.; Fahey, J.L.

    1974-01-01

    Adherent cells, presumably macrophages, obtained from the peritoneal cavity shortly after rejection of the allogeneic leukemia EL4, produced effective cell-mediated cytotoxicity (CMC) in vitro. These cytotoxic cells were sensitive to anti-macrophage serum and resistant to anti-thymocyte serum and 10,000 roentgen irradiation. In contrast, a second population of specifically cytotoxic cells were nonadherent, sensitive to x-rays and anti-thymocyte serum, but not to anti-macrophage serum. The two cell populations had a cooperative cytotoxic effect in vitro against allogeneic tumor cells

  2. Delayed allogeneic skin graft rejection in CD26-deficient mice.

    Science.gov (United States)

    Zhao, Xiangli; Zhang, Kai; Daniel, Peter; Wisbrun, Natali; Fuchs, Hendrik; Fan, Hua

    2018-03-23

    Organ transplantation is an effective therapeutic tool for treating many terminal diseases. However, one of the biggest challenges of transplantation is determining how to achieve the long-term survival of the allogeneic or xenogeneic transplant by, for example, preventing transplant rejection. In the current study, CD26 gene-knockout mice were used to investigate the potential role of CD26/dipeptidyl peptidase-4 (DPPIV) in allogeneic skin graft rejection by tail-skin transplantation. Compared with wild-type (CD26 +/+ ) counterparts, CD26 -/- mice showed reduced necrosis of grafts and delayed graft rejection after skin transplantation. Concentrations of serum IgG, including its subclasses IgG1 and IgG2a, were significantly reduced in CD26 -/- mice during graft rejection. Moreover, after allogeneic skin transplantation, the secretion levels of the cytokines IFN-γ, IL-2, IL-6, IL-4, and IL-13 were significantly reduced, whereas the level of the cytokine IL-10 was increased in the serum of CD26 -/- mice compared with that in the serum of CD26 +/+ mice. Additionally, the concentration of IL-17 in serum and the percentage of cells secreting IL-17 in mouse peripheral blood lymphocytes (MPBLs) were both significantly lower, while the percentage of regulatory T cells (Tregs) was significantly higher in MPBLs of CD26 -/- mice than in those of CD26 +/+ mice. Furthermore, a lower percentage of CD8 + T cells in MPBLs and fewer infiltrated macrophages and T cells in graft tissues of CD26 -/- mice were detected during graft rejection. These results indicate that CD26 is involved in allogeneic skin graft rejection and provides another hint that CD26 deficiency leads to less rejection due to lower activation and proliferation of host immune cells.

  3. Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis.

    Science.gov (United States)

    Silvestre, Marilene Chaves; Sato, Maria Notomi; Reis, Vitor Manoel Silva Dos

    2018-03-01

    Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

  4. Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis*

    Science.gov (United States)

    Silvestre, Marilene Chaves; Sato, Maria Notomi; dos Reis, Vitor Manoel Silva

    2018-01-01

    Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation. PMID:29723367

  5. Small and Long Regulatory RNAs in the Immune System and Immune Diseases

    OpenAIRE

    Stachurska, Anna; Zorro, Maria M.; van der Sijde, Marijke R.; Withoff, Sebo

    2014-01-01

    Cellular differentiation is regulated on the level of gene expression, and it is known that dysregulation of gene expression can lead to deficiencies in differentiation that contribute to a variety of diseases, particularly of the immune system. Until recently, it was thought that the dysregulation was governed by changes in the binding or activity of a class of proteins called transcription factors. However, the discovery of micro-RNAs and recent descriptions of long non-coding RNAs (lncRNAs...

  6. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

    Directory of Open Access Journals (Sweden)

    Barbara Ensoli

    2010-11-01

    Full Text Available Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002. Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002, served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+ and CD8(+ cellular activation (CD38 and HLA-DR together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+ T cells and B cells with reduction of CD8(+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+ and CD8(+ T cells were accompanied by increases of CD4(+ and CD8(+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite

  7. Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity.

    Science.gov (United States)

    Kaufman, Gabriel N; Massoud, Amir H; Dembele, Marieme; Yona, Madelaine; Piccirillo, Ciriaco A; Mazer, Bruce D

    2015-01-01

    Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment.

  8. [Regulatory Mechanisms of PD-L1 Expression and Its Role in Immune Evasion].

    Science.gov (United States)

    Kataoka, Keisuke

    2017-11-01

    Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption.

  9. Immune regulation in Chandipura virus infection: characterization of CD4+ T regulatory cells from infected mice

    Directory of Open Access Journals (Sweden)

    Shahir Prajakta

    2011-05-01

    Full Text Available Abstract Back ground Chandipura virus produces acute infection in mice. During infection drastic reduction of CD4+, CD8+ and CD19 + cell was noticed. Depletion of lymphocytes also noticed in spleen. The reduction may be due to the regulatory mechanism of immune system to prevent the bystander host tissue injury. There are several mechanisms like generation of regulatory cells, activation induced cell death (ACID etc were indicated to control the activation and maintain cellular homeostasis. Role of regulatory cells in homeostasis has been described in several viral diseases. This study was undertaken to characterize CD4+T regulatory cells from the infected mice. Method In this study we purified the CD4+ T cells from Chandipura virus infected susceptible Balb/c mice. CD4+ T regulatory cells were identified by expression of cell surface markers CD25, CD127 and CTLA-4 and intracellular markers Foxp3, IL-10 and TGF-beta. Antigen specificity and ability to suppress the proliferation of other lymphocytes were studied in vitro by purified CD4+CD25+T regulatory cells from infected mice. The proliferation was calculated by proliferation module of Flow Jo software. Expression of death receptors on regulatory cells were studied by flowcytometer. Results The CD4+ T cells isolated from infected mice expressed characteristic markers of regulatory phenotype at all post infective hours tested. The CD4+ T regulatory cells were proliferated when stimulated with Chandipura virus antigen. The regulatory cells did not suppress the proliferation of splenocytes stimulated with anti CD3 antibody when co cultured with them. Interesting observation was, while purification of CD4+ T cells by negative selection, the population of cells negative for CD4 also co purified along with CD4+ T cell. Flow cytometry analysis and light microscopy revealed that CD4 negative cells were of different size and shape (atypical compared to the normal lymphocytes. Greater percentage of

  10. Interleukin-4 Supports the Suppressive Immune Responses Elicited by Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Wei-Cheng Yang

    2017-11-01

    Full Text Available Interleukin-4 (IL-4 has been considered as one of the tolerogenic cytokines in many autoimmune animal models and clinical settings. Despite its role in antagonizing pathogenic Th1 responses, little is known about whether IL-4 possesses functions that affect regulatory T cells (Tregs. Tregs are specialized cells responsible for the maintenance of peripheral tolerance through their immune modulatory capabilities. Interestingly, it has been suggested that IL-4 supplement at a high concentration protects responder T cells (Tresps from Treg-mediated immune suppression. In addition, such supplement also impedes TGF-β-induced Treg differentiation in vitro. However, these phenomena may contradict the tolerogenic role of IL-4, and the effects of IL-4 on Tregs are therefore needed to be further elucidated. In this study, we utilized IL-4 knockout (KO mice to validate the role of IL-4 on Treg-mediated immune suppression. Although IL-4 KO and control animals harbor similar frequencies of Tregs, Tregs from IL-4 KO mice weakly suppressed autologous Tresp activation. In addition, IL-4 deprivation impaired the ability of Tregs to modulate immune response, whereas IL-4 supplementation reinforced IL-4 KO Tregs in their function in suppressing Tresps. Finally, the presence of IL-4 was associated with increased cell survival and granzyme expression of Tregs. These results suggest the essential role of IL-4 in supporting Treg-mediated immune suppression, which may benefit the development of therapeutic strategies for autoimmune diseases.

  11. Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.

    Directory of Open Access Journals (Sweden)

    Xinghui Li

    Full Text Available Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6, and number of IFN-γ (+ CD4(+ and IFN-γ (+ CD8(+ T cells in the spleen and liver. In contrast, CD4(+CD25(+Foxp3(+ Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction.

  12. Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb.

    Science.gov (United States)

    Dias, Sheila; D'Amico, Angela; Cretney, Erika; Liao, Yang; Tellier, Julie; Bruggeman, Christine; Almeida, Francisca F; Leahy, Jamie; Belz, Gabrielle T; Smyth, Gordon K; Shi, Wei; Nutt, Stephen L

    2017-01-17

    FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells.

    Science.gov (United States)

    Manlove, Luke S; Berquam-Vrieze, Katherine E; Pauken, Kristen E; Williams, Richard T; Jenkins, Marc K; Farrar, Michael A

    2015-10-15

    BCR-ABL(+) acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL(+) leukemia progression although ultimately this immune response fails. To address how BCR-ABL(+) leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4(+) T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL(+) leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-β1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL(+) leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells. Copyright © 2015 by The American Association of Immunologists, Inc.

  14. Regulatory effects of intrinsic IL-10 in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Friedl, H P

    1995-01-01

    IL-10 has regulatory effects in vitro on cytokine production by activated macrophages. In the IgG immune complex model of lung injury, exogenously administered IL-10 has been shown to suppress in vivo formation of TNF-alpha, up-regulation of vascular ICAM-1, neutrophil recruitment, and ensuing lung....... Blocking of IL-10 by Ab resulted in a 52% increase in lung vascular permeability, a 56% increase in TNF-alpha activity in bronchoalveolar lavage fluids, and a 47 to 48% increase in bronchoalveolar lavage neutrophils and lung myeloperoxidase content. These findings suggest that IL-10 is an important natural...

  15. Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia.

    Science.gov (United States)

    Li, Peiying; Mao, Leilei; Zhou, Guoqing; Leak, Rehana K; Sun, Bao-Liang; Chen, Jun; Hu, Xiaoming

    2013-12-01

    Cerebral ischemia has been shown to result in peripheral inflammatory responses followed by long-lasting immunosuppression. Our recent study demonstrated that intravenous delivery of regulatory T cells (Tregs) markedly protected against transient cerebral ischemia by suppressing neutrophil-derived matrix metallopeptidase 9 production in the periphery. However, the effect of Tregs on systemic inflammatory responses and immune status has not been fully characterized. Cerebral ischemia was induced by middle cerebral artery occlusion for 60 minutes in mice or 120 minutes in rats. Tregs were isolated from donor animals by CD4 and CD25 double selection and transferred intravenously to ischemic recipients at 2 hours after middle cerebral artery occlusion. Animals were euthanized on different days after reperfusion. The effects of Tregs on systemic inflammation and immune status were evaluated using flow cytometry, ELISAs, and immunohistochemistry. Systemic administration of purified Tregs raises functional Tregs in the blood and peripheral organs, including spleen and lymph nodes. These exogenous Tregs remain in the blood and peripheral organs for ≥12 days. Functionally, Treg adoptive transfer markedly inhibits middle cerebral artery occlusion-induced elevation of inflammatory cytokines (interleukin-6 and tumor necrosis factor α) in the blood. Furthermore, Treg treatment corrects long-term lymphopenia and improves cellular immune functions after ischemic brain injury. As a result, Treg-treated animals exhibit decreased bacterial loads in the blood during recovery from cerebral ischemic attack. Treg treatment did not exacerbate poststroke immunosuppression. On the contrary, Treg-treated animals displayed improved immune status after focal cerebral ischemia.

  16. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

    Science.gov (United States)

    De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

    2017-06-01

    Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Antioxidant and Ex Vivo Immune System Regulatory Properties of Boswellia serrata Extracts

    Directory of Open Access Journals (Sweden)

    Daniela Beghelli

    2017-01-01

    Full Text Available Boswellia serrata (BS is an important traditional medicinal plant that currently represents an interesting topic for pharmaceutical research since it possesses several pharmacological properties (e.g., anti-inflammatory, antimicrobial, and antitumour. The safety and versatility of this dietary supplement should allow for its use in numerous pathological conditions; however the quality of the extracts needs to be standardized to increase the clinical success rate resulting from its use. In the present study, different commercially available B. serrata extracts were employed to compare their AKBA content and in vitro antioxidant power. Furthermore, their ability to modulate the immune system regulatory properties was investigated. Our results showed that the AKBA content varied from 3.83±0.10 to 0.03±0.004%, with one sample in which it was not detectable. The highest antioxidant power and phenolic content were shown by the same extract, which also exhibited the highest AKBA concentration. Finally, the BS extracts showed the ability to influence the regulatory and effector T-cell compartments. Our results suggest that frankincense should be further investigated for its promising potentiality to modulate not only inflammation/oxidative stress but also immune dysregulation, but attention should be paid to the composition of the commercial extracts.

  18. Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells.

    Science.gov (United States)

    Curti, Antonio; Trabanelli, Sara; Onofri, Chiara; Aluigi, Michela; Salvestrini, Valentina; Ocadlikova, Darina; Evangelisti, Cecilia; Rutella, Sergio; De Cristofaro, Raimondo; Ottaviani, Emanuela; Baccarani, Michele; Lemoli, Roberto M

    2010-12-01

    The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia. Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels. We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4(+)CD25(+) Foxp3(+) T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4(+)CD25(+) T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms' tumor protein. These data identify

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

    Science.gov (United States)

    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.

  20. Allogenic lyophilized cartilage grafts for craniomaxillofacial reconstruction

    International Nuclear Information System (INIS)

    Pill Hoon Choung

    1999-01-01

    Allogenic lyophilized cartilages were made in our clinic after Sailer methods and some modification. In our clinic, we have used allogenic cartilage grafts on 102 defects of craniomaxillofacial area; 1) for defects from cyst or ameloblastoma, 2) for lack of continuity of the mandible, 3) for rhinoplasty, 4) for paranasal augmentation, 5) for augmentation genioplasty, 6) for reconstruction of orbital floor, 7) for oroantral fistula, 8) for temporal augmentation, 9) for TMJ surgery 10) for condyle defect as a costochondral graft, 11) for filling of tooth socket and alveolus augmentation,12) for correction or orbital height and 13) for guided bone regeneration in peripheral implant. The types of lyophilized cartilage used were chip, sheet and block types developed by freeze-dried methods. Some grafts showed change of ossification, in which case we could perform implant on it. We have good results on reconstruction of craniomaxillofacial defects. Allogenic cartilage have advantages such as 1) it has no immune reaction clinically, 2) it is more tolerable to infection than that of autogenous cartilage, 3) it has character of less resorption which require no over correction, 4) it is easy to manipulate contouring, and 5) it has possibility of undergoing ossification. Allogenic cartilage has been considered as good substitutes for bone. The author would like to report the results on 102 allogenic cartilage have

  1. Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERON-CMV® assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications.

    Directory of Open Access Journals (Sweden)

    Siok-Keen Tey

    Full Text Available The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT is crucial in preventing cytomegalovirus (CMV-associated complications. Thus immunological monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV® to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2% showed CMV reactivation and 29 (70.7% developed acute graft-versus-host disease (GvHD. Patients with acute GvHD (grade ≥ 2 within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013 and a higher risk of CMV viremia (p = 0.026. The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031. Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002. Hence, QuantiFERON-CMV® testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation.

  2. Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system.

    Science.gov (United States)

    Monzón-Sandoval, Jimena; Castillo-Morales, Atahualpa; Crampton, Sean; McKelvey, Laura; Nolan, Aoife; O'Keeffe, Gerard; Gutierrez, Humberto

    2015-01-01

    During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune-related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS. In order to gain insights into the scale and wider functional organization of immune-related genetic networks in the NS, we examined the large scale pattern of expression of these genes in the brain. Our results show a highly significant correlated expression and transcriptional clustering among immune-related genes in the developing and adult brain, and this correlation was the highest in the brain when compared to muscle, liver, kidney and endothelial cells. We experimentally tested the regulatory clustering of immune system (IS) genes by using microarray expression profiling in cultures of dissociated neurons stimulated with the pro-inflammatory cytokine TNF-alpha, and found a highly significant enrichment of immune system-related genes among the resulting differentially expressed genes. Our findings strongly suggest a coherent recruitment of entire immune-related genetic regulatory modules by the neural-specific genetic programme that shapes the NS.

  3. Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: new therapeutic challenging opportunities.

    Science.gov (United States)

    Alijotas-Reig, Jaume; Melnychuk, Taisiia; Gris, Josep Maria

    2015-03-15

    Because maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to play a key role in altering the maternal immune response. Peripheral T regulatory cells (pTregs) at the maternal-foetal interface are necessary in situ to prevent early abortion, but only those pTregs that have been previously exposed to paternal alloantigens. It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3(+)CD4(+)CD25(+) (Foxp3Tregs) cells with foetal specificity. Interestingly, after delivery, foetal-specific pTregs persist at elevated levels, maintain tolerance to pre-existing foetal antigen, and rapidly re-accumulate during subsequent pregnancy. pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  4. Regulatory T cells (Treg and Their Roles in Immune System with Respect to Immunopathological Disorders

    Directory of Open Access Journals (Sweden)

    Kateřina Kondělková

    2010-01-01

    Full Text Available Regulatory T cells (Tregs are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. Different subsets with various functions of Treg cells exist. Tregs can be usually identified by flow cytometry. The most specific marker for these cells is FoxP3, which is localized intracellulary. Selected surface markers such as CD25high (high molecular density and CD127low (low molecular density could serve as surrogate markers to detect Tregs in a routine clinical practice. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease. Therapeutical Treg modulation is considered to be a promising therapeutical approach to treat some selected disorders, such as allergies, and to prevent allograft rejection.

  5. Kosten van allogene stamceltransplantaties

    NARCIS (Netherlands)

    M. van Agthoven (Michel); M.T. Groot (Martijn); C.A. Uyl-de Groot (Carin)

    2001-01-01

    textabstractAllogene stamceltransplantatie is een topspecialistische procedure die met succes kan worden ingezet in de behandeling van (hematologische) maligniteiten, met name bij leukemie. Van oudsher worden transplantaten van verwante donoren gebruikt, maar met de mogelijkheden om transplantaten

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

    Directory of Open Access Journals (Sweden)

    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.

  7. 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...

  8. Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  9. Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis.

    Science.gov (United States)

    Janssens, Kris; Van den Haute, Chris; Baekelandt, Veerle; Lucas, Sophie; van Horssen, Jack; Somers, Veerle; Van Wijmeersch, Bart; Stinissen, Piet; Hendriks, Jerome J A; Slaets, Helena; Hellings, Niels

    2015-03-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4(+) T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro. Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.

    Science.gov (United States)

    Kol, Amir; Wood, Joshua A; Carrade Holt, Danielle D; Gillette, Jessica A; Bohannon-Worsley, Laurie K; Puchalski, Sarah M; Walker, Naomi J; Clark, Kaitlin C; Watson, Johanna L; Borjesson, Dori L

    2015-04-15

    Intravenous (IV) injection of mesenchymal stem cells (MSCs) is used to treat systemic human diseases and disorders but is not routinely used in equine therapy. In horses, MSCs are isolated primarily from adipose tissue (AT) or bone marrow (BM) and used for treatment of orthopedic injuries through one or more local injections. The objective of this study was to determine the safety and lymphocyte response to multiple allogeneic IV injections of either AT-derived MSCs (AT-MSCs) or BM-derived MSCs (BM-MSCs) to healthy horses. We injected three doses of 25 × 10(6) allogeneic MSCs from either AT or BM (a total of 75 × 10(6) MSCs per horse) into five and five, respectively, healthy horses. Horses were followed up for 35 days after the first MSC infusion. We evaluated host inflammatory and immune response, including total leukocyte numbers, serum cytokine concentration, and splenic lymphocyte subsets. Repeated injection of allogeneic AT-MSCs or BM-MSCs did not elicit any clinical adverse effects. Repeated BM-MSC injection resulted in increased blood CD8(+) T-cell numbers. Multiple BM-MSC injections also increased splenic regulatory T cell numbers compared with AT-MSC-injected horses but not controls. These data demonstrate that multiple IV injections of allogeneic MSCs are well tolerated by healthy horses. No clinical signs or clinico-pathologic measurements of organ toxicity or systemic inflammatory response were recorded. Increased numbers of circulating CD8(+) T cells after multiple IV injections of allogeneic BM-MSCs may indicate a mild allo-antigen-directed cytotoxic response. Safety and efficacy of allogeneic MSC IV infusions in sick horses remain to be determined.

  11. 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

  12. 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

  13. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

    International Nuclear Information System (INIS)

    Stoop, Jeroen N.; Molen, Renate G. van der; Kuipers, Ernst J.; Kusters, Johannes G.; Janssen, Harry L.A.

    2007-01-01

    Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-γ production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response

  14. Trans-sialidase-based vaccine candidate protects against Trypanosoma cruzi infection, not only inducing an effector immune response but also affecting cells with regulatory/suppressor phenotype

    Science.gov (United States)

    Prochetto, Estefanía; Roldán, Carolina; Bontempi, Iván A.; Bertona, Daiana; Peverengo, Luz; Vicco, Miguel H.; Rodeles, Luz M.; Pérez, Ana R.; Marcipar, Iván S.; Cabrera, Gabriel

    2017-01-01

    Prophylactic and/or therapeutic vaccines have an important potential to control Trypanosoma cruzi (T. cruzi)infection. The involvement of regulatory/suppressor immune cells after an immunization treatment and T. cruzi infection has never been addressed. Here we show that a new trans-sialidase-based immunogen (TSf) was able to confer protection, correlating not only with beneficial changes in effector immune parameters, but also influencing populations of cells related to immune control. Regarding the effector response, mice immunized with TSf showed a TS-specific antibody response, significant delayed-type hypersensitivity (DTH) reactivity and increased production of IFN-γ by CD8+ splenocytes. After a challenge with T. cruzi, TSf-immunized mice showed 90% survival and low parasitemia as compared with 40% survival and high parasitemia in PBS-immunized mice. In relation to the regulatory/suppressor arm of the immune system, after T. cruzi infection TSf-immunized mice showed an increase in spleen CD4+ Foxp3+ regulatory T cells (Treg) as compared to PBS-inoculated and infected mice. Moreover, although T. cruzi infection elicited a notable increase in myeloid derived suppressor cells (MDSC) in the spleen of PBS-inoculated mice, TSf-immunized mice showed a significantly lower increase of MDSC. Results presented herein highlight the need of studying the immune response as a whole when a vaccine candidate is rationally tested. PMID:28938533

  15. Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression.

    Science.gov (United States)

    Lee, DaHae; Keymeulen, Bart; Hilbrands, Robert; Ling, Zhidong; Van de Velde, Ursule; Jacobs-Tulleneers-Thevissen, Daniel; Maleux, Geert; Lapauw, Bruno; Crenier, Laurent; De Block, Christophe; Mathieu, Chantal; Pipeleers, Daniel; Gillard, Pieter

    2017-09-01

    Induction therapy with a T cell-depleting agent followed by mycophenolate mofetil and tacrolimus is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients. Fifty-one patients (age, between 29 and 63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin-mycophenolate mofetil-tacrolimus protocol. They were followed up for over 48 months for function of the implant and adverse events. Severe hypoglycemia and diabetic ketoacidosis were absent in patients with functioning graft. Immune suppressive therapy was maintained for 48 months in 29 recipients with sustained function (group A), whereas 16 patients stopped earlier due to graft failure (group B) and in 6 for other reasons. Group A was significantly older at the time of implantation and achieved higher graft function at posttransplantation month 6 under similar dose of IS. Prevalence of IS-related side effects was similar in groups A and B, occurring predominantly during the first year posttransplantation. IS-related serious adverse events (SAE) were reported in 47% of patients, with 4 presenting with cytomegalovirus infection and 4 (age, 42-59 years) diagnosed with cancer. Except in 1 patient with cancer, all SAEs resolved after appropriate treatment. These risk/benefit data serve as a basis for clinical decision-making before entering an intraportal islet transplantation protocol. A longer benefit is observed in recipients of higher age (≥40 years), but it is not associated with more side effects and SAE.

  16. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells

    OpenAIRE

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L.; Liao, Gongxian; Hoffman, Brad E.; Leong, Kam W.; Terhorst, Cox; Daniell, Henry; Herzog, Roland W.

    2015-01-01

    Coadministering FIX orally and systemically induces tolerance via complex immune regulation, involving tolerogenic dendritic and T-cell subsets.Induced CD4+CD25−LAP+ regulatory T cells with increased IL-10 and TGF-β expression and CD4+CD25+ regulatory T cells suppress antibody formation against FIX.

  17. Immunization

    Science.gov (United States)

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  18. Adaptive immunity to leukemia is inhibited by cross-reactive induced regulatory T cells

    OpenAIRE

    Manlove, Luke S.; Berquam-Vrieze, Katherine E.; Pauken, Kristen E.; Williams, Richard T.; Jenkins, Marc K.; Farrar, Michael A.

    2015-01-01

    BCR-ABL+ acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific antigen that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL+ leukemia progression although ultimately this immune response fails. To address how BCR-ABL+ leukemia escapes immune surveillance, we developed a peptide: MHC-II tetramer that labels endogenous BCR-ABL-specific CD4+ T cell...

  19. Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy

    Science.gov (United States)

    Bhattacharya, Palash; Budnick, Isadore; Singh, Medha; Thiruppathi, Muthusamy; Alharshawi, Khaled; Elshabrawy, Hatem; Holterman, Mark J.

    2015-01-01

    Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them “tolerogenic,” which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility. PMID:25803788

  20. Forkhead-Box-P3 Gene Transfer in Human CD4+ T Conventional Cells for the Generation of Stable and Efficient Regulatory T Cells, Suitable for Immune Modulatory Therapy

    Directory of Open Access Journals (Sweden)

    Laura Passerini

    2017-10-01

    Full Text Available The development of novel approaches to control immune responses to self- and allogenic tissues/organs represents an ambitious goal for the management of autoimmune diseases and in transplantation. Regulatory T cells (Tregs are recognized as key players in the maintenance of peripheral tolerance in physiological and pathological conditions, and Treg-based cell therapies to restore tolerance in T cell-mediated disorders have been designed. However, several hurdles, including insufficient number of Tregs, their stability, and their antigen specificity, have challenged Tregs clinical applicability. In the past decade, the ability to engineer T cells has proven a powerful tool to redirect specificity and function of different cell types for specific therapeutic purposes. By using lentivirus-mediated gene transfer of the thymic-derived Treg transcription factor forkhead-box-P3 (FOXP3 in conventional CD4+ T cells, we converted effector T cells into Treg-like cells, endowed with potent in vitro and in vivo suppressive activity. The resulting CD4FOXP3 T-cell population displays stable phenotype and suppressive function. We showed that this strategy restores Treg function in T lymphocytes from patients carrying mutations in FOXP3 [immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX], in whom CD4FOXP3 T cell could be used as therapeutics to control autoimmunity. Here, we will discuss the potential advantages of using CD4FOXP3 T cells for in vivo application in inflammatory diseases, where tissue inflammation may undermine the function of natural Tregs. These findings pave the way for the use of engineered Tregs not only in IPEX syndrome but also in autoimmune disorders of different origin and in the context of stem cell and organ transplantation.

  1. Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation.

    Science.gov (United States)

    Sackett, S D; Brown, M E; Tremmel, D M; Ellis, T; Burlingham, W J; Odorico, J S

    2016-04-01

    Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. MATERNAL-FETAL TOLERANCE AS A MANIFESTATION OF REGULATORY CONTINUUM AND PLASTICITY OF THEIR IMMUNE SYSTEMS (in memory of I.P. Ashmarin

    Directory of Open Access Journals (Sweden)

    E. P. Kharchenko

    2011-01-01

    Full Text Available Abstract. Relations of immune tolerance between mother and fetus are considered in view of a common regulatory continuum which is formed under the influence of a growing fetus. To explain such an immune tolerance, a notion of immune system plasticity is introduced, as an analogue to the nervous system plasticity, which develops in response to a continuum of changes occurring in fetal and maternal organisms during the nine months of pregnancy. The immune system plasticity in females is supposed to be among possible factors causing collisions upon conception and in the course of pregnancy. (Med. Immunol., 2011, vol. 13, N 2-3, pp 121-132

  3. Allogeneic transplantation following non-myeloablative conditioning in renal carcinoma. New evidence of the immune mechanisms responsible for the activity of this form of immunotherapy and the pathogenetic role of endogenous retroviruses

    Directory of Open Access Journals (Sweden)

    Camillo Porta

    2011-12-01

    Full Text Available In 2000, the influential New England Journal of Medicine published the first impressive results of the use of allogeneic stem cell transplantation following nonmyeloblative conditioning (the so-called ‘mini-allo transplant’ in the treatment of patients with advanced kidney cancer...

  4. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

    Science.gov (United States)

    Yin, Yuan; Cai, Xing; Chen, Xi; Liang, Hongwei; Zhang, Yujing; Li, Jing; Wang, Zuoyun; Chen, Xiulan; Zhang, Wen; Yokoyama, Seiji; Wang, Cheng; Li, Liang; Li, Limin; Hou, Dongxia; Dong, Lei; Xu, Tao; Hiroi, Takachika; Yang, Fuquan; Ji, Hongbin; Zhang, Junfeng; Zen, Ke; Zhang, Chen-Yu

    2014-01-01

    An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. PMID:25223704

  5. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells.

    Science.gov (United States)

    Chow, Lyndah; Johnson, Valerie; Regan, Dan; Wheat, William; Webb, Saiphone; Koch, Peter; Dow, Steven

    2017-12-01

    Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC); as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders. Copyright © 2017. Published by Elsevier B.V.

  6. Human Epidermal Langerhans Cells Maintain Immune Homeostasis in Skin by Activating Skin Resident Regulatory T Cells

    Science.gov (United States)

    Seneschal, Julien; Clark, Rachael A.; Gehad, Ahmed; Baecher-Allan, Clare M.; Kupper, Thomas S.

    2013-01-01

    Recent discoveries indicate that the skin of a normal individual contains 10-20 billion resident memory T cells ( which include various T helper, T cytotoxic, and T regulatory subsets, that are poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LC) selectively and specifically induced the activation and proliferation of skin resident regulatory T cells (Treg), a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LC activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells activation. These underappreciated properties of LC: namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LC in skin. PMID:22560445

  7. Thioredoxin priming prolongs lung allograft survival by promoting immune tolerance.

    Directory of Open Access Journals (Sweden)

    Hanbo Hu

    Full Text Available Tolerance to allograft antigen is the major challenge and final goal of transplant medicine. Our previous study demonstrated that thioredoxin-1 (Trx priming of donor lung significantly protected allogeneic lung graft. To determine whether Trx priming of donor lung inhibits allograft rejection, extends allograft survival and induces immune tolerance, orthotopic left lung transplantation was performed from Lewis to Sprague-Dawley rats without immunosuppression. Donor lungs were primed with Trx at 4°C for 4 hr prior to transplantation. After up to 37 days post-transplantation, allograft lung morphology, recipient T cell and humoral alloantigen-specific immune responses were examined. We found that Trx-primed lungs exhibited much reduced acute rejection and associated lung injuries resulting in loss of graft functional area at 5-37 days post-transplant in contrast to the control groups. CD4+ T cells from the recipients with Trx-primed grafts responded to the stimulation of dendritic cells (DCs of donor origin, in contrast to DCs from the third party, with significantly reduced proliferation. Consistent with above findings, we observed that CD4+Foxp3+ regulatory T cells in spleen cells from the recipients with Trx-primed grafts were significantly increased compared to controls, and CD4+ T cells from the recipients with Trx-primed grafts produced much higher levels of immunosuppressive cytokine, IL-10 when stimulated with allogeneic donor DCs. In addition, humoral immune tolerance was also induced as there was no significant increase levels of serum antibodies against donor antigens in Trx-lung recipients when re-challenged with allogeneic donor antigens. Our results demonstrate that one-time Trx-priming of donor lung grafts prior to transplantation significantly prolongs the survival of the grafts through inducing or promoting cellular and humoral alloantigen-specific immune tolerance, which might be associated with the induction of

  8. Improving engraftment and immune reconstitution in umbilical cord blood transplantation

    Directory of Open Access Journals (Sweden)

    Robert eDanby

    2014-02-01

    Full Text Available Umbilical cord blood (UCB is an important source of haematopoietic stem cells (HSC for allogeneic transplantation when HLA-matched sibling and unrelated donors (MUD are unavailable. Although the overall survival rates of UCB transplantation are comparable to the results with MUD, UCB transplants are associated with slow engraftment, delayed immune reconstitution, and increased opportunistic infections. While this may be a consequence of the lower cell dose in UCB grafts, it also reflects the relative immaturity of cellular immunity within cord blood. Furthermore, the limited number of cells and the non-availability of donor lymphocyte infusions (DLI currently prevent the use of post-transplant cellular immunotherapy to boost donor-derived immunity to treat infection, mixed chimerism and disease relapse. Therefore, to further develop UCB transplantation, many strategies to enhance engraftment and immune reconstitution are currently under investigation. This review summarises our current understanding of engraftment and immune recovery following UCB transplantation and why this differs from allogeneic transplants using other sources of HSC. It also provides an comprehensive overview of the promising techniques being used to improve myeloid and lymphoid recovery, including expansion, homing, and delivery of UCB HSC; combined use of UCB with third party donors; isolation and expansion of NK cells, pathogen specific T cells, and regulatory T cells; methods to protect and/or improve thymopoiesis. As many of these strategies are now in clinical trials, it is anticipated that UCB transplantation will continue to advance, further expanding our understanding of UCB biology and HSC transplantation.

  9. Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

    Directory of Open Access Journals (Sweden)

    Vedran Brezar

    2015-03-01

    Full Text Available The role of regulatory T cells (Tregs in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC loaded with HIV-lipopeptides (LIPO-5-DC vaccine in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs. Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3 before vaccination (week -4 to 2.1% (IQR 1.1-3.9 at week 16 following 4 immunizations (p=0.001 and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001. Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5-DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16 and inversely correlated with HIV-specific IFN-γ-producing cells (r=-0.64, p=0.002. We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI.

  10. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.

    Science.gov (United States)

    Heit, Antje; Gebhardt, Friedemann; Lahl, Katharina; Neuenhahn, Michael; Schmitz, Frank; Anderl, Florian; Wagner, Hermann; Sparwasser, Tim; Busch, Dirk H; Kastenmüller, Kathrin

    2008-06-01

    Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.

  11. A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response.

    Science.gov (United States)

    Ikebuchi, Ryoyo; Teraguchi, Shunsuke; Vandenbon, Alexis; Honda, Tetsuya; Shand, Francis H W; Nakanishi, Yasutaka; Watanabe, Takeshi; Tomura, Michio

    2016-10-19

    Foxp3 + regulatory T cells (Tregs) migrating from the skin to the draining lymph node (dLN) have a strong immunosuppressive effect on the cutaneous immune response. However, the subpopulations responsible for their inhibitory function remain unclear. We investigated single-cell gene expression heterogeneity in Tregs from the dLN of inflamed skin in a contact hypersensitivity model. The immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs. Although Il10-expressing Tregs were rare, unexpectedly, the majority of Il10-expressing Tregs co-expressed Gzmb and displayed Th1-skewing. Single-cell profiling revealed that CD43 + CCR5 + Tregs represented the main subset within the Il10/Gzmb-expressing cell population in the dLN. Moreover, CD43 + CCR5 + CXCR3 - Tregs expressed skin-tropic chemokine receptors, were preferentially retained in inflamed skin and downregulated the cutaneous immune response. The identification of a rare Treg subset co-expressing multiple immunosuppressive molecules and having tissue-remaining capacity offers a novel strategy for the control of skin inflammatory responses.

  12. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation

    Science.gov (United States)

    Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-r...

  13. Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4.

    Science.gov (United States)

    Tietjen, Gregory T; Gong, Zhiliang; Chen, Chiu-Hao; Vargas, Ernesto; Crooks, James E; Cao, Kathleen D; Heffern, Charles T R; Henderson, J Michael; Meron, Mati; Lin, Binhua; Roux, Benot; Schlossman, Mark L; Steck, Theodore L; Lee, Ka Yee C; Adams, Erin J

    2014-04-15

    Recognition of phosphatidylserine (PS) lipids exposed on the extracellular leaflet of plasma membranes is implicated in both apoptotic cell removal and immune regulation. The PS receptor T cell immunoglobulin and mucin-domain-containing molecule 4 (Tim4) regulates T-cell immunity via phagocytosis of both apoptotic (high PS exposure) and nonapoptotic (intermediate PS exposure) activated T cells. The latter population must be removed at lower efficiency to sensitively control immune tolerance and memory cell population size, but the molecular basis for how Tim4 achieves this sensitivity is unknown. Using a combination of interfacial X-ray scattering, molecular dynamics simulations, and membrane binding assays, we demonstrate how Tim4 recognizes PS in the context of a lipid bilayer. Our data reveal that in addition to the known Ca(2+)-coordinated, single-PS binding pocket, Tim4 has four weaker sites of potential ionic interactions with PS lipids. This organization makes Tim4 sensitive to PS surface concentration in a manner capable of supporting differential recognition on the basis of PS exposure level. The structurally homologous, but functionally distinct, Tim1 and Tim3 are significantly less sensitive to PS surface density, likely reflecting the differences in immunological function between the Tim proteins. These results establish the potential for lipid membrane parameters, such as PS surface density, to play a critical role in facilitating selective recognition of PS-exposing cells. Furthermore, our multidisciplinary approach overcomes the difficulties associated with characterizing dynamic protein/membrane systems to reveal the molecular mechanisms underlying Tim4's recognition properties, and thereby provides an approach capable of providing atomic-level detail to uncover the nuances of protein/membrane interactions.

  14. Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    Science.gov (United States)

    Cook, Donald N.; Kang, Hong Soon; Jetten, Anton M.

    2015-01-01

    In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated. PMID:26878025

  15. Retinoic Acid-Related Orphan Receptors (RORs: Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    Directory of Open Access Journals (Sweden)

    Donald N. Cook

    2015-12-01

    Full Text Available In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs. We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated.

  16. Immune Regulatory Effect of Newly Isolated Lactobacillus delbrueckii from Indian Traditional Yogurt.

    Science.gov (United States)

    Hong, Yi-Fan; Lee, Yoon-Doo; Park, Jae-Yeon; Jeon, Boram; Jagdish, Deepa; Jang, Soojin; Chung, Dae Kyun; Kim, Hangeun

    2015-08-01

    Lactic acid bacteria (LAB) are microorganisms that are believed to provide health benefits. Here, we isolated LAB from Indian fermented foods, such as traditional Yogurt and Dosa. LAB from Yogurt most significantly induced TNF-α and IL-1β production, whereas LAB from Dosa induced mild cytokine production. After 16S rRNA gene sequencing and phylogenetic analysis, a Yogurt-borne lactic acid bacterium was identified and classified as Lactobacillus delbrueckii subsp. bulgaricus, and it was renamed L. delbrueckii K552 for the further studies. Our data suggest that the newly isolated L. delbrueckii can be used for the treatment of immune deficiency disorders.

  17. Mesenchymal Stem Cells May Ameliorate Nephrotic Syndrome Post-Allogeneic Hematopoietic Stem Cell Transplantation-Case Report

    Directory of Open Access Journals (Sweden)

    Xin Zhang

    2017-08-01

    Full Text Available IntroductionBecause of their immunomodulatory and anti-inflammatory effects, mesenchymal stem cells (MSCs have been considered as potential therapeutic agents for treating immune-related or autoimmune diseases, such as graft-versus-host disease (GVHD. Nephrotic syndrome (NS after allogeneic hematopoietic stem cell transplantation (allo-HSCT is an uncommon complication with unclear etiology and pathogenesis. It may be an immune disorder involving immune complex deposition, B cells, regulatory T cells (Tregs, and Th1 cytokines and be a manifestation of chronic GVHD. Corticosteroids and calcium antagonists, alone or in combination, are the most common therapeutic agents in this setting. Rituximab is commonly administered as salvage treatment. However, treatment failure and progressive renal function deterioration has been reported to occur in approximately 20% of patients in a particular cohort.Case presentationWe present a patient who developed NS 10 months after allo-HSCT. After treatment failure with cyclosporine A, prednisone, and rituximab, she achieved a complete response with MSC treatment. The clinical improvement of this patient was accompanied by a decreased B cell population together with an increased frequency of regulatory B cells (Bregs and Tregs after MSC treatment.ConclusionMSCs could modulate NS after allo-HSCT by suppressing B cell proliferation, inducing Tregs and Bregs, and inhibiting inflammatory cytokine production by monocytes and NK cells. Among all these, Bregs might play an important role in ameliorating the NS of this patient.

  18. Current issues in allogeneic islet transplantation.

    Science.gov (United States)

    Chang, Charles A; Lawrence, Michael C; Naziruddin, Bashoo

    2017-10-01

    Transplantation of allogenic pancreatic islets is a minimally invasive treatment option to control severe hypoglycemia and dependence on exogenous insulin among type 1 diabetes (T1D) patients. This overview summarizes the current issues and progress in islet transplantation outcomes and research. Several clinical trials from North America and other countries have documented the safety and efficacy of clinical islet transplantation for T1D patients with impaired hypoglycemia awareness. A recently completed phase 3 clinical trial allows centres in the United States to apply for a Food and Drug Administration Biologics License for the procedure. Introduction of anti-inflammatory drugs along with T-cell depleting induction therapy has significantly improved long-term function of transplanted islets. Research into islet biomarkers, immunosuppression, extrahepatic transplant sites and potential alternative beta cell sources is driving further progress. Allogeneic islet transplantation has vastly improved over the past two decades. Success in restoration of glycemic control and hypoglycemic awareness after islet transplantation has been further highlighted by clinical trials. However, lack of effective strategies to maintain long-term islet function and insufficient sources of donor tissue still impose limitations to the widespread use of islet transplantation. In the United States, wide adoption of this technology still awaits regulatory approval and, importantly, a financial mechanism to support the use of this technology.

  19. Antibody responses in allogeneic radiation chimeras

    International Nuclear Information System (INIS)

    Coico, R.F.

    1982-01-01

    The construction of long-lived allogeneic radiation chimeras, free of graft-versus-host disease, has been achieved using serologic elimination of Thy 1 + cells from donor bone marrow. Humoral immune function was not restored in these animals as evidenced by lack of primary antibody responses to a T cell-dependent antigen, namely, sheep erythrocytes (SRBC) both in vivo and in vitro. No evidence for a suppressor cell-mediated mechanism was found. Using separated chimera spleen cell populations and specific helper cell soluble mediators, the functional capabilities of chimera B cells, T cells, and macrophages were assessed. These findings suggested that the failure of chimeras to produce antibody is not the result of impaired B cell, T cell, or macrophage function, but rather, that it is due to ineffective cellular interactions. Physiologic cellular interactions depend upon the sharing of major histocompatibility complex (MHC) determinants between interacting cells. However, the self-recognition repertoire of developing T cells may be influenced by the environment which these cells differentiate such that they learn to recognize host MHC determinants as self. These findings support the interpretation that the immunologic hyporeactivity of allogeneic bone marrow chimeras reflects the role of the host environment in restricting the interactive capabilities of donor-derived cells

  20. [Zinc signaling : a novel regulatory system on bone homeostasis, and immune and allergic responses].

    Science.gov (United States)

    Fukada, Toshiyuki; Nishida, Keigo; Yamasaki, Satoru; Hojyo, Shintaro

    2012-11-01

    Zinc (Zn) is an essential trace element that is required for proliferation, differentiation, and variety of cellular functions, and unbalanced homeostasis of Zn ion (Zn(2 + )) results in health problems such as abnormal bone formation and immunodeficiency. Recent studies have shed light on important roles of Zn(2 + )as a signaling mediator, called Zn signal. Zn(2 + )homeostasis is regulated through Zn transporters and cation channels. Advances of genetic and molecular approaches have revealed that Zn signal regulates mammalian physiology and pathogenesis. We will address that Zn signal undoubtedly contributes to our health, by highlighting it in bone homeostasis and immune regulation, and discuss that the "Zn signal axis" selectively controls intracellular signal transduction to fine-tune cellular functions.

  1. Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.

    Directory of Open Access Journals (Sweden)

    Maria Jesus Iglesias

    Full Text Available Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS.To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches--gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII, which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF, was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines, was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40% was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at

  2. Immuno-regulatory function of indoleamine 2,3 dioxygenase through modulation of innate immune responses.

    Directory of Open Access Journals (Sweden)

    Malihe-Sadat Poormasjedi-Meibod

    Full Text Available Successful long-term treatment of type-1 diabetes mainly relies on replacement of β-cells via islet transplantation. Donor shortage is one of the main obstacles preventing transplantation from becoming the treatment of choice. Although animal organs could be an alternative source for transplantation, common immunosuppressive treatments demonstrate low efficacy in preventing xenorejection. Immunoprotective effects of indoleamine 2,3-dioxygenase (IDO on T-cell mediated allorejection has been extensively studied. Our studies revealed that IDO expression by fibroblasts, induced apoptosis in T-cells while not affecting non-immune cell survival/function. Since macrophages play a pivotal role in xenograft rejection, herein we investigated the effect of IDO-induced tryptophan deficiency/kynurenine accumulation on macrophage function/survival. Moreover, we evaluated the local immunosuppressive effect of IDO on islet-xenograft protection. Our results indicated that IDO expression by bystander fibroblasts significantly reduced the viability of primary macrophages via apoptosis induction. Treatment of peritoneal macrophages by IDO-expressing fibroblast conditioned medium significantly reduced their proinflammatory activity through inhibition of iNOS expression. To determine whether IDO-induced tryptophan starvation or kynurenine accumulation is responsible for macrophage apoptosis and inhibition of their proinflammatory activity, Raw264.7 cell viability and proinflammatory responses were evaluated in tryptophan deficient medium or in the presence of kynurenine. Tryptophan deficiency, but not kynurenine accumulation, reduced Raw264.7 cell viability and suppressed their proinflammatory activity. Next a three-dimensional islet-xenograft was engineered by embedding rat islets within either control or IDO-expressing fibroblast-populated collagen matrix. Islets morphology and immune cell infiltration were then studied in the xenografts transplanted into the C57

  3. Non-pharmacological treatment effects on psychosomatic and immune regulatory mechanisms in patients with rheumatic arthritis

    Directory of Open Access Journals (Sweden)

    Zharikova I.P.

    2014-12-01

    Full Text Available Objective: comparative analysis of the influence of the methods of the lateral ophthalmotilapia and low-intensity magnetic therapy on the Central and peripheral nervous system and the immune status in patients with rheumatoid arthritis. Material and methods: a comparative analysis of the impact of the 44 patients with rheumatoid arthritis aged 18 to 65 years, of which 19 patients (43.2 percent — 1 group received low-frequency low-intensity magnetic therapy and 25 patients (56.8 per cent — group 2, the lateral ophthalmotilapia. Results. In group 1 significantly improved memory both short-term (from 69.2±9.0 to 81,7±12,7, p=0.003, and the reminiscence relating to medium-term characteristics of memory (57,3±22 to 79,0±14,5; p=0.004. In patients of the 2nd group in the course of treatment was observed more pronounced dynamics of improvement of parameters of higher nervous activity, namely short-term memory (79,4±17 to 88,2±12, p=0.003and reminiscences of memory (from 69.4±27 to 82.4±19,5, p=0,0016. Conclusion. Lateral ophthalmotilapia and low-frequency magnetotherapy for help expand the list of rehabilitation programs in rheumatoid arthritis, the disease having dual autoimmune and psychosomatic genesis.

  4. Direct regulatory immune activity of lactic acid bacteria on Der p 1-pulsed dendritic cells from allergic patients.

    Science.gov (United States)

    Pochard, Pierre; Hammad, Hamida; Ratajczak, Céline; Charbonnier-Hatzfeld, Anne-Sophie; Just, Nicolas; Tonnel, André-Bernard; Pestel, Joël

    2005-07-01

    Lactic acid bacteria (LAB) are suggested to play a regulatory role in the development of allergic reactions. However, their potential effects on dendritic cells (DCs) directing the immune polarization remain unclear. The immunologic effect of Lactobacillus plantarum NCIMB 8826 (LAB1) on monocyte-derived dendritic cells (MD-DCs) from patients allergic to house dust mite was evaluated. MD-DCs were stimulated for 24 hours with the related allergen Der p 1 in the presence or absence of LAB1. Cell-surface markers were assessed by means of FACS analysis, and the key polarizing cytokines IL-12 and IL-10 were quantified. The subsequent regulatory effect of pulsed MD-DCs on naive or memory T cells was evaluated by determining the T-cell cytokine profile. LAB1 induced the maturation of MD-DCs, even if pulsed with Der p 1. Interestingly, after incubation with LAB1 and Der p 1, MD-DCs produced higher amounts of IL-12 than Der p 1-pulsed DCs. Indeed, the T H 2 cytokine (IL-4 and IL-5) production observed when naive or memory autologous T cells were cocultured with Der p 1-pulsed MD-DCs was highly reduced in the presence of LAB1. Finally, in contrast to naive or memory T cells exposed once to Der p 1-pulsed DCs, T cells stimulated by MD-DCs pulsed with Der p 1 and LAB1 failed to produce T H 2 cytokines in response to a new stimulation with Der p 1-pulsed DCs. Thus in the presence of LAB1, MD-DCs from allergic patients tend to reorientate the T-cell response toward a beneficial T H 1 profile.

  5. Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis.

    Science.gov (United States)

    Xing, Chen; Ma, Ning; Xiao, He; Wang, Xiaoqian; Zheng, Mingke; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Li, Yan; Wang, Renxi

    2015-03-01

    This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19(+)CD5(+)CD1d(high) B cell subset that may play a critical role in the maintenance of immune homeostasis. Indeed, this population was identified in the murine thymus, and furthermore, when cocultured with CD4(+) T cells, this population of B cells supported the maintenance of CD4(+)Foxp3(+) Tregs in vitro, in part, via the CD5-CD72 interaction. Mice homozygous for Cd19(Cre) (CD19(-/-)) express B cells with impaired signaling and humoral responses. Strikingly, CD19(-/-) mice produce fewer CD4(+)Foxp3(+) Tregs and a greater percentage of CD4(+)CD8(-) and CD4(-)CD8(+) T cells. Consistent with these results, transfer of thymic CD19(+)CD5(+)CD1d(hi) B cells into CD19(-/-) mice resulted in significantly up-regulated numbers of CD4(+)Foxp3(+) Tregs with a concomitant reduction in CD4(+)CD8(-) and CD4(-)CD8(+) T cell populations in the thymus, spleen, and LNs but not in the BM of recipient mice. In addition, thymic CD19(+)CD5(+)CD1d(hi) B cells significantly suppressed autoimmune responses in lupus-like mice via up-regulation of CD4(+)Foxp3(+) Tregs and IL-10-producing Bregs. This study suggests that thymic CD19(+)CD5(+)CD1d(hi)IL-10(+) Bregs play a critical role in the maintenance of immune homeostasis. © Society for Leukocyte Biology.

  6. Natural CD8{sup +}25{sup +} regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yufeng; Zhang, Xueshu; Zhao, Tuo; Li, Wei; Xiang, Jim, E-mail: jim.xiang@saskcancer.ca

    2013-08-16

    Highlights: •CD8{sup +}25{sup +} regulatory T cells secrete tolerogenic exosomes. •CD8{sup +}25{sup +} regulatory T cell-derived exosomes exhibit immunosuppressive effect. •CD8{sup +}25{sup +} regulatory T cell-derived exosomes inhibit antitumor immunity. -- Abstract: Natural CD4{sup +}25{sup +} and CD8{sup +}25{sup +} regulatory T (Tr) cells have been shown to inhibit autoimmune diseases. Immune cells secrete exosomes (EXOs), which are crucial for immune regulation. However, immunomodulatory effect of natural Tr cell-secreted EXOs is unknown. In this study, we purified natural CD8{sup +}25{sup +} Tr cells from C57BL/6 mouse naive CD8{sup +} T cells, and in vitro amplified them with CD3/CD28 beads. EXOs (EXO{sub Tr}) were purified from Tr cell’s culture supernatants by differential ultracentrifugation and analyzed by electron microscopy, Western blot and flow cytometry. Our data showed that EXO{sub Tr} had a “saucer” or round shape with 50–100 nm in diameter, contained EXO-associated markers LAMP-1 and CD9, and expressed natural Tr cell markers CD25 and GITR. To assess immunomodulatory effect, we i.v. immunized C57BL/6 mice with ovalbumin (OVA)-pulsed DCs (DC{sub OVA}) plus Tr cells or EXO{sub Tr}, and then assessed OVA-specific CD8{sup +} T cell responses using PE-H-2K{sup b}/OVA tetramer and FITC-anti-CD8 antibody staining by flow cytometry and antitumor immunity in immunized mice with challenge of OVA-expressing BL6–10{sub OVA} melanoma cells. We demonstrated that DC{sub OVA}-stimulated CD8{sup +} T cell responses and protective antitumor immunity significantly dropped from 2.52% to 1.08% and 1.81% (p < 0.05), and from 8/8 to 2/8 and 5/8 mice DC{sub OVA} (p < 0.05) in immunized mice with co-injection of Tr cells and EXO{sub Tr}, respectively. Our results indicate that natural CD8{sup +}25{sup +} Tr cell-released EXOs, alike CD8{sup +}25{sup +} Tr cells, can inhibit CD8{sup +} T cell responses and antitumor immunity. Therefore, EXOs derived from

  7. Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset.

    Science.gov (United States)

    Dasgupta, Suryasarathi; Kumar, Vipin

    2016-08-01

    Type II natural killer T cells (NKT) are a subset of the innate-like CD1d-restricted lymphocytes that are reactive to lipid antigens. Unlike the type I NKT cells, which express a semi-invariant TCR, type II NKT cells express a broader TCR repertoire. Additionally, other features, such as their predominance over type I cells in humans versus mice, the nature of their ligands, CD1d/lipid/TCR binding, and modulation of immune responses, distinguish type II NKT cells from type I NKT cells. Interestingly, it is the self-lipid-reactivity of type II NKT cells that has helped define their physiological role in health and in disease. The discovery of sulfatide as one of the major antigens for CD1d-restricted type II NKT cells in mice has been instrumental in the characterization of these cells, including the TCR repertoire, the crystal structure of the CD1d/lipid/TCR complex, and their function. Subsequently, several other glycolipids and phospholipids from both endogenous and microbial sources have been shown to activate type II NKT cells. The activation of a specific subset of type II NKT cells following administration with sulfatide or lysophosphatidylcholine (LPC) leads to engagement of a dominant immunoregulatory pathway associated with the inactivation of type I NKT cells, conventional dendritic cells, and inhibition of the proinflammatory Th1/Th17 cells. Thus, type II NKT cells have been shown to be immunosuppressive in autoimmune diseases, inflammatory liver diseases, and in cancer. Knowing their relatively higher prevalence in human than type I NKT cells, understanding their biology is imperative for health and disease.

  8. Epigenetic regulatory pathways involving microRNAs may modulate the host immune response following major trauma.

    Science.gov (United States)

    Owen, Helen C; Torrance, Hew D T; Jones, Timothy F; Pearse, Rupert M; Hinds, Charles J; Brohi, Karim; O'Dwyer, Michael J

    2015-11-01

    Posttraumatic nosocomial pneumonia is a common complication resulting in significant morbidity. Trauma-induced immunocompromise is associated with an enhanced susceptibility to pneumonia. In this study, we explore the hypothesis that posttranscriptional epigenetic regulation of gene expression may be an important factor in determining this immune phenotype. We describe the pattern of production of microRNAss (miRs) and their association with nosocomial pneumonia following severe trauma. A convenience sample of 30 ventilated polytrauma patients ( 5637) and 16 healthy controls were recruited. Messenger RNA and protein levels of key cytokines were quantified within 2 hours of the injury and at 24 hours. Three miRs per cytokine were then selected based on miRBase target prediction scores and quantified using polymerase chain reaction. Nosocomial pneumonia was defined using the Centers for Disease Control and Prevention definitions. Median Injury Severity Score (ISS) was 29, and 47% of the patients developed nosocomial pneumonia. miR-125a and miR-202 decreased by 34% and 77%, respectively, immediately following injury, whereas their target, IL-10, increased messenger RNA levels 3-fold and protein levels 180-fold. Tumor necrosis factor α (TNF-α) and IL-12 gene expression decreased by 68% and 43%, respectively, following injury, and this was mirrored by a 10-fold increase in miR-181, an miR predicted to target TNF-α transcripts. Lower levels of miR-125a and miR-374b were associated with the later acquisition of hospital-acquired pneumonia. Alteration in the expression of miRs with highly predicted complementarity to IL-10 and TNF-α may be an important mechanism regulating the posttraumatic immunosuppressive phenotype in intensive care unit patients. Retrospective observational study, level III.

  9. Allogeneic tumor cell vaccines: the promise and limitations in clinical trials.

    Science.gov (United States)

    Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

    2014-01-01

    The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies.

  10. Immunization in pregnancy clinical research in low- and middle-income countries - Study design, regulatory and safety considerations.

    Science.gov (United States)

    Kochhar, Sonali; Bonhoeffer, Jan; Jones, Christine E; Muñoz, Flor M; Honrado, Angel; Bauwens, Jorgen; Sobanjo-Ter Meulen, Ajoke; Hirschfeld, Steven

    2017-12-04

    Immunization of pregnant women is a promising public health strategy to reduce morbidity and mortality among both the mothers and their infants. Establishing safety and efficacy of vaccines generally uses a hybrid design between a conventional interventional study and an observational study that requires enrolling thousands of study participants to detect an unknown number of uncommon events. Historically, enrollment of pregnant women in clinical research studies encountered many barriers based on risk aversion, lack of knowledge, and regulatory ambiguity. Conducting research enrolling pregnant women in low- and middle-income countries can have additional factors to address such as limited availability of baseline epidemiologic data on disease burden and maternal and neonatal outcomes during and after pregnancy; challenges in recruiting and retaining pregnant women in research studies, variability in applying and interpreting assessment methods, and variability in locally acceptable and available infrastructure. Some measures to address these challenges include adjustment of study design, tailoring recruitment, consent process, retention strategies, operational and logistical processes, and the use of definitions and data collection methods that will align with efforts globally. Copyright © 2017. Published by Elsevier Ltd.

  11. Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.

    Science.gov (United States)

    Ureshino, Hiroshi; Shindo, Takero; Nishikawa, Hiroyoshi; Watanabe, Nobukazu; Watanabe, Eri; Satoh, Natsuko; Kitaura, Kazutaka; Kitamura, Hiroaki; Doi, Kazuko; Nagase, Kotaro; Kimura, Hiromi; Samukawa, Makoto; Kusunoki, Susumu; Miyahara, Masaharu; Shin-I, Tadasu; Suzuki, Ryuji; Sakaguchi, Shimon; Kimura, Shinya

    2016-08-01

    The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Natural CD8+25+ regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma

    International Nuclear Information System (INIS)

    Xie, Yufeng; Zhang, Xueshu; Zhao, Tuo; Li, Wei; Xiang, Jim

    2013-01-01

    Highlights: •CD8 + 25 + regulatory T cells secrete tolerogenic exosomes. •CD8 + 25 + regulatory T cell-derived exosomes exhibit immunosuppressive effect. •CD8 + 25 + regulatory T cell-derived exosomes inhibit antitumor immunity. -- Abstract: Natural CD4 + 25 + and CD8 + 25 + regulatory T (Tr) cells have been shown to inhibit autoimmune diseases. Immune cells secrete exosomes (EXOs), which are crucial for immune regulation. However, immunomodulatory effect of natural Tr cell-secreted EXOs is unknown. In this study, we purified natural CD8 + 25 + Tr cells from C57BL/6 mouse naive CD8 + T cells, and in vitro amplified them with CD3/CD28 beads. EXOs (EXO Tr ) were purified from Tr cell’s culture supernatants by differential ultracentrifugation and analyzed by electron microscopy, Western blot and flow cytometry. Our data showed that EXO Tr had a “saucer” or round shape with 50–100 nm in diameter, contained EXO-associated markers LAMP-1 and CD9, and expressed natural Tr cell markers CD25 and GITR. To assess immunomodulatory effect, we i.v. immunized C57BL/6 mice with ovalbumin (OVA)-pulsed DCs (DC OVA ) plus Tr cells or EXO Tr , and then assessed OVA-specific CD8 + T cell responses using PE-H-2K b /OVA tetramer and FITC-anti-CD8 antibody staining by flow cytometry and antitumor immunity in immunized mice with challenge of OVA-expressing BL6–10 OVA melanoma cells. We demonstrated that DC OVA -stimulated CD8 + T cell responses and protective antitumor immunity significantly dropped from 2.52% to 1.08% and 1.81% (p OVA (p Tr , respectively. Our results indicate that natural CD8 + 25 + Tr cell-released EXOs, alike CD8 + 25 + Tr cells, can inhibit CD8 + T cell responses and antitumor immunity. Therefore, EXOs derived from natural CD4 + 25 + and CD8 + 25 + Tr cells may become an alternative for immunotherapy of autoimmune diseases

  13. Daratumumab depletes CD38sup>+> immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

    DEFF Research Database (Denmark)

    Krejcik, Jakub; Casneuf, Tineke; Nijhof, Inger S

    2016-01-01

    target non-plasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from two daratumumab monotherapy studies were analyzed before and during therapy......Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with cross-linking. These mechanisms may also...... and at relapse. Regulatory B cells (Bregs) and myeloid-derived suppressor cells (MDSCs), previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified...

  14. Activation of counter-regulatory mechanisms in a rat renal acute rejection model

    Directory of Open Access Journals (Sweden)

    Salomon Daniel R

    2008-02-01

    Full Text Available Abstract Background Microarray analysis provides a powerful approach to identify gene expression alterations following transplantation. In patients the heterogeneity of graft specimens, co-morbidity, co-medications and the challenges in sample collection and preparation complicate conclusions regarding the underlying mechanisms of graft injury, rejection and immune regulation. Results We used a rat kidney transplantation model with strict transplant and sample preparation procedures to analyze genome wide changes in gene expression four days after syngeneic and allogeneic transplantation. Both interventions were associated with substantial changes in gene expression. After allogeneic transplantation, genes and pathways related to transport and metabolism were predominantly down-regulated consistent with rejection-mediated graft injury and dysfunction. Up-regulated genes were primarily related to the acute immune response including antigen presentation, T-cell receptor signaling, apoptosis, interferon signaling and complement cascades. We observed a cytokine and chemokine expression profile consistent with activation of a Th1-cell response. A novel finding was up-regulation of several regulatory and protective genes after allogeneic transplantation, specifically IL10, Bcl2a1, C4bpa, Ctla4, HO-1 and the SOCS family. Conclusion Our data indicate that in parallel with the predicted activation of immune response and tissue injury pathways, there is simultaneous activation of pathways for counter regulatory and protective mechanisms that would balance and limit the ongoing inflammatory/immune responses. The pathophysiological mechanisms behind and the clinical consequences of alterations in expression of these gene classes in acute rejection, injury and dysfunction vs. protection and immunoregulation, prompt further analyses and open new aspects for therapeutic approaches.

  15. Dynamics of regulatory T-cells during pregnancy: effect of HIV infection and correlations with other immune parameters.

    Directory of Open Access Journals (Sweden)

    Kelly Richardson

    Full Text Available Regulatory T cells (Treg increase in the context of HIV infection and pregnancy. We studied Treg subpopulations in HIV-infected and uninfected women during pregnancy and their relationship with inflammation, activation and cell-mediated immunity (CMI.Blood obtained from 20 HIV-infected and 18 uninfected women during early and late gestation was used to measure Treg and activated T cells (Tact by flow cytometry; plasma cytokines and inflammatory markers by ELISA and chemoluminescence; and CMI against varicella-zoster virus (VZV by lymphocyte proliferation.Compared with uninfected women, HIV-infected participants had higher frequencies of Treg subpopulations in early pregnancy, including CD4+CD25+FoxP3+%, CD8+CD25+FoxP3+%, CD4+TGFβ+% and CD4+IL10+%. In contrast, Treg frequencies were lower during late pregnancy in HIV-infected compared with uninfected women, including CD8+TGFβ+%, CD4+CTLA4+% and CD8+CTLA4+%. VZV-CMI, which was lower in HIV-infected compared with uninfected pregnant women, was inversely correlated with CD4+FoxP3+%, CD8+FoxP3+% and CD8+TGFβ+% in HIV-infected, but not in uninfected pregnant women. β₂-microglobulin, neopterin, IL1, IL4, IL8, IL10, IFNγ and TNFα plasma concentrations as well as Tact were higher in HIV-infected compared with uninfected women throughout pregnancy. In HIV-infected, but not in uninfected women, inflammatory, Th1, Th2 and regulatory cytokines increased with higher Treg%, suggesting that inflammation and regulation have a common pathophysiologic origin in the context of HIV infection. In HIV-infected and more commonly in uninfected pregnant women, higher Treg% correlated with lower Tact%. We conclude that Treg have different dynamics during pregnancy in HIV-infected and uninfected women. Higher levels of inflammatory cytokines and lower Treg% during late pregnancy in HIV-infected women may contribute to their increased incidence of maternal-fetal morbidity.

  16. Mansonella perstans microfilaremic individuals are characterized by enhanced type 2 helper T and regulatory T and B cell subsets and dampened systemic innate and adaptive immune responses.

    Directory of Open Access Journals (Sweden)

    Manuel Ritter

    2018-01-01

    Full Text Available The filarial nematode Mansonella perstans is endemic throughout Africa, northern South America and the Caribbean. Interestingly, M. perstans-infected individuals present no distinct clinical picture associated with certain pathology. Due to its relatively silent nature, research on this tropical disease has been neglected, especially M. perstans-driven immune responses. A hindrance in obtaining data on M. perstans-specific responses has been the inability to obtain adult worms since their habitats in serous cavities are difficult to access. Thus, in this study, for the first time, we used Mansonella perstans worm antigen extract as stimulant to obtain filarial-specific recall and immunoglobulin responses from M. perstans microfilaremic individuals (Mp MF+ from Cameroon. Moreover, systemic immune profiles in sera and immune cell composition in peripheral blood from Mp MF+ and amicrofilaremic individuals (Mp MF- were obtained. Our data reveal that Mp MF+ individuals showed significantly reduced cytokine (IL-4, IL-6 and IL-12p70 and chemokine levels (IL-8 and RANTES, but significantly higher MIP-1β as well as increased M. perstans-specific IgG4 levels compared to Mp MF- individuals. In contrast, upon re-stimulation with worm antigen extract, IFN-γ, IL-13, IL-10 and IL-17A secretion was enhanced in cell cultures from Mp MF+ individuals when compared to those from cultures of healthy European individuals. Moreover, analysis of immune cell composition in peripheral blood from Mp MF+ individuals revealed increased type 2 helper T (Th2, natural killer (NK, regulatory B and T cell (Breg and Treg subsets but decreased type 1 regulatory T (Tr1 cells. In summary, this study deciphers for the first time, M. perstans-specific immune responses using worm antigen extract and shows that patent M. perstans infections have distinct Th2, Breg and Treg subsets accompanied with reduced systemic innate and adaptive immune responses and dominant filarial-specific Ig

  17. Gene expression profiles of immune-regulatory genes in whole blood of cattle with a subclinical infection of Mycobacterium avium subsp. paratuberculosis.

    Directory of Open Access Journals (Sweden)

    Hyun-Eui Park

    Full Text Available Johne's disease is a chronic wasting disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP, resulting in inflammation of intestines and persistent diarrhea. The initial host response against MAP infections is mainly regulated by the Th1 response, which is characterized by the production of IFN-γ. With the progression of disease, MAP can survive in the host through the evasion of the host's immune response by manipulating the host immune response. However, the host response during subclinical phases has not been fully understood. Immune regulatory genes, including Th17-derived cytokines, interferon regulatory factors, and calcium signaling-associated genes, are hypothesized to play an important role during subclinical phases of Johne's disease. Therefore, the present study was conducted to analyze the expression profiles of immune regulatory genes during MAP infection in whole blood. Different expression patterns of genes were identified depending on the infection stages. Downregulation of IL-17A, IL-17F, IL-22, IL-26, HMGB1, and IRF4 and upregulation of PIP5K1C indicate suppression of the Th1 response due to MAP infection and loss of granuloma integrity. In addition, increased expression of IRF5 and IRF7 suggest activation of IFN-α/β signaling during subclinical stages, which induced indoleamine 2,3-dioxygenase mediated depletion of tryptophan metabolism. Increased expression of CORO1A indicate modulation of calcium signaling, which enhanced the survival of MAP. Taken together, distinct host gene expression induced by MAP infection indicates enhanced survival of MAP during subclinical stages.

  18. [Alternatives to allogenous blood transfusion].

    Science.gov (United States)

    Cernea, Daniela; Vlădoianu, Alice; Stoica, Maria; Novac, M; Berteanu, Cristina

    2009-01-01

    Blood transfusion is usually meant to lower morbidity and mortality rates. Allogenous blood transfusion implies certain risks that can be avoided by autologous blood transfusions techniques including: preoperatory autologous blood donation, acute normovolemic hemodilution, intraoperatory and postoperatory blood salvage. Preoperatory blood donation and acute normovolemic hemodilution are used for planned interventions with an estimated blood loss higher than 20% of blood volume. These methods imply Erythropoietin and iron treatment. Intraoperatory and postoperatory blood salvage is performed by personnel trained in blood donation, handling and storage. Autologous blood transfusions are used for certain surgical procedures that commonly require transfusions: orthopedic surgery, radical prostatectomy, cardiovascular surgery, organ transplantation. An alternative to allogenous blood transfusion is the use of artificial oxygen transporters: human or animal hemoglobin solutions or pefluorocarbonate solutions. These solutions do not require cross reactions, do not carry diseases and are generally well tolerated and easily stored in the operating room, ambulance and other transport means. They have however a slight degree of toxicity.

  19. Allogenic bone grafts in post-traumatic juxta-articular defects: Need for allogenic bone banking.

    Science.gov (United States)

    Mishra, Anil Kumar; Vikas, Rohit; Agrawal, H S

    2017-07-01

    Allogenic bone banking provide both structural and granular bone grafts for various orthopaedic, spinal, oncological and dental surgeries. However allogenic bones, presently, are not readily available. This article discusses the clinical applications of the allogenic grafts, the screening criteria and procedure for maintenance of such a bone banking facility. This article demonstrates the effective role of allogenic bone in a case of post-traumatic bone loss situation and discusses the growing need and present situation of bone banking in our country.

  20. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Jordan, Karina; Pontoppidan, Peter; Uhlving, Hilde Hylland

    2017-01-01

    Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immun...

  1. The risks of using allogeneic cell lines for vaccine production : The example of Bovine Neonatal Pancytopenia

    NARCIS (Netherlands)

    Benedictus, Lindert; Bell, Charlotte R

    2017-01-01

    INTRODUCTION: Bovine neonatal pancytopenia (BNP) is a hemorrhagic disease that emerged in calves across Europe in 2007. Its occurrence is attributed to immunization of the calf's mother with a vaccine produced using an allogeneic cell line. Vaccine-induced alloantibodies specific for

  2. Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells.

    Directory of Open Access Journals (Sweden)

    Nahzli Dilek

    Full Text Available CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs. What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff but inhibition of suppression by regulatory T cells (Tregs, while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.

  3. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

    Directory of Open Access Journals (Sweden)

    Sean D. Owens

    2016-01-01

    Full Text Available Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM or adipose tissue derived MSCs (ad-MSCs were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89% were positive for anti-bovine serum albumin (BSA antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection.

  4. Ex vivo generation of human alloantigen-specific regulatory T cells from CD4(posCD25(high T cells for immunotherapy.

    Directory of Open Access Journals (Sweden)

    Jorieke H Peters

    Full Text Available BACKGROUND: Regulatory T cell (Treg based immunotherapy is a potential treatment for several immune disorders. By now, this approach proved successful in preclinical animal transplantation and auto-immunity models. In these models the success of Treg based immunotherapy crucially depends on the antigen-specificity of the infused Treg population. For the human setting, information is lacking on how to generate Treg with direct antigen-specificity ex vivo to be used for immunotherapy. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that in as little as two stimulation cycles with HLA mismatched allogeneic stimulator cells and T cell growth factors a very high degree of alloantigen-specificity was reached in magnetic bead isolated human CD4(posCD25(high Treg. Efficient increases in cell numbers were obtained. Primary allogeneic stimulation appeared a prerequisite in the generation of alloantigen-specific Treg, while secondary allogeneic or polyclonal stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies enriched alloantigen-specificity and cell yield to a similar extent. CONCLUSIONS/SIGNIFICANCE: The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.

  5. ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells.

    Science.gov (United States)

    Lecciso, Mariangela; Ocadlikova, Darina; Sangaletti, Sabina; Trabanelli, Sara; De Marchi, Elena; Orioli, Elisa; Pegoraro, Anna; Portararo, Paola; Jandus, Camilla; Bontadini, Andrea; Redavid, Annarita; Salvestrini, Valentina; Romero, Pedro; Colombo, Mario P; Di Virgilio, Francesco; Cavo, Michele; Adinolfi, Elena; Curti, Antonio

    2017-01-01

    Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC) cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML), ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs) with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1), was significantly increased. Moving from these results, initial in vitro data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1), which induced anti-leukemia Tregs. These data were confirmed in vivo as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1 + CD39 + DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.

  6. ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Mariangela Lecciso

    2017-12-01

    Full Text Available Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML, ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1, was significantly increased. Moving from these results, initial in vitro data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1, which induced anti-leukemia Tregs. These data were confirmed in vivo as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1+CD39+ DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.

  7. The interaction between regulatory T cells and NKT cells in the liver: a CD1d bridge links innate and adaptive immunity.

    Science.gov (United States)

    Hua, Jing; Liang, Shuwen; Ma, Xiong; Webb, Tonya J; Potter, James P; Li, Zhiping

    2011-01-01

    Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells. The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis. CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury. NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity.

  8. Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells

    Science.gov (United States)

    de Vos, Paul; Mujagic, Zlatan; de Haan, Bart J.; Siezen, Roland J.; Bron, Peter A.; Meijerink, Marjolein; Wells, Jerry M.; Masclee, Ad A. M.; Boekschoten, Mark V.; Faas, Marijke M.; Troost, Freddy J.

    2017-01-01

    Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1) or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT)-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non-steroidal anti-inflammatory drug (NSAID)]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+/Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that might be responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L. plantarum on

  9. Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells

    Directory of Open Access Journals (Sweden)

    Paul de Vos

    2017-08-01

    Full Text Available Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1 or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non-steroidal anti-inflammatory drug (NSAID]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+/Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that might be responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L

  10. In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial.

    Science.gov (United States)

    Adotevi, O; Godet, Y; Galaine, J; Lakkis, Z; Idirene, I; Certoux, J M; Jary, M; Loyon, R; Laheurte, C; Kim, S; Dormoy, A; Pouthier, F; Barisien, C; Fein, F; Tiberghien, P; Pivot, X; Valmary-Degano, S; Ferrand, C; Morel, P; Delabrousse, E; Borg, C

    2018-01-01

    Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.10 6 , 8.10 6 and 12.10 6 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3 + regulatory T cells and PD-1 + T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

  11. Kidney dysfunction after allogeneic stem cell transplantation

    NARCIS (Netherlands)

    Kersting, S.

    2008-01-01

    Allogeneic stem cell transplantation (SCT) is a widely accepted approach for malignant and nonmalignant hematopoietic diseases. Unfortunately complications can occur because of the treatment, leading to treatment-related mortality. We studied kidney dysfunction after allogeneic SCT in 2 cohorts of

  12. Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer

    Directory of Open Access Journals (Sweden)

    Liang S

    2017-08-01

    Full Text Available Shuzhen Liang,1,2 Kecheng Xu,1,2 Lizhi Niu,1,2 Xiaohua Wang,1 Yingqing Liang,1 Mingjie Zhang,3 Jibing Chen,1,2 Mao Lin1,2 1Department of Central Laboratory, Fuda Cancer Hospital, Jinan University School of Medicine, Guangzhou, Guangdong, China; 2Fuda Cancer Institute, Guangzhou, Guangdong, China; 3Hank Bioengineering Co., Ltd, Shenzhen, China Abstract: In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18 and allogeneic NK cells immunotherapy group (group II, n=18. The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3 expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer. Keywords: clinical outcome, autogeneic, allogeneic, natural killer cells, recurrent breast cancer

  13. [Change of CD4(+) CD25(+) regulatory T cells and NK Cells in peripheral blood of children with acute leukemia and its possible significance in tumor immunity].

    Science.gov (United States)

    Wu, Ze-Lin; Hu, Guan-Yu; Chen, Fu-Xiong; Lu, Hui-Min; Wu, Zi-Liang; Li, Hua-Mei; Wei, Feng-Gui; Guan, Jing-Ming; Wu, Li-Ping

    2010-06-01

    This study was purposed to investigate the changes of CD4(+) CD25(+) regulatory T cells and NK cells in peripheral blood of acute leukemia children at different stages, the function of immune system and the possible roles of the CD4(+) CD25(+) regulatory T cells as well as NK cells in leukemia immunity. The number and proportion of CD4(+) CD25(+) regulatory T cells and NK cells were detected by flow cytometry in the peripheral blood of 53 acute leukemia children, including 25 patients in new diagnosis and 28 patients in continuous complete remission (CCR), and were compared with that of 20 normal children. The results indicated that the mean proportion of CD4(+) CD25(+) CD127(+) in CD4(+) T cells of peripheral blood in newly diagnosed patients, patients with CCR and normal children were (9.55 +/- 2.41)%, (8.54 +/- 2.51)% and (6.25 +/- 0.85)% respectively, the mean proportions of CD4(+)CD25(+)CD127(+) in newly diagnosed patients and patients with CCR were higher than that in normal children, the mean proportion of CD4(+)CD25(+)CD127(+) in newly diagnosed patients were higher than that in patients with CCR (p cell count in patients with acute leukaemia decreased as compared with normal control, while after achieving CCR, the NK cell count in patients were also less than that in normal control (4.11 +/- 3.87% and 10.41 +/- 7.20% vs 14.06 +/- 5.95%, p regulatory T cells is a simple, reproductive and accurate method, and the CD4(+) CD25(+) CD127(+) T cells can better reflect the proportion of CD4(+)CD25(+) regulatory T cells. The increase of regulatory T cells and decrease of NK cells in pediatric patients with acute leukemia indicate that the function of NK cells may be depressed. Treg T cells play a role in occurrence and development of leukemia, and are involved in down-regulating NK cell function.

  14. Modulation of allogeneic stimulation in man. I. Characterization of an in vitro induced suppressor macrophage population

    International Nuclear Information System (INIS)

    Stux, S.V.; Dubey, D.P.; Yunis, E.J.

    1981-01-01

    Cultured human peripheral blood mononuclear cells suppressed the allogeneic response of fresh autologous lymphocytes. This suppressor activity developed gradually over a period of one week. The cells primarily responsible for this effect were enriched by Ficoll density gradient centrifugation. It was found that the suppressor cell is a large, low density nylon wool adherent, radioresistant, phagocytic, and nonspecific esterase positive mononuclear cell. Moreover, these cells did not form E rosettes and were Fc positive. Electron microscopy confirmed that suppressor cells were macrophage like. Suppressor activity was not due to cytotoxicity, crowding, or steric hinderance by the cultured cells. The suppressor macrophage population did not appear to inhibit the allogeneic response via prostaglandin or arginase release, or interfere with the tritiated thymidine uptake by release of endogenous thymidine. The above system is viewed as an in vitro model of immune regulation by suppressor macrophages, in the context of allogeneic response

  15. Allogenic bone grafts used at Central Hospital during June 1995 to July 1998

    International Nuclear Information System (INIS)

    Yolchai Jongjirasiri; Yongyudh Vajaradul

    1999-01-01

    Producing and using allogenic bone graft in Thailand began ten years ago. There are approximately 1,000 cases a year on orthopaedic surgery at Central Hospital. For using allogenic bone graft from the Bangkok Biomaterial Center, 66 cases were operated since June 1995. This was generated by 30 in males, 36 in females and by ages between 12-81 years old. After the operation, 43 cases had bone gap from injuries and 19 cases, fusion of spondylolisthesis and scoliosis were done. Four cases had tumor surgery, and 59 out of 66 cases had good bone union that is 89%. Delayed union happened in 6 cases only. Immune response to allogenic bone graft has not been found yet

  16. Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies.

    Science.gov (United States)

    Wiendl, Heinz; Mitsdoerffer, Meike; Schneider, Dagmar; Chen, Lieping; Lochmüller, Hanns; Melms, Arthur; Weller, Michael

    2003-10-01

    B7-H1 is a novel B7 family protein attributed to costimulatory and immune regulatory functions. Here we report that human myoblasts cultured from control subjects and patients with inflammatory myopathies as well as TE671 muscle rhabdomyosarcoma cells express high levels of B7-H1 after stimulation with the inflammatory cytokine IFN-gamma. Coculture experiments of MHC class I/II-positive myoblasts with CD4 and CD8 T cells in the presence of antigen demonstrated the functional consequences of muscle-related B7-H1 expression: production of inflammatory cytokines, IFN-gamma and IL-2, by CD4 as well CD8 T cells was markedly enhanced in the presence of a neutralizing anti-B7-H1 antibody. This observation was paralleled by an augmented expression of the T cell activation markers CD25, ICOS, and CD69, thus showing B7-H1-mediated inhibition of T cell activation. Further, we investigated 23 muscle biopsy specimens from patients with polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM), and nonmyopathic controls for B7-H1 expression by immunohistochemistry: B7-H1 was expressed in PM, IBM, and DM specimens but not in noninflammatory and nonmyopathic controls. Staining was predominantly localized to areas of strong inflammation and to muscle cells as well as mononuclear cells. These data highlight the immune regulatory properties of muscle cells and suggest that B7-H1 expression represents an inhibitory mechanism induced upon inflammatory stimuli and aimed at protecting muscle fibers from immune aggression.

  17. Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.

    Science.gov (United States)

    Singpiel, Alena; Kramer, Julia; Maus, Regina; Stolper, Jennifer; Bittersohl, Lara Friederike; Gauldie, Jack; Kolb, Martin; Welte, Tobias; Sparwasser, Tim; Maus, Ulrich A

    2018-03-01

    Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγ pos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

  18. Ancient duplications and functional divergence in the interferon regulatory factors of vertebrates provide insights into the evolution of vertebrate immune systems.

    Science.gov (United States)

    Du, Kang; Zhong, Zaixuan; Fang, Chengchi; Dai, Wei; Shen, Yanjun; Gan, Xiaoni; He, Shunping

    2018-04-01

    Interferon regulatory factors (IRFs) were first discovered as transcription factors that regulate the transcription of human interferon (IFN)-β. Increasing evidence shows that they might be important players involved in Adaptive immune system (AIS) evolution. Although numbers of IRFs have been identified in chordates, the evolutionary history and functional diversity of this gene family during the early evolution of vertebrates have remained obscure. Using IRF HMM profile and HMMER searches, we identified 148 IRFs in 11 vertebrates and 4 protochordates. For them, we reconstructed the phylogenetic relationships, determined the synteny conservation, investigated the profile of natural selection, and analyzed the expression patterns in four "living fossil" vertebrates: lamprey, elephant shark, coelacanth and bichir. The results from phylogeny and synteny analysis imply that vertebrate IRFs evolved from three predecessors, instead of four as suggested in a previous study, as results from an ancient duplication followed by special expansions and lost during the vertebrate evolution. The profile of natural selection and expression reveals functional dynamics during the process. Together, they suggest that the 2nd whole-genome duplication (2WGD) provided raw materials for innovation in the IRF family, and that the birth of type-I IFN might be an important factor inducing the establishment of IRF-mediated immune networks. As a member involved in the AIS evolution, IRF provide insights into the process and mechanism involved in the complexity and novelties of vertebrate immune systems. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Trichomonas vaginalis α-Actinin 2 Modulates Host Immune Responses by Inducing Tolerogenic Dendritic Cells via IL-10 Production from Regulatory T Cells.

    Science.gov (United States)

    Lee, Hye-Yeon; Kim, Juri; Ryu, Jae-Sook; Park, Soon-Jung

    2017-08-01

    Trichomonas vaginalis is a pathogen that triggers severe immune responses in hosts. T. vaginalis α-actinin 2, Tvα-actinin 2, has been used to diagnose trichomoniasis. This study was undertaken to examine the role of Tvα-actinin 2 as an antigenic molecule to induce immune responses from humans. Western blot analysis using anti-Tvα-actinin 2 antibodies indicated its presence in the secreted proteins of T. vaginalis. ELISA was employed to measure cytokine production by vaginal epithelial cells, prostate cells, mouse dendritic cells (DCs), or T cells stimulated with T. vaginalis or Tvα-actinin 2 protein. Both T. vaginalis and rTvα-actinin 2 induced cytokine production from epithelial cell lines, including IL-10. Moreover, CD4+CD25- regulatory T cells (Treg cells) incubated with rTvα-actinin 2-treated DCs produced high levels of IL-10. These data indicate that Tvα-actinin 2 modulates immune responses via IL-10 production by Treg cells.

  20. The Role of Allogeneic Transplantation in the Treatment of Multiple Myeloma.

    Science.gov (United States)

    Majolino, I

    1998-01-01

    In multiple myeloma (MM) attempts to improve upon the results of standard melphalanpredisone with other conventional dose drug combinations, have generally been unsuccessful, producing only minor improvements in response rate, with little effect on survival. The only treatment capable of producing a dramatic change in response and life expectancy is high-dose chemo-radiotherapy followed by stem cell transplantation. However, after autologous transplant relapse will almost inevitably occur, and freedom from recurrence curves show no plateau in most studies. Besides the resistance of the disease to chemotherapy, another possible explanation is tumor contamination of the graft. This is one major advantage of allogeneic transplantation over autologous, the other being an immune mediated mechanism of tumor suppression in part related to GVHD. Application of allogeneic transplantation to MM has met a number of obstacles, but is now entering a phase of reappraisal, due in part to a tendency to earlier transplantation, in part to the use of novel technologies such as allogeneic peripheral blood stem cells instead of marrow. The goal should be the reduction of transplant related deaths, to better exploit the higher eradication potential of allogeneic cell therapies. The most intriguing perspectives are those related to immune manipulation of recipient and/or donor.

  1. CD4+PD-1+T Cells Acting as Regulatory Cells during the Induction of Anterior Chamber-Associated Immune Devation

    NARCIS (Netherlands)

    Meng, Q.; Yang, P.; Li, B.; Zhou, H.; Huang, X.; Zhu, L.; Ren, Y.; Kijlstra, A.

    2006-01-01

    To study the expression and functional characteristics of programmed death-1 (PD-1) and its ligands in the spleens of mice undergoing anterior chamber-associated immune deviation (ACAID). METHODS: ACAID was induced in BALB/c mice by intracameral injection of ovalbumin (OVA). The expression of PD-1

  2. Proliferation and Differentiation of Autologic and Allogenic Stem Cells in Supralethally X-Irradiated Dogs

    Energy Technology Data Exchange (ETDEWEB)

    Chertkov, I. L. [Department of Radiobiology, Central Institute of Haematology and Blood Transfusion, Moscow, USSR (Russian Federation)

    1967-07-15

    Full text: Allogenic bone marrow after transplantation into dogs irradiated with 1000 R X-rays differentiates in the normal way only for 3-4 days, afterwards transforming into lymphoid cells. This transformation is due to the antigen stimulus of the host on the grafted stem cells. The lymphoid cells, obtained from the host's blood on the 7-8th day after grafting, showed specific, immune activity under the Immune Lymphocyte Transfer test. Within a short duration of the immune response immunoblasts and immunocytes Undergo degenerative changes: destroyed mitochondria, formation of autophagic vacuoles and, finally, lysis of the cells. These changes are suggested to be the result of overloading of immune cells with antigen. Preliminary sensitization of the donor with prospective host's haemopoietic tissue does not hasten the immune transformation of haemopoiesis. Injections of bacterial pyrogen, cortisone or 6-mercaptopurine into recipients, as well as incubation of bone marrow at 37 Degree-Sign C for 2 hours, do not prevent the immune transformation. Preliminary thymectomy of the prospective recipients prevents in some of the cases immune transformation of the bone-marrow graft. The delay of allogenic bone-marrow transplantation for 5-6 days prevents in some dogs (X-irradiated with 1000 R, but not with 1200 R) the immune transformation. Transplantation of autologic bone marrow or shielding of the legs during irradiation is accompanied with good restoration of normal haemopoiesis without lymphoid transformation. (author)

  3. T cell immunity

    OpenAIRE

    Emel Bülbül Başkan

    2013-01-01

    Since birth, our immune system is constantly bombarded with self-antigens and foreign pathogens. To stay healthy, complex immune strategies have evolved in our immune system to maintain self-tolerance and to defend against foreign pathogens. Effector T cells are the key players in steering the immune responses to execute immune functions. While effector T cells were initially identified to be immune promoting, recent studies unraveled negative regulatory functions of effector T cells...

  4. Comparative immune phenotypic analysis of cutaneous Squamous Cell Carcinoma and Intraepidermal Carcinoma in immune-competent individuals: proportional representation of CD8+ T-cells but not FoxP3+ Regulatory T-cells is associated with disease stage.

    Directory of Open Access Journals (Sweden)

    Andrew Freeman

    Full Text Available Squamous Cell Carcinoma (SCC is a type of non-melanoma skin cancer prevalent in immune-suppressed transplant recipients and older individuals with a history of chronic sun-exposure. SCC itself is believed to be a late-stage manifestation that can develop from premalignant lesions including Intraepidermal Carcinoma (IEC. Notably, while SCC regression is rare, IEC typically regresses in response to immune modifying topical treatments, however the underlying immunological reasons for these differential responses remain unclear. This study aimed to define whether IEC and SCC are associated with distinct immune profiles. We investigated the immune cell infiltrate of photo-damaged skin, IEC, and SCC tissue using 10-colour flow cytometry following fresh lesion digest. We found that IEC lesions contain higher percentages of CD3+ T-cells than photo-damaged skin, however, the abundance of CD3-CD56+ Natural Killer (NK cells, CD11c+HLA-DR+ conventional Dendritic Cells (cDC, BDCA-2+HLA-DR+ plasmacytoid DC (pDC, FoxP3+ Regulatory T-cells (T-reg, Vα24+Vβ11+ invariant NKT-cells, and γδ Tcells did not alter with disease stage. Within the total T-cell population, high percentages of CD4+ T-cells were associated with SCC, yet CD8+ T-cells were less abundant in SCC compared with IEC. Our study demonstrates that while IEC lesions contain a higher proportion of T-cells than SCC lesions in general, SCC lesions specifically display a lower abundance of CD8+ T-cells than IEC. We propose that differences in CD8+ T-cell abundance contribute critically to the different capacity of SCC and IEC to regress in response to immune modifying topical treatments. Our study also suggests that a high ratio of CD4+ T-cells to CD8+ T-cells may be a immunological diagnostic indicator of late-stage SCC development in immune-competent patients.

  5. Polymorphism in the 5' upstream regulatory and 3' untranslated regions of the HLA-G gene in relation to soluble HLA-G and IL-10 expression

    DEFF Research Database (Denmark)

    Hviid, Thomas Vauvert F; Rizzo, Roberta; Melchiorri, Loredana

    2006-01-01

    The nonclassical human leukocyte antigen (HLA) class Ib gene HLA-G may be important for the induction and maintenance of immune tolerance between the mother and the semi-allogeneic fetus during pregnancy. Expression of HLA-G can influence cytokine and cytotoxic T-lymphocyte responses. Different HLA......-G peripheral blood mononuclear cells after lipopolysaccharide (LPS) stimulation. This study finds that polymorphism in the 5' upstream regulatory region (5'URR) of the HLA-G gene may also be implicated in differences in IL-10 secretion. However, this may also be due to linkage disequilibrium with the 14-bp...

  6. Allogeneic Peripheral Blood Stem Cell Harvest

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Allogeneic Peripheral Blood Stem Cell Harvest. Mobilization protocol. G-CSF 10 mcg/Kg / day for 5 days. Pheresis. Cobe Spectra; Haemonetics mcs+. Enumeration. CD34 counts; Cfu-GM assays.

  7. Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review.

    Science.gov (United States)

    Pollack, Seth M; O'Connor, Thomas P; Hashash, Jana; Tabbara, Imad A

    2009-12-01

    Allogeneic hematopoietic stem cell transplantation provides many patients, with hematological and malignant diseases, hope of remission and in some cases cure. Because the toxicities of this approach are severe, its use has been limited to younger healthier patients. Nonmyeloablative and reduced intensity conditioning regimens depend more on donor cellular immune effects and less on the cytotoxic effects of the conditioning regimen to eradicate the underlying disease. This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocytes infusions. Accumulated clinical data have been encouraging, and prospective studies are underway to compare this approach to conventional myeloablative allogeneic stem cell transplantation with regard to outcome, durability of responses, effects on the immune system, and the consequences of late complications such as chronic graft-versus-host disease.

  8. Effects of total glucosides of paeony on immune regulatory toll-like receptors TLR2 and 4 in the kidney from diabetic rats.

    Science.gov (United States)

    Xu, Xing-xin; Qi, Xiang-Ming; Zhang, Wei; Zhang, Chao-Qun; Wu, Xiao-Xu; Wu, Yong-Gui; Wang, Kun; Shen, Ji-Jia

    2014-05-15

    TLRs are a family of receptors that play a critical role in the pathogenesis of diabetic nephropathy. TGP have been shown to have anti-inflammatory and immuno-regulatory activities. However, the relation between TGP and TLRs on diabetic nephropathy remains unknown. In this study, we examined effects of TGP on immune regulatory TLR2 and 4 in the kidney from streptozotocin-induced diabetic rats. TGP decreased the levels of 24h urinary albumin excretion rate significantly in diabetic rats. Western blot analysis showed that TGP significantly inhibited the expression of TLR2 and 4, MyD88, p-IRAK1, NF-κB p65, p-IRF3, TNF-α and IL-1β. Quantitative real-time PCR analysis showed that the significantly increased levels of TLR2 and 4, and MyD88mRNA in the kidneys of diabetic rats were significantly suppressed by TGP treatment. Macrophages infiltration were also markedly increased in the kidneys of the diabetic rats, but were significantly inhibited by TGP in a dose-dependent manner. These results suggest that TGP has protective effects on several pharmacological targets in the progress of diabetic nephropathy by selectively blocking TLRs activation in vivo. Copyright © 2013 Elsevier GmbH. All rights reserved.

  9. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

    Science.gov (United States)

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L; Liao, Gongxian; Hoffman, Brad E; Leong, Kam W; Terhorst, Cox; Daniell, Henry; Herzog, Roland W

    2015-04-09

    Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. © 2015 by The American Society of Hematology.

  10. Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Liqing Wang

    2016-11-01

    Full Text Available Foxp3+ T-regulatory (Treg cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or “secondary” modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3+ Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.

  11. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Francesco Orio

    2014-01-01

    Full Text Available Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo- and autologous- (auto- stem cell transplant (HSCT. This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma, gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.

  12. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles

    NARCIS (Netherlands)

    van Noort, J.M.; Bsibsi, M.; Nacken, P.J.; Gerritsen, W.H.; Amor, S.; Holtman, I.R.; Boddeke, E.; van Ark, I.; Leusink-Muis, T.; Folkerts, G.; Hennink, W.E.; Amidi, M.

    2013-01-01

    As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via

  13. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles

    NARCIS (Netherlands)

    van Noort, Johannes M.; Bsibsi, Malika; Nacken, Peter J.; Gerritsen, Wouter H.; Amor, Sandra; Holtman, Inge R.; Boddeke, Erik; van Ark, Ingrid; Leusink-Muis, Thea; Folkerts, Gert; Hennink, Wim E.; Amidi, Maryam

    As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via

  14. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and preeclampsia

    Directory of Open Access Journals (Sweden)

    Peter eHsu

    2014-03-01

    Full Text Available Maternal immune tolerance of the fetus is indispensible for a healthy pregnancy outcome. Nowhere is this immune tolerance more important than at the fetal-maternal interface – the decidua, the site of implantation and placentation. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, preeclampsia. Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. On the other hand, within the adaptive immune system, Foxp3+ regulatory T (Treg cells are crucial for ensuring immune tolerance towards the semi-allogeneic fetus. Additionally, another population of CD4+HLA-G+ suppressor T cells has also been identified as a potential player in the maintenance of immune tolerance. More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy. In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy.

  15. Allogeneic fetal stem cell transplantation to child with psychomotor retardation: A case report

    Directory of Open Access Journals (Sweden)

    Dajić Katerina

    2016-01-01

    Full Text Available Introduction. The consequences of autologous and allogeneic stem cell transplantation (stem cells of hematopoiesis, applied in adults and children suffering from leukemia or some other malignant disease, are well-known and sufficiently recognizable in pediatric clinical practice regardless of the indication for the treatment. However, the efficacy of fetal stem cell transplantation is unrecognizable when the indications are psychomotor retardation and epilepsy. Case Outline. With the exception of neurological psychiatric problems, a boy aged 9.5 years was in good general health before transplantation with allogeneic fetal stem cells. The main aim of allogeneic fetal stem cell transplantation was treatment of psychomotor retardation and epilepsy. After 13 months of treatment, he was admitted to hospital in a very serious, life-threatening condition due to sepsis and severe pleuropneumonia. The humoral immunity in the boy was adequate, unlike cellular immunity. The immune imbalance in terms of predominance of T-suppressor lymphocytes contributes to delayed and late development of sepsis and severe pleuropneumonia. The boy still shows the same severity of psychomotor retardation, dyslalia, epilepsy, strabismus and amblyopia. Conclusion. Implementation of fetal stem cell therapy for unconfirmed indications abuses the therapeutic approach, harms patients, misleads parents, and brings financial harm to the healthcare system of any country, including Serbia.

  16. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses.

    Science.gov (United States)

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G; Davies, Jeffrey K

    2016-07-07

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. © 2016 by The American Society of Hematology.

  17. Alternatives to allogeneic platelet transfusion.

    Science.gov (United States)

    Desborough, Michael J R; Smethurst, Peter A; Estcourt, Lise J; Stanworth, Simon J

    2016-11-01

    Allogeneic platelet transfusions are widely used for the prevention and treatment of bleeding in thrombocytopenia. Recent evidence suggests platelet transfusions have limited efficacy and are associated with uncertain immunomodulatory risks and concerns about viral or bacterial transmission. Alternatives to transfusion are a well-recognised tenet of Patient Blood Management, but there has been less focus on different strategies to reduce bleeding risk by comparison to platelet transfusion. Direct alternatives to platelet transfusion include agents to stimulate endogenous platelet production (thrombopoietin mimetics), optimising platelet adhesion to endothelium by treating anaemia or increasing von Willebrand factor levels (desmopressin), increasing formation of cross-linked fibrinogen (activated recombinant factor VII, fibrinogen concentrate or recombinant factor XIII), decreasing fibrinolysis (tranexamic acid or epsilon aminocaproic acid) or using artificial or modified platelets (cryopreserved platelets, lyophilised platelets, haemostatic particles, liposomes, engineered nanoparticles or infusible platelet membranes). The evidence base to support the use of these alternatives is variable, but an area of active research. Much of the current randomised controlled trial focus is on evaluation of the use of thrombopoietin mimetics and anti-fibrinolytics. It is also recognised that one alternative strategy to platelet transfusion is choosing not to transfuse at all. © 2016 John Wiley & Sons Ltd.

  18. Human embryo immune escape mechanisms rediscovered by the tumor.

    Science.gov (United States)

    Ridolfi, Laura; Petrini, Massimiliano; Fiammenghi, Laura; Riccobon, Angela; Ridolfi, Ruggero

    2009-01-01

    Towards the end of the 1990s, the two opposing theories on immunosurveillance and immunostimulation were extensively studied by researchers in an attempt to understand the complex mechanisms that regulate the relation between tumors and the host's immune system. Both theories probably have elements that would help us to comprehend how the host can induce anti-tumor clinical responses through stimulation of the immune system and which could also give us a deeper insight into the mechanisms of tumor immunosuppression. The model that most resembles the behavior of tumor cells in terms of growth, infiltration and suppression of the immune system of the environment in which they live is undoubtedly that of the embryonic cell. The fetus behaves like an allogenic transplant within the mother's body, using every means it has to escape from and defend itself against the mother's immune system. The majority of these mechanisms are the same as those found in tumor cells: antigenic loss, lack of expression of classic HLA-I molecules, production of immunosuppressive cytokines, induction of lack of expression of co-stimulatory molecules in antigen presenting cells, and induction of apoptosis in infiltrating lymphocytes, with activation of a type Th2 regulatory lymphocyte response. A careful and comparative study of key mechanisms capable of triggering tolerance or cytotoxicity in both embryonic and tumor cells could prove immensely valuable in designing new strategies for anti-tumor immunotherapy.

  19. An immune-modulating diet increases the regulatory T cells and reduces T helper 1 inflammatory response in Leishmaniosis affected dogs treated with standard therapy.

    Science.gov (United States)

    Cortese, Laura; Annunziatella, Mariangela; Palatucci, Anna Teresa; Lanzilli, Sarah; Rubino, Valentina; Di Cerbo, Alessandro; Centenaro, Sara; Guidetti, Gianandrea; Canello, Sergio; Terrazzano, Giuseppe

    2015-12-03

    Clinical appearance and evolution of Canine Leishmaniosis (CL) are the consequence of complex interactions between the parasite and the genetic and immunological backgrounds. We investigated the effect of an immune-modulating diet in CL. Dogs were treated with anti- Leishmania pharmacological therapy combined with standard diet (SD Group) or with the immune-modulating diet (IMMD Group). CD3+ CD4+ Foxp3+ Regulatory T cells (Treg) and CD3+ CD4+ IFN-γ + T helper 1 (Th1) were analyzed by flow cytometry. All sick dogs showed low platelet number at diagnosis (T0). A platelet increase was observed after six months (T6) SD Group, with still remaining in the normal range at twelve months (T12). IMMD Group showed an increase in platelet number becoming similar to healthy dogs at T6 and T12. An increase of CD4/CD8 ratio was revealed in SD Group after three months (T3), while at T6 and at T12 the values resembled to T0. The increase in CD4/CD8 ratio at T3 was maintained at T6 and T12 in IMMD Group. A reduction in the percentage of Treg of all sick dogs was observed at T0. A recovery of Treg percentage was observed only at T3 in SD Group, while this effect disappeared at T6 and T12. In contrast, Treg percentage became similar to healthy animals in IMDD Group at T3, T6 and T12. Sick dogs showed an increase of Th1 cells at T0 as compared with healthy dogs. We observed the occurrence of a decrease of Th1 cells from T3 to T12 in SD Group, although a trend of increase was observed at T6 and T12. At variance, IMMD Group dogs showed a progressive decrease of Th1 cells, whose levels became similar to healthy controls at T6 and T12. The immune-modulating diet appears to regulate the immune response in CL during the standard pharmacological treatment. The presence of nutraceuticals in the diet correlates with the decrease of Th1 cells and with the increase of Treg in sick dogs. Therefore, the administration of the specific dietary supplement improved the clinical response to the

  20. G-CSF-primed BM for allogeneic SCT: revisited.

    Science.gov (United States)

    Pessach, I; Resnick, I; Shimoni, A; Nagler, A

    2015-07-01

    G-SCF-mobilized PBSC (GPB) grafts have a higher cell dose and somewhat more committed progenitor cells than steady-state BM (SBM), resulting in faster engraftment and faster immunological reconstitution. On the other hand, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) are similar both for PB and for BM. In contrast to SBM, G-CSF-primed BM (GBM) grafts stimulate HSC proliferation, increasing cell dose and thus resulting in faster engraftment because of higher cell dose infused, or because of treatment with G-CSF. Furthermore, GBM may induce tolerance and functional modulations in donor hematopoiesis and immunity, further reducing GVHD incidence, which is already lower with SBM compared with GPB grafts. Overall, a growing body of clinical evidence suggests that GBM transplants may share the advantages of GPB transplantations, without the associated increased risk of GVHD, and might be an attractive graft source for allogeneic SCTs.

  1. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

    Science.gov (United States)

    Ustun, Celalettin; Miller, Jeffrey S; Munn, David H; Weisdorf, Daniel J; Blazar, Bruce R

    2011-11-10

    The microenviroment of acute myelogenous leukemia (AML) is suppressive for immune effector cells. Regulatory T cells (Tregs) have been recognized as a contributor factor and may be recruited and exploited by leukemic cells to evade immunesurveillance. Studies have shown that the frequencies of marrow and blood Tregs are greater in patients with AML than in control patients. Although increased Tregs have been associated with a decreased risk of GVHD after allogeneic HCT and hence may impede the graft-versus-tumor effect, recent findings indicate that that this may not be the case. Because there is a need to improve outcomes of standard treatment (chemotherapy with or without allogeneic HCT) in AML, targeting Tregs present an outstanding opportunity in AML because discoveries may apply throughout its treatment. Here, we review data on the roles of Tregs in mediating immune system-AML interactions. We focused on in vitro, animal, and observational human studies of Tregs in AML biology, development, prognosis, and therapy in different settings (eg, vaccination and HCT). Manipulation of Tregs or other types of immunomodulation may become a part of AML treatment in the future.

  2. Transplantation of Allogeneic PW1pos/Pax7neg Interstitial Cells Enhance Endogenous Repair of Injured Porcine Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Fiona C. Lewis, BSc, PhD

    2017-12-01

    Full Text Available Skeletal muscle-derived PW1pos/Pax7neg interstitial cells (PICs express and secrete a multitude of proregenerative growth factors and cytokines. Utilizing a porcine preclinical skeletal muscle injury model, delivery of allogeneic porcine PICs (pPICs significantly improved and accelerated myofiber regeneration and neocapillarization, compared with saline vehicle control-treated muscles. Allogeneic pPICs did not contribute to new myofibers or capillaries and were eliminated by the host immune system. In conclusion, allogeneic pPIC transplantation stimulated the endogenous stem cell pool to bring about enhanced autologous skeletal muscle repair and regeneration. This allogeneic cell approach is considered a cost-effective, easy to apply, and readily available regenerative therapeutic strategy.

  3. TGF-β1 exerts opposing effects on grass carp leukocytes: implication in teleost immunity, receptor signaling and potential self-regulatory mechanisms.

    Directory of Open Access Journals (Sweden)

    Mu Yang

    Full Text Available In fish immunity, the regulatory role of transforming growth factor-β1 (TGF-β1 has not been fully characterized. Here we examined the immunoregulatory effects of TGF-β1 in grass carp peripheral blood leukocytes (PBL and head kidney leukocytes (HKL. It is interesting that TGF-β1 consistently stimulated the cell viability and the mRNA levels of pro-inflammatory cytokines (Tnfα and Ifnγ and T/B cell markers [Cd4-like (Cd4l, Cd8α, Cd8β and Igμ] in PBL, which contrasted with its inhibitory tone in HKL. Further studies showed that grass carp TGF-β1 type I receptor, activin receptor-like kinase 5 (ALK5, was indispensable for the immunoregulatory effects of TGF-β1 in PBL and HKL. Notably, TGF-β1 persistently attenuated ALK5 expression, whereas immunoneutralization of endogenous grass carp TGF-β1 could increase ALK5 mRNA and protein levels. It is consistent with the observation that TGF-β1 decreased the number of ALK5(+ leukocytes in PBL and HKL, revealing a negative regulation of TGF-β1 signaling at the receptor level. Moreover, transient treatment with TGF-β1 for 24 h was sufficient to induce similar cellular responses compared with the continuous treatment. This indicated a possible mechanism by which TGF-β1 triggered the down-regulation of ALK5 mRNA and protein, leading to the desensitization of grass carp leukocytes toward TGF-β1. Accordingly, our data revealed a dual role of TGF-β1 in teleost immunity in which it can serve as a positive or negative control device and provided additional mechanistic insights as to how TGF-β1 controls its signaling in vertebrate leukocytes.

  4. Anti-regulatory T cells

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2017-01-01

    responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells......Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...

  5. Tissues Expression, Polymorphisms of IFN Regulatory Factor 6 (IRF6 Gene and Their Associated with Immune Traits in Three Pig Populations

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2012-02-01

    Full Text Available Interferon regulatory factor 6 (IRF6 gene is a member of the IRF-family, and plays functionally diverse roles in the regulation of the immune system. In this report, the 13,720 bp porcine IRF6 genomic DNA structure was firstly identified with a putative IRF6 protein of 467 amino acids. Alignment and phylogenetic analysis of the porcine IRF6 amino acid sequences with their homologies to other species showed high identity (over 96%. Tissues expression of IRF6 mRNA was observed by RT-PCR, the results revealed IRF6 expressed widely in eight tissues. One SNP (HQ026023:1383 G>C in exon7 and two SNPs (HQ026023:130 G>A; 232 C>T in the 5 ′ promoter region of porcine IRF6 gene were demonstrated b y DNA sequencing analysis. A further analysis of SNP genotypes associated with immune traits including IFN-γ and IL10 concentrations in serum was carried out in three pig populations including Large White, Landraces and Songliao Black pig (a Chinese indigenous breed. The results showed that the SNP (HQ026023:1383 G>C was significantly associated with the level of IFN-γ (d 20 in serum (p = 0.038 and the ratio of IFN-γ to IL10 (d 20 in serum (p = 0.041; The other two SNPs (HQ026023:130 G>A; 232 C>T were highly significantly associated with IL10 level in serum both at the day 20 (p = 0.005; p = 0.001 and the day 35 (p = 0.004; p = 0.006. Identification of the porcine IRF6 gene will help our further understanding of the molecular basis of the IFN regulation pathway in the porcine immune response. All these results should indicate that the IRF6 gene can be regarded as a molecular marker associated with the IL10 level in serum and used for genetic selection in the pig breeding.

  6. T-regulatory cells depletion is the main cause for enhanced antitumor immunity during radio-sensitization of tumors by 2-deoxy-D-glucose

    International Nuclear Information System (INIS)

    Farooque, Abdullah; Verma, Amit; Singh, Niharika; Chauhan, Sachin Kumar Singh; Jethani, Jyoti; Adhikari, J.S.; Dwarakanath, B.S.; Afrin, Farhat

    2014-01-01

    Regulatory T cells (Tregs) are known to have profound effects in blocking anti-tumor immunity. Therefore, Tregs are seen as a major hurdle that must be overcome in order to improve the efficacy of cancer therapy. The glycolytic inhibitor, 2-deoxy-d-glucose (2-DG) enhances radiation and chemotherapeutics induced death of many cancer cells in vitro and local tumor control in vivo, which was found to be associated with the enhanced anti-tumor immunity. Therefore, we investigated the role of Tregs in determining the tumor response to the combined treatment of 2-DG plus ionizing radiation. Ehrlich ascites tumor bearing mice were administered with a single dose of 2-DG (2 gm/Kg/b.wt) intravenously just before focal irradiation (10 Gy). Immuno-phenotyping of Tregs in secondary lymphoid organs was carried out using flow cytometry, while related cytokines were analyzed using bead array and ELISA. Further, mRNA and protein levels of transcription factors were assessed in sorted splenic CD4 + cells and CD4 + CD25 + using real time PCR and Western blot techniques. Results clearly showed depletion (TRAIL mediated apoptosis) of T regs (CD4 + CD25 + FoxP3 + CD39 + FR4 + GITR + CD127 - ), in blood, spleen, lymph node and tumor following the combined treatment. This led to the immune activation in the periphery, secondary lymphoid organs and massive infiltration of CD4 + , CD8 + and NK cells in the tumor, which correlated well with the complete response (cure; tumor free survival). Association of Treg depletion with the tumor response was further confirmed using low doses of cyclophosphamide (which depletes Tegs) and rapamycin (activator of Tregs),wherein the depletor of Tregs enhanced the efficacy of combined treatment, while Tregs enhancer compromised the efficacy. These studies unequivocally established the role of Tregs in determining the therapeutic response and can be used as a target for enhancing the efficacy of this combined treatment, besides establishing the potential of

  7. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Luca Laurenti

    2010-08-01

    Full Text Available Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment. Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%: A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity. The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients. Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

  8. Chondrocytic Potential of Allogenic Mesenchymal Stem Cells Transplanted without Immunosuppression to Regenerate Physeal Defect in Rabbits

    Directory of Open Access Journals (Sweden)

    P. Gál

    2007-01-01

    Full Text Available Mesenchymal stem cells (MSCs from bone marrow are multipotent cells capable of forming cartilage, bone, and other connective tissues. The objective of this study was to determine whether the use of allogenic mesenchymal stem cells could functionally heal a defect in the distal femoral physis in rabbits without the use of immunosuppressive therapy. A iatrogenic defect was created in the lateral femoral condyle of thirty-two New Zealand white rabbits, 7 weeks old, weighing 2.25 ± 0.24 kg. Each defect, 3.5 mm in width and 12 mm in length, in the right distal femoral physis was treated with allogenic mesenchymal stem cells in new composite hyaluronate/collagen type I/fibrin scaffold. The healing response was evaluated radiographically, by MRI (three weeks and four months after implantation and also histologically, by Pearl’s reaction and with immunofluorescence (four months after implantation. The results were compared with the data for the control defects (without stem cell implantation in left distal femoral physes. On average, right femurs with a damaged distal physis and transplanted MSCs grew more in length (0.55 ± 0.21 cm compared with left femurs with a physeal defect without stem cell transplantation (0.46 ± 0.23 cm. Valgus deformity of right femurs with a physeal defect and transplanted MSCs was mild (0.2 ± 0.1 °. On the contrary, left femurs with a physeal defect without transplanted MSCs showed a significant valgus deformity (2.7 ± 1.6 °. For defects treated with allogenic mesenchymal stem cell implants, no adverse immune response and implant rejection were detected in this model. Histologically, no lymphocytic infiltration occurred. At four months after transplantation, hyaline cartilage had formed throughout the defects treated with allogenic MSCs. Labelled mesenchymal stem cells/differentiated chondrocytes were detected in the physeal defects based on magnetic resonance imaging and immunofluorescence. The results of this study

  9. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo

    International Nuclear Information System (INIS)

    Lee, Miyoung; Jeong, Sang Young; Ha, Jueun; Kim, Miyeon; Jin, Hye Jin; Kwon, Soon-Jae; Chang, Jong Wook; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Kim, Jae-Sung; Jeon, Hong Bae

    2014-01-01

    Highlights: • hUCB-MSCs maintained low immunogenicity even after immune challenge in vitro. • Humanized NSG mice were established using human UCB CD34+ cells. • Repeated intravenous hUCB-MSC injection into mice did not lead to immune responses and adverse events. • Allogeneic hUCB-MSCs maintained low immunogenicity in vitro and in vivo. - Abstract: Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore “immunologically safe” for use in allogeneic clinical applications

  10. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Miyoung; Jeong, Sang Young; Ha, Jueun; Kim, Miyeon; Jin, Hye Jin; Kwon, Soon-Jae [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of); Chang, Jong Wook [Research Institute for Future Medicine Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Seoul 137-710 (Korea, Republic of); Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of); Kim, Jae-Sung [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-709 (Korea, Republic of); Jeon, Hong Bae, E-mail: jhb@medi-post.co.kr [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of)

    2014-04-18

    Highlights: • hUCB-MSCs maintained low immunogenicity even after immune challenge in vitro. • Humanized NSG mice were established using human UCB CD34+ cells. • Repeated intravenous hUCB-MSC injection into mice did not lead to immune responses and adverse events. • Allogeneic hUCB-MSCs maintained low immunogenicity in vitro and in vivo. - Abstract: Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore “immunologically safe” for use in allogeneic clinical applications.

  11. Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation

    Directory of Open Access Journals (Sweden)

    Maribel Marquina

    2017-11-01

    Full Text Available Xenogeneic chondrocytes and allogeneic mesenchymal stem cells (MSC are considered a potential source of cells for articular cartilage repair. We here assessed the immune response triggered by xenogeneic chondrocytes when injected intraarticularly, as well as the immunoregulatory effect of allogeneic bone marrow-derived MSC after systemic administration. To this end, a discordant xenotransplantation model was established by injecting three million porcine articular chondrocytes (PAC into the femorotibial joint of Lewis rats and monitoring the immune response. First, the fate of MSC injected using various routes was monitored in an in vivo imaging system. The biodistribution revealed a dependency on the injection route with MSC injected intravenously (i.v. succumbing early after 24 h and MSC injected intraperitoneally (i.p. lasting locally for at least 5 days. Importantly, no migration of MSC to the joint was detected in rats previously injected with PAC. MSC were then administered either i.v. 1 week before PAC injection or i.p. 3 weeks after to assess their immunomodulatory function on humoral and adaptive immune parameters. Anti-PAC IgM and IgG responses were detected in all PAC-injected rats with a peak at week 2 postinjection and reactivity remaining above baseline levels by week 18. IgG2a and IgG2b were the predominant and long-lasting IgG subtypes. By contrast, no anti-MSC antibody response was detected in the cohort injected with MSC only, but infusion of MSC before PAC injection temporarily augmented the anti-PAC antibody response. Consistent with a cellular immune response to PAC in PAC-injected rats, cytokine/chemokine profiling in serum by antibody array revealed a distinct pattern relative to controls characterized by elevation of multiple markers at week 2, as well as increases in proliferation in draining lymph nodes. Notably, systemic administration of allogeneic MSC under the described conditions did not diminish the immune

  12. Gender-Dependent Survival of Allogeneic Trophoblast Stem Cells in Liver

    Science.gov (United States)

    Epple-Farmer, Jessica; Debeb, Bisrat G.; Smithies, Oliver; Binas, Bert

    2012-01-01

    In view of the well-known phenomenon of trophoblast immune privilege, trophoblast stem cells (TSCs) might be expected to be immune privileged, which could be of interest for cell or gene therapies. Yet in the ectopic sites tested so far, TSC transplants fail to show noticeable immune privilege and seem to lack physiological support. However, we show here that after portal venous injection, green fluorescent protein (GFP)-labeled TSCs survive for several months in the livers of allogeneic female but not male mice. Gonadectomy experiments revealed that this survival does not require the presence of ovarian hormones but does require the absence of testicular factors. By contrast, GFP-labeled allogeneic embryonic stem cells (ESCs) are reliably rejected; however, these same ESCs survive when mixed with unlabeled TSCs. The protective effect does not require immunological compatibility between ESCs and TSCs. Tumors were not observed in animals with either successfully engrafted TSCs or coinjected ESCs. We conclude that in a suitable hormonal context and location, ectopic TSCs can exhibit and confer immune privilege. These findings suggest applications in cell and gene therapy as well as a new model for studying trophoblast immunology and physiology. PMID:19523327

  13. Identification of orange-spotted grouper (Epinephelus coioides) interferon regulatory factor 3 involved in antiviral immune response against fish RNA virus.

    Science.gov (United States)

    Huang, Youhua; Huang, Xiaohong; Cai, Jia; OuYang, Zhengliang; Wei, Shina; Wei, Jingguang; Qin, Qiwei

    2015-02-01

    Interferon regulatory factor 3 (IRF3) is an important transcription factor which regulates the expression of interferon (IFN) and IFN-stimulated genes (ISGs) following virus recognition. In this study, a novel IRF3 gene was cloned from grouper Epinephelus coioides (EcIRF3) and its effects against Singapore grouper iridovirus (SGIV) and red spotted grouper nervous necrosis virus (RGNNV) was investigated. The full-length of EcIRF3 cDNA was composed of 2513 bp and encoded a polypeptide of 458 amino acids which shared 82% identity with European seabass (Dicentrarchus labrax). EcIRF3 contained three conserved domains including a DNA-binding domain (DBD), an IRF associated domain (IAD) and a serine-rich domain. Expression profile analysis revealed that EcIRF3 was abundant in head kidney, kidney, spleen and gill. Upon different stimuli in vitro, the transcript of EcIRF3 was significantly up-regulated after RGNNV infection or treatment with polyinosin-polycytidylic acid (poly I:C). During SGIV infection, the increase of the EcIRF3 transcription was only detected at the late stage, suggesting that EcIRF3 was differently regulated by different stimuli. Immune fluorescence assay indicated that the fluorescence signal of EcIRF3 was increased significantly after infection with RGNNV or treatment with poly I:C, but moderately at the late stage of SGIV infection. Reporter gene assay showed that EcIRF3 activated zebrafish type I IFN and type III IFN promoter in vitro. The viral gene transcription and virus production of RGNNV were significantly decreased in EcIRF3 overexpressing cells. However, the ectopic expression of EcIRF3 did not affect the gene transcription and virus production of SGIV. Moreover, the mRNA expression levels of type I IFN and IFN-inducible genes (MxI, ISG15 and ISG56) were increased in RGNNV infected EcIRF3 overexpressing cells compared to empty vector transfected cells. Together, our results demonstrated that IFN immune response mediated by grouper IRF3 was

  14. АВ0-INCOMPATIBILITY IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: 15-YEARS EXPERIENCE OF R.M. GORBACHEVA MEMORIAL RESEARCH INSTITUTE FOR CHILDREN ONCOLOGY, HEMATOLOGY AND TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    M. A. Kucher

    2016-01-01

    Full Text Available Introduction. AB0-incompatibility in different types of allogeneic hematopoietic stem cell transplantation (HSCT may be an additional aggravating factor for the development of immunological complications and decrease treatment efficacy.Materials and methods. From May 1999 to December 2015 in R.M. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation 1131 patients with malignancies and hereditary diseases were included to the study, which were performed 1428 allogeneic HSCT: allogeneic unrelated – 814 (57.0 %, allogeneic related – 344 (24.1 %, haploidentical – 267 (18.7 %, umbilical cord blood in 3 patients (0.2 %. Age was 0–76 years, median – 25 years.Results. In 54.6 % of cases (n = 780 АВ0-incompatibility was determined: major – 37.8 % (n = 295; minor – 45.4 % (n = 354; combined – 16.8 % (n = 131. АВ0-incompatibility in allogeneic HSCT did not influence overall survival (p = 0.56, frequency of acute graftversus-host disease (GVHD (p = 0.2. There was an increased frequency of acute GVHD in combination with reduced intensity conditioning regimens and АВ0-incompatibility (30.8 % compared with myeloablative regimens (15.3 %; p = 0.002.Conclusion. The presence of АВ0-incompatibility is not a limiting factor to perform allogeneic HSCT, however, it demands high quality prophylaxis and sophisticated transfusion therapy to prevent immune complications.

  15. Clostridium butyricum CGMCC0313.1 Protects against Autoimmune Diabetes by Modulating Intestinal Immune Homeostasis and Inducing Pancreatic Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Lingling Jia

    2017-10-01

    Full Text Available Recent evidence indicates that indigenous Clostridium species induce colonic regulatory T cells (Tregs, and gut lymphocytes are able to migrate to pancreatic islets in an inflammatory environment. Thus, we speculate that supplementation with the well-characterized probiotics Clostridium butyricum CGMCC0313.1 (CB0313.1 may induce pancreatic Tregs and consequently inhibit the diabetes incidence in non-obese diabetic (NOD mice. CB0313.1 was administered daily to female NOD mice from 3 to 45 weeks of age. The control group received an equal volume of sterile water. Fasting glucose was measured twice a week. Pyrosequencing of the gut microbiota and flow cytometry of mesenteric lymph node (MLN, pancreatic lymph node (PLN, pancreatic and splenic immune cells were performed to investigate the effect of CB0313.1 treatment. Early oral administration of CB0313.1 mitigated insulitis, delayed the onset of diabetes, and improved energy metabolic dysfunction. Protection may involve increased Tregs, rebalanced Th1/Th2/Th17 cells and changes to a less proinflammatory immunological milieu in the gut, PLN, and pancreas. An increase of α4β7+ (the gut homing receptor Tregs in the PLN suggests that the mechanism may involve increased migration of gut-primed Tregs to the pancreas. Furthermore, 16S rRNA gene sequencing revealed that CB0313.1 enhanced the Firmicutes/Bacteroidetes ratio, enriched Clostridium-subgroups and butyrate-producing bacteria subgroups. Our results provide the basis for future clinical investigations in preventing type 1 diabetes by oral CB0313.1 administration.

  16. Allogeneic radiation chimeras induced in SPF mice

    International Nuclear Information System (INIS)

    Sado, Toshihiko; Kamisaku, Hitoko

    1977-01-01

    During the past two decades much has been learned concerning the immunobiology of bone marrow chimeras induced in experimental animals as well as in man. However, from the basic as well as clinical points of view, there still remain many unsolved questions yet to be resolved. In this presentation, we discussed some of our recent results on the immunobiology of radiation chimeras induced in specific-pathogen-free (SPF) mice. These included the following: (a) contribution of graft versus host reaction (GVHR) as well non- GVHR mediated immunologic mechanism(s) to the expression of immunologic dysfunctions observed in allogeneic and certain semiallogeneic chimeras, (b) existence of immunoregulatory mechanism as a basis for the apparent lack of immunologic reactivity (tolerance) to the host- as well as to the donor-type alloantigens in situ in successful allogeneic bone marrow chimeras, and (c) the effect of microflora of the environment on the stability of such immunoregulatory mechanisms and its possible mechanism of action. (auth.)

  17. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Patrizia Chiusolo

    2010-05-01

    Full Text Available

    Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.

    Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%:

    A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity.

    The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.

    Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

     

  18. Influence of HLA Matching on the Efficacy of Allogeneic Mesenchymal Stromal Cell Therapies for Osteoarthritis and Degenerative Disc Disease

    Directory of Open Access Journals (Sweden)

    Javier García-Sancho, MD, PhD

    2017-09-01

    Conclusions. This lack of reactivity is presumably due to the cooperation of 2 factors, (1 downregulation of the host immune responses by the transplanted MSCs and (2 effective insulation of these cells inside the articular cavity or the intervertebral disc, respectively. Interestingly, better HLA matching did not enhance efficacy. These observations have medical relevance as they support the clinical use of allogeneic cells, at least as a single-dose administration. Multiple-dose applications will require further research to exclude possible sensitization.

  19. Late taste disorders in bone marrow transplantation: clinical evaluation with taste solutions in autologous and allogeneic bone marrow recipients.

    Science.gov (United States)

    Marinone, M G; Rizzoni, D; Ferremi, P; Rossi, G; Izzi, T; Brusotti, C

    1991-01-01

    The aim of this work was to determine the type and the significance of taste disorders in allogeneic bone marrow transplanted patients. In a retrospective study the taste threshold of a cohort of 15 allogeneic bone marrow transplanted patients, 4-51 months after transplantation (mean: 30.6 +/- 15.8), was compared to the taste threshold of 8 autologous bone marrow recipients, 4-48 months after transplantation (mean: 24.12 +/- 12.18), and to the taste threshold of a group of 20 consecutive normal subjects. Allogeneic bone marrow transplanted patients showed a significant hypogeusia for salt (Pearson's chi square p = 0.0002; Yates' correction p = 0.0007) and sour (Pearson's chi square p = 0.001; Yates' correction p = 0.008). No significant variations were observed for sweet and bitter. Autologous bone marrow recipients did not show any significant variation of taste acuity for sweet, salt or sour; a constant reduction of the taste threshold for bitter was observed, but the values were not significantly different from normal (Pearson's chi square p = 0.47; Yates' correction p = 0.83). So, late and selective taste disorders are observed in allogeneic bone marrow transplanted patients. Since the severity of the disorders is not strictly related to the severity of chronic oral G.V.H.D., taste analysis could discover the slightest, clinically undetectable cases of chronic oral G.V.H.D. The mechanism of immune aggression on the sensorial taste cells is poorly understood. Further trials are needed to define variations of taste acuity not only after allogeneic bone marrow transplantation, but also in systemic immune diseases.

  20. Imbalanced immune homeostasis in immune thrombocytopenia.

    Science.gov (United States)

    Yazdanbakhsh, Karina

    2016-04-01

    Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder resulting from low platelet counts caused by inadequate production as well as increased destruction by autoimmune mechanisms. As with other autoimmune disorders, chronic ITP is characterized by perturbations of immune homeostasis with hyperactivated effector cells as well as defective regulatory arm of the adaptive immune system, which will be reviewed here. Interestingly, some ITP treatments are associated with restoring the regulatory imbalance, although it remains unclear whether the immune system is redirected to a state of tolerance once treatment is discontinued. Understanding the mechanisms that result in breakdown of immune homeostasis in ITP will help to identify novel pathways for restoring tolerance and inhibiting effector cell responses. This information can then be translated into developing therapies for averting autoimmunity not only in ITP but also many autoimmune disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.

    Science.gov (United States)

    Faraci, Maura; Zecca, Marco; Pillon, Marta; Rovelli, Attilio; Menconi, Maria Cristina; Ripaldi, Mimmo; Fagioli, Franca; Rabusin, Marco; Ziino, Ottavio; Lanino, Edoardo; Locatelli, Franco; Daikeler, Thomas; Prete, Arcangelo

    2014-02-01

    Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  2. Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent.

    Science.gov (United States)

    Papeta, Natalia; Chen, Tao; Vianello, Fabrizio; Gererty, Lyle; Malik, Ashish; Mok, Ying-Ting; Tharp, William G; Bagley, Jessamyn; Zhao, Guiling; Stevceva, Liljana; Yoon, Victor; Sykes, Megan; Sachs, David; Iacomini, John; Poznansky, Mark C

    2007-01-27

    Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected. Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy. Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue. This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.

  3. A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Caroline Aspord

    Full Text Available BACKGROUND: The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. METHODS AND FINDINGS: Stimulation of PBMC from HLA-A*0201(+ donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer(+ CD8 T cells. The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. CONCLUSIONS: These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer.

  4. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mayu O Frank

    2010-09-01

    Full Text Available Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.

  5. Storage and allogeneic transplantation of peripheral nerve using a green tea polyphenol solution in a canine model

    Directory of Open Access Journals (Sweden)

    Noguchi Takashi

    2010-11-01

    Full Text Available Abstract Background In our previous study, allogeneic-transplanted peripheral nerve segments preserved for one month in a polyphenol solution at 4°C could regenerate nerves in rodents demonstrated the same extent of nerve regeneration as isogeneic fresh nerve grafts. The present study investigated whether the same results could be obtained in a canine model. Methods A sciatic nerve was harvested from a male beagle dog, divided into fascicules of Sry and β-actin to investigate whether cells of donor origin remained in the allogeneic nerve segments. FK506 concentration was measured in blood samples taken before the animals were killed. Results The total myelinated axon numbers and amplitudes of the muscle action potentials correlated significantly with the blood FK506 concentration. Few axons were observed in the allogeneic-transplanted nerve segments in the PA0.025 group. PCR showed clear Sry-specific bands in specimens from the PA0.1 and PA0.05 groups but not from the PA0.025 group. Conclusions Successful nerve regeneration was observed in the polyphenol-treated nerve allografts when transplanted in association with a therapeutic dose of FK506. The data indicate that polyphenols can protect nerve tissue from ischemic damage for one month; however, the effects of immune suppression seem insufficient to permit allogeneic transplantation of peripheral nerves in a canine model.

  6. 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.

    Directory of Open Access Journals (Sweden)

    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.

  7. Complications of allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Arnaout, Karim; Patel, Nihar; Jain, Maneesh; El-Amm, Joelle; Amro, Farah; Tabbara, Imad A

    2014-08-01

    Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.

  8. Mesenchymal Stem Cells Enhance Allogeneic Islet Engraftment in Nonhuman Primates

    Science.gov (United States)

    Berman, Dora M.; Willman, Melissa A.; Han, Dongmei; Kleiner, Gary; Kenyon, Norman M.; Cabrera, Over; Karl, Julie A.; Wiseman, Roger W.; O'Connor, David H.; Bartholomew, Amelia M.; Kenyon, Norma S.

    2010-01-01

    OBJECTIVE To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND METHODS Cynomolgus MSCs were obtained from iliac crest aspirate and characterized through passage 11 for phenotype, gene expression, differentiation potential, and karyotype. Allogeneic donor MSCs were cotransplanted intraportally with islets on postoperative day (POD) 0 and intravenously with donor marrow on PODs 5 and 11. Recipients were followed for stabilization of blood glucose levels, reduction of exogenous insulin requirement (EIR), C-peptide levels, changes in peripheral blood T regulatory cells, and chimerism. Destabilization of glycemia and increases in EIR were used as signs of rejection; additional intravenous MSCs were administered to test the effect on reversal of rejection. RESULTS MSC phenotype and a normal karyotype were observed through passage 11. IL-6, IL-10, vascular endothelial growth factor, TGF-β, hepatocyte growth factor, and galectin-1 gene expression levels varied among donors. MSC treatment significantly enhanced islet engraftment and function at 1 month posttransplant (n = 8), as compared with animals that received islets without MSCs (n = 3). Additional infusions of donor or third-party MSCs resulted in reversal of rejection episodes and prolongation of islet function in two animals. Stable islet allograft function was associated with increased numbers of regulatory T-cells in peripheral blood. CONCLUSIONS MSCs may provide an important approach for enhancement of islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence. Furthermore, MSCs may serve as a new, safe, and effective antirejection therapy. PMID:20622174

  9. Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity.

    Science.gov (United States)

    Wells, James W; Cowled, Chris J; Darling, David; Guinn, Barbara-Ann; Farzaneh, Farzin; Noble, Alistair; Galea-Lauri, Joanna

    2007-12-01

    Alloreactive T-cell responses are known to result in the production of large amounts of proinflammatory cytokines capable of activating and maturing dendritic cells (DC). However, it is unclear whether these allogeneic responses could also act as an adjuvant for concurrent antigen-specific responses. To examine effects of simultaneous alloreactive and antigen-specific T-cell responses induced by semi-allogeneic DC. Semi-allogeneic DC were generated from the F(1) progeny of inbred strains of mice (C57BL/6 and C3H, or C57BL/6 and DBA). We directly primed antigen-specific CD8(+) and CD4(+) T-cells from OT-I and OT-II mice, respectively, in the absence of allogeneic responses, in vitro, and in the presence or absence of alloreactivity in vivo. In vitro, semi-allogeneic DC cross-presented ovalbumin (OVA) to naïve CD8(+) OT-I transgenic T-cells, primed naïve CD4(+) OT-II transgenic T-cells and could stimulate strong alloreactive T-cell proliferation in a primary mixed lymphocyte reaction (MLR). In vivo, semi-allogeneic DC migrated efficiently to regional lymph nodes but did not survive there as long as autologous DC. In addition, they were not able to induce cytotoxic T-lymphocyte (CTL) activity to a target peptide, and only weakly stimulated adoptively transferred OT-II cells. The CD4(+) response was unchanged in allo-tolerized mice, indicating that alloreactive T-cell responses could not provide help for concurrently activated antigen-specific responses. In an EL4 tumour-treatment model, vaccination with semi-allogeneic DC/EL4 fusion hybrids, but not allogeneic DC/EL4 hybrids, significantly increased mouse survival. Expression of self-Major histocompatibility complex (MHC) by semi-allogeneic DC can cause the induction of antigen-specific immunity, however, concurrently activated allogeneic bystander responses do not provide helper or adjuvant effects.

  10. Sclerodermatous GVHD after Allogeneic Bone Marrow Transplant: a Review

    Directory of Open Access Journals (Sweden)

    Gagan Raju

    2017-05-01

    Full Text Available Chronic graft versus host disease (cGVHD is the leading cause of non-relapse mortality after allogeneic hematopoietic bone marrow transplantation (HCT for blood malignancy in patients who survive for more than two years. cGVHD can significantly affect quality of life and cause decreased mobility amongst other grave consequences such as end-organ damage, contributing to morbidity and mortality rates for recipients of HCT. Unlike acute GVHD (aGVHD, the chronic variant of graft versus host disease (GVHD has complex immunopathology involving both humoral and cell immunity. It typically affects the integumentary system, though is known to also affect myofascial, mucocutaneous tissues as well as cause end organ damage ultimately resulting in death. Sclerodermatous cGVHD is a type of cGVHD characterized by involvement of the skin, subcutaneous tissue and fascia without evidence of disease in the viscera. Manifestations of this disease are often evocative of autoimmune disease, which is a self-directed inflammatory reaction to the innate and adaptive immune system in various tissues or multiple organ systems. This inflammatory reaction gives rise to autoantibodies as well as B-cell and T-cell mediated direct toxicity which can cause chronic inflammatory changes of tissues ultimately resulting in tissue scarring and end organ dysfunction. We aim to review the literature on this grave disease and elucidate aspects of the immunopathology of chronic sclerodermatous GVHD in hopes that it may lead to revelations inspiring novel therapies after its diagnosis or preventative measures before stem cell transplantation for malignancy.

  11. Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.

    Science.gov (United States)

    Biasibetti, Elena; Valazza, Alberto; Capucchio, Maria T; Annovazzi, Laura; Battaglia, Luigi; Chirio, Daniela; Gallarate, Marina; Mellai, Marta; Muntoni, Elisabetta; Peira, Elena; Riganti, Chiara; Schiffer, Davide; Panciani, Pierpaolo; Lanotte, Michele

    2017-03-01

    Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.

  12. Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis.

    Science.gov (United States)

    Weinger, Jason G; Plaisted, Warren C; Maciejewski, Sonia M; Lanier, Lewis L; Walsh, Craig M; Lane, Thomas E

    2014-10-01

    Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2(b) ) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1(+) NPCs were susceptible to NK cell-mediated killing whereas RAE-1(-) cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2(d) ) mice resulted in infiltration of NKG2D(+) CD49b(+) NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1(-) allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway. © 2014 AlphaMed Press.

  13. Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells

    Directory of Open Access Journals (Sweden)

    Lise ePasquet

    2011-12-01

    Full Text Available The major obstacle in transplantation medicine is rejection of donor tissues by the host’s immune system. Immunosuppressive drugs can delay but not prevent loss of transplants, and their efficiency is strongly impacted by inter-individual pharmacokinetic differences. Moreover, due to the global immunosuppression induced and to the broad distribution of their targets amongst human tissues, these drugs have severe side effects. Induction of donor-specific non-responsiveness (i.e. immunological tolerance to transplants would solve these problems and would substantially ameliorate patients’ quality of life. It is widely believed that bone marrow or hematopoietic stem cell transplantation, and resulting (mixed hematopoietic chimerism, invariably leads to immunological tolerance to organs of the same donor. A careful analysis of the literature, reviewed here, indeed shows that chimerism consistently prolongs allograft survival. However, in absence of additional conditioning leading to the development of active regulatory mechanisms, it does not prevent chronic rejection. A central role for active tolerance in transplantation-tolerance is also supported by recent data showing that genuine immunological tolerance to organ allografts can be achieved by combining induction of hematopoietic chimerism with infusion of regulatory T lymphocytes. Therefore, conditioning regimens that lead to the establishment of hematopoietic chimerism plus active regulatory mechanisms appear required for induction of genuine tolerance to allogeneic grafts.

  14. A specific immune tolerance toward offspring cells is to exist after the mother lymphocyte infusion.

    Science.gov (United States)

    Xing, Haizhou; Liu, Shiqin; Chen, Xue; Fang, Fang; Wu, Xueqiang; Zhu, Ping

    2017-04-01

    To examine immune tolerance between maternal lymphocytes and offspring tissue after a donor lymphocyte infusion. Mouse models were established by mating female BALB/c mice with male C57BL mice. Splenic lymphocytes from donors of different genetic backgrounds were labeled with carboxyfluorescein succinimidyl ester (CFSE), and 1×10 7 of the labeled cells were intravenously injected into a recipient. At 6h, 24h, 72h and 120h after the infusion, mononuclear cells in recipient spleen, liver, thymus, lymph nodes, and peripheral blood were collected. CFSE+, CFSE-, CD3+, CD8+, CD4+, CD19+, NK1.1+, CD25+, and CD127+ lymphocytes in those samples were analyzed by flow cytometry. The distribution of donor T cells, B cells, NK cells, helper T cells, cytotoxic T cells, and recipient regulatory T cells in the tissues were then analyzed. Maternal lymphocytes were more likely to survive in offspring. At 120h after infusion, the percentages of maternal cells in the offspring were 0.52±0.11% in lymph nodes, 0.97±0.04% in peripheral blood, and 0.97±0.11% in the spleen. Few donor cells, if any, were detected in these tissues at 120h after aunt to child, father to child, and unrelated allogeneic infusions were performed. The subtype proportion of donor lymphocytes changed significantly in the recipient tissues. Recipient Treg cells increased in the mother to child group, but not in the aunt to child, father to child, and unrelated allogeneic groups, suggesting a decreased cellular immune response to allogeneic cells in the mother to child group. At 120h after the infusion, no donor cells were detected in the recipient livers and thymuses of all groups, implying that donor cells were barely able to colonize in the liver and thymus. Specific immune tolerance to maternal lymphocytes exists in offspring. An infusion of maternal donor lymphocytes may produce a relatively persistent effect of adoptive immunotherapy with reduced side-effects. Copyright © 2017 Elsevier GmbH. All rights

  15. Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

    DEFF Research Database (Denmark)

    Toh, Han Chong; Wang, Who-Whong; Chia, Whay Kuang

    2009-01-01

    PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs...... were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 x 10(6) cells per dose) at biweekly intervals. RESULTS: Twenty......-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding...

  16. T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression.

    Science.gov (United States)

    Kurmyshkina, Olga V; Kovchur, Pavel I; Schegoleva, Ludmila V; Volkova, Tatyana O

    2017-01-01

    Processes and mechanisms responsible for systemic immune suppression in early-stage cervical cancer remain substantially underinvestigated. In this work, we focused on studying the frequencies of circulating regulatory T (CD4 and CD8 Tregs) and NK (NKregs) cells in parallel with assessment of apoptotic markers expression in T cells from patients with preinvasive and microinvasive cervical cancer, with the aim to determine whether up-regulation of apoptosis-associated markers in Т lymphocytes accompanies cervical cancer development and correlates with the change in percentages of regulatory cell populations at systemic level during the initial stages of invasive cervical cancer progression. Fourty two women with histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3, including carcinoma in situ) or cervical cancer (stage IA) and 30 healthy women (control) were enrolled in the study. Peripheral blood samples were taken immediately before surgery or any treatment and immediately subjected to multicolor flow cytometry. Analysis of a combination of CD4/CD8, CD25, CD127, and FoxP3 markers revealed a statistically significant increase in the frequencies of Tregs within both the CD4 and CD8 subsets of circulating lymphocytes in patients with CIN3 and stage IA cancer. In contrast, lower numbers of NKregs (defined as CD16 dim/neg CD56 bright subpopulation) and increased CD56 dim /CD56 bright NK ratio were found in patients compared to controls, with the percentage of CD16 bright CD56 dim cells (major subtype of circulating NKs) showing no difference. Patients also exhibited an increased expression of CD95 in total peripheral blood T lymphocytes, along with increased level of Annexin V binding to CD95-positive cells, suggesting higher susceptibility of T cells to apoptosis and potential involvement of CD95-dependent pathway in early-stage cervical cancer. Differential analysis of CD4 and CD8 T cells revealed different trends in the change of CD95

  17. The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

    Directory of Open Access Journals (Sweden)

    Razavy Haide

    2007-04-01

    Full Text Available Abstract Background Transplant rejection has been considered to occur primarily because donor antigens are not present during the development of the recipient's immune system to induce tolerance. Thus, transplantation prior to recipient immune system development (pre-immunocompetence transplants should induce natural tolerance to the donor. Surprisingly, tolerance was often not the outcome in such 'natural tolerance models'. We explored the ability of natural tolerance to prevent immune responses to alloantigens, and the reasons for the disparate outcomes of pre-immunocompetence transplants. Results We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance. Conclusion These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited. Reviewers This article was reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott.

  18. Novel positive regulatory role for the SPL6 transcription factor in the N TIR-NB-LRR receptor-mediated plant innate immunity.

    Directory of Open Access Journals (Sweden)

    Meenu S Padmanabhan

    2013-03-01

    Full Text Available Following the recognition of pathogen-encoded effectors, plant TIR-NB-LRR immune receptors induce defense signaling by a largely unknown mechanism. We identify a novel and conserved role for the SQUAMOSA PROMOTER BINDING PROTEIN (SBP-domain transcription factor SPL6 in enabling the activation of the defense transcriptome following its association with a nuclear-localized immune receptor. During an active immune response, the Nicotiana TIR-NB-LRR N immune receptor associates with NbSPL6 within distinct nuclear compartments. NbSPL6 is essential for the N-mediated resistance to Tobacco mosaic virus. Similarly, the presumed Arabidopsis ortholog AtSPL6 is required for the resistance mediated by the TIR-NB-LRR RPS4 against Pseudomonas syringae carrying the avrRps4 effector. Transcriptome analysis indicates that AtSPL6 positively regulates a subset of defense genes. A pathogen-activated nuclear-localized TIR-NB-LRR like N can therefore regulate defense genes through SPL6 in a mechanism analogous to the induction of MHC genes by mammalian immune receptors like CIITA and NLRC5.

  19. A Model of an Integrated Immune System Pathway in Homo sapiens and Its Interaction with Superantigen Producing Expression Regulatory Pathway in Staphylococcus aureus: Comparing Behavior of Pathogen Perturbed and Unperturbed Pathway

    Science.gov (United States)

    Tomar, Namrata; De, Rajat K.

    2013-01-01

    Response of an immune system to a pathogen attack depends on the balance between the host immune defense and the virulence of the pathogen. Investigation of molecular interactions between the proteins of a host and a pathogen helps in identifying the pathogenic proteins. It is necessary to understand the dynamics of a normally behaved host system to evaluate the capacity of its immune system upon pathogen attack. In this study, we have compared the behavior of an unperturbed and pathogen perturbed host system. Moreover, we have developed a formalism under Flux Balance Analysis (FBA) for the optimization of conflicting objective functions. We have constructed an integrated pathway system, which includes Staphylococcal Superantigen (SAg) expression regulatory pathway and TCR signaling pathway of Homo sapiens. We have implemented the method on this pathway system and observed the behavior of host signaling molecules upon pathogen attack. The entire study has been divided into six different cases, based on the perturbed/unperturbed conditions. In other words, we have investigated unperturbed and pathogen perturbed human TCR signaling pathway, with different combinations of optimization of concentrations of regulatory and signaling molecules. One of these cases has aimed at finding out whether minimization of the toxin production in a pathogen leads to the change in the concentration levels of the proteins coded by TCR signaling pathway genes in the infected host. Based on the computed results, we have hypothesized that the balance between TCR signaling inhibitory and stimulatory molecules can keep TCR signaling system into resting/stimulating state, depending upon the perturbation. The proposed integrated host-pathogen interaction pathway model has accurately reflected the experimental evidences, which we have used for validation purpose. The significance of this kind of investigation lies in revealing the susceptible interaction points that can take back the

  20. Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model.

    Science.gov (United States)

    Wada, Satoshi; Yoshimura, Kiyoshi; Hipkiss, Edward L; Harris, Tim J; Yen, Hung-Rong; Goldberg, Monica V; Grosso, Joseph F; Getnet, Derese; Demarzo, Angelo M; Netto, George J; Anders, Robert; Pardoll, Drew M; Drake, Charles G

    2009-05-15

    To study the immune response to prostate cancer, we developed an autochthonous animal model based on the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in which spontaneously developing tumors express influenza hemagglutinin as a unique, tumor-associated antigen. Our prior studies in these animals showed immunologic tolerance to hemagglutinin, mirroring the clinical situation in patients with cancer who are generally nonresponsive to their disease. We used this physiologically relevant animal model to assess the immunomodulatory effects of cyclophosphamide when administered in combination with an allogeneic, cell-based granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapy. Through adoptive transfer of prostate/prostate cancer-specific CD8 T cells as well as through studies of the endogenous T-cell repertoire, we found that cyclophosphamide induced a marked augmentation of the antitumor immune response. This effect was strongly dependent on both the dose and the timing of cyclophosphamide administration. Mechanistic studies showed that immune augmentation by cyclophosphamide was associated with a transient depletion of regulatory T cells in the tumor draining lymph nodes but not in the peripheral circulation. Interestingly, we also noted effects on dendritic cell phenotype; low-dose cyclophosphamide was associated with increased expression of dendritic cell maturation markers. Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy.

  1. Allogeneic cellular immunotherapy for chronic B-cell leukemia

    NARCIS (Netherlands)

    Hoogendoorn, Mels

    2007-01-01

    Allogeneic stem cell transplantation (SCT) following reduced-intensity conditioning (RIC) as treatment modality has curative potential in patients suffering from chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), illustrating susceptibility of these leukemic cells for the

  2. Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells

    NARCIS (Netherlands)

    de Vos, Paul; Mujagic, Zlatan; de Haan, Bart J.; Siezen, Roland J.; Bron, Peter A.; Meijerink, Marjolein; Wells, Jerry M.; Masclee, Ad A. M.; Boekschoten, Mark V.; Faas, Marijke M.; Troost, Freddy J.

    2017-01-01

    Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or

  3. Lactobacillus plantarum strains can enhance human mucosal and systemic immunity and prevent non-steroidal anti-inflammatory drug induced reduction in T regulatory Cells

    NARCIS (Netherlands)

    Vos, de Paul; Mujagic, Zlatan; Haan, de Bart J.; Siezen, Roland J.; Bron, Peter A.; Meijerink, Marjolein; Wells, Jerry M.; Masclee, Ad A.M.; Boekschoten, Mark V.; Faas, Marijke M.; Troost, Freddy J.

    2017-01-01

    Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or

  4. Experimental studies on possible regulatory role of nitric oxide on the differential effects of chronic predictable and unpredictable stress on adaptive immune responses.

    Science.gov (United States)

    Thakur, Tarun; Gulati, Kavita; Rai, Nishant; Ray, Arunabha

    2017-09-01

    The present study was designed to investigate the effects of chronic predictable stress (CPS) and chronic unpredictable stress (CUS) on immunological responses in KLH-sensitized rats and involvement of NOergic signaling pathways mediating such responses. Male Wistar rats (200-250g) were exposed to either CPS or CUS for 14days and IgG antibody levels and delayed type hypersensitivity (DTH) response was determined to assess changes in adaptive immunity. To evaluate the role of nitric oxide during such immunomodulation, biochemical estimation of stable metabolite of nitric oxide (NOx) and 3-nitrotyrosine (3-NT, a marker of peroxynitrite formation) were done in both blood and brain. Chronic stress exposure resulted in suppression of IgG and DTH response and elevated NOx and 3-NT levels, with a difference in magnitude of response in CPS vs CUS. Pretreatment with aminoguanidine (iNOS inhibitor) caused further reduction of adaptive immune responses and attenuated the increased NOx and 3-NT levels in CPS or CUS exposed rats. On the other hand 7-NI (nNOS inhibitor) did not significantly affect these estimated parameters. The results suggest involvement of iNOS and lesser/no role of nNOS during modulation of adaptive immunity to stress. Thus, the result showed that predictability of stressors results in differential degree of modulation of immune responses and complex NO-mediated signaling mechanisms may be involved during responses. Copyright © 2017. Published by Elsevier B.V.

  5. Immune tolerance in radiation chimeras

    International Nuclear Information System (INIS)

    Awaya, Kazuhiko; Kuniki, Hiromichi; Neki, Miyuki

    1978-01-01

    Establishment of immune tolerance in radiation chimeras and the mechanism of maintaining it were discussed from certain points. Semiallogeneic radiation chimeras are mostly of long-living, and the hematopoietic organ of this individual consists mainly of the cells derived from the marrow donor, i. e., F 1 -type cells. F 1 -type lymphocytes can distinguish parental strain cells from themselves. In these chimeras, a F 1 -skin graft maintains to be fresh as long as the host is alive, showing immune tolerance effective through its life. In establishment and maintenance of this immune tolerance, the suppressing mechanism of host-type or F 1 -type seems to be involved. The allogeneic radiation chimera has very poor long-survival rate compared with that of the semiallogeneic radiation chimera. To raise this survival rate, efforts are now being made from the immunological point of view. (Ueda, J.)

  6. Regulatory Eosinophils Suppress T Cells Partly through Galectin-10.

    Science.gov (United States)

    Lingblom, Christine; Andersson, Jennie; Andersson, Kerstin; Wennerås, Christine

    2017-06-15

    Eosinophils have the capacity to regulate the function of T cell subsets. Our aim was to test the hypothesis of the existence of a regulatory subset of eosinophils. Human eosinophils were incubated with T cells that were stimulated with allogeneic leukocytes or CD3/CD28 cross-linking. After 2 d of coculture, 11% of the eosinophils gained CD16 expression. A CD16 hi subset of eosinophils, encompassing 1-5% of all eosinophils, was also identified in the blood of healthy subjects. FACS sorting showed that these CD16 hi eosinophils were significantly stronger suppressors of T cell proliferation than were conventional CD16 neg eosinophils. Human eosinophils contain stores of the immunoregulatory protein galectin-10. We found that Ab-mediated neutralization of galectin-10 partially abrogated the suppressive function of the eosinophils. Moreover, recombinant galectin-10 by itself was able to suppress T cell proliferation. Finally, we detected galectin-10-containing immune synapses between eosinophils and lymphocytes. To conclude, we describe a subset of suppressive eosinophils expressing CD16 that may escape detection because CD16-based negative selection is the standard procedure for the isolation of human eosinophils. Moreover, we show that galectin-10 functions as a T cell-suppressive molecule in eosinophils. Copyright © 2017 by The American Association of Immunologists, Inc.

  7. Present and future of allogeneic natural killer cell therapy

    Directory of Open Access Journals (Sweden)

    Okjae eLim

    2015-06-01

    Full Text Available Natural killer (NK cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA-haploidentical hematopoietic stem cell transplantation revealed the anti-tumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor (KIR ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions.

  8. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell--depleted SCT

    NARCIS (Netherlands)

    van Esser, J W; van der Holt, B; Meijer, E; Niesters, H G; Trenschel, R; Thijsen, S F; van Loon, A M; Frassoni, F; Bacigalupo, A; Schaefer, U W; Osterhaus, A D; Gratama, J W; Löwenberg, B; Verdonck, L F; Cornelissen, J J

    2001-01-01

    Reactivation of the Epstein-Barr virus (EBV) after allogeneic stem cell transplantation (allo-SCT) may evoke a protective cellular immune response or may be complicated by the development of EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known about the incidence, recurrence, and

  9. Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells

    OpenAIRE

    Curti, A; Trabanelli, S; Onofri, C; Aluigi, M; Salvestrini, V; Ocadlikova, D; Evangelisti, C; Rutella, S; De Cristofaro, R; Ottaviani, E; Baccarani, M; Lemoli, RM

    2010-01-01

    Background: The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia.\\ud Design and Methods: Leukemic d...

  10. 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.

  11. Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy.

    Science.gov (United States)

    Hensley, Michael Taylor; Tang, Junnan; Woodruff, Kathleen; Defrancesco, Teresa; Tou, Sandra; Williams, Christina M; Breen, Mathew; Meurs, Kathryn; Keene, Bruce; Cheng, Ke

    2017-08-01

    Cardiosphere-derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non-ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c-kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  12. T cells for viral infections after allogeneic hematopoietic stem cell transplant.

    Science.gov (United States)

    Bollard, Catherine M; Heslop, Helen E

    2016-06-30

    Despite recent advances in the field of allogeneic hematopoietic stem cell transplantation (HSCT), viral infections are still a major complication during the period of immune suppression that follows the procedure. Adoptive transfer of donor-derived virus-specific cytotoxic T cells (VSTs) is a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after HSCT. Early proof of principle studies demonstrated that the administration of donor-derived T cells specific for cytomegalovirus or Epstein-Barr virus (EBV) could effectively restore virus-specific immunity and control viral infections. Subsequent studies using different expansion or direct selection techniques have shown that donor-derived VSTs confer protection in vivo after adoptive transfer in 70% to 90% of recipients. Because a major cause of failure is lack of immunity to the infecting virus in a naïve donor, more recent studies have infused closely matched third-party VSTs and reported response rates of 60% to 70%. Current efforts have focused on broadening the applicability of this approach by: (1) extending the number of viral antigens being targeted, (2) simplifying manufacture, (3) exploring strategies for recipients of virus-naïve donor grafts, and (4) developing and optimizing "off the shelf" approaches. © 2016 by The American Society of Hematology.

  13. Tissue-Related Hypoxia Attenuates Proinflammatory Effects of Allogeneic PBMCs on Adipose-Derived Stromal Cells In Vitro

    Directory of Open Access Journals (Sweden)

    Polina I. Bobyleva

    2016-01-01

    Full Text Available Human adipose tissue-stromal derived cells (ASCs are considered a perspective tool for regenerative medicine. Depending on the application mode ASC/allogeneic immune cell interaction can occur in the systemic circulation under plenty high concentrations of O2 and in target tissues at lower O2 levels. Here we examined the effects of allogeneic PHA-stimulated peripheral blood mononuclear cells (PBMCs on ASCs under ambient (20% oxygen and “physiological” hypoxia (5% O2. As revealed with microarray analysis ASCs under 20% O2 were more affected by activated PBMCs, which was manifested in differential expression of more than 300 genes, whereas under 5% O2 only 140 genes were changed. Altered gene pattern was only partly overlapped at different O2 conditions. Under O2 ASCs retained their proliferative and differentiative capacities, mesenchymal phenotype, and intracellular organelle’ state. ASCs were proinflammatory activated on transcription level that was confirmed by their ability to suppress activation and proliferation of mitogen-stimulated PBMCs. ASC/PBMCs interaction resulted in anti-inflammatory shift of paracrine mediators in conditioning medium with significant increase of immunosuppressive LIF level. Our data indicated that under both ambient and tissue-related O2 ASCs possessed immunosuppressive potential and maintained functional activity. Under “physiological” hypoxia ASCs were less susceptible to “priming” by allogeneic mitogen-activated PBMCs.

  14. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization.

    Science.gov (United States)

    Li, Junjie; Xie, Jiangang; Liu, Shanshou; Li, Xiao; Zhang, Dongliang; Wang, Xianqi; Jiang, Jinquan; Hu, Wei; Zhang, Yuan; Jin, Boquan; Zhuang, Ran; Yin, Wen

    2018-04-25

    ADAR1 (adenosine deaminase acting on double-stranded RNA 1) is an RNA-editing enzyme that mediates adenosine-to-inosine RNA editing events, an important post-transcriptional modification mechanism that can alter the coding properties of mRNA or regulate microRNA biogenesis. ADAR1 also regulates the innate immune response. Here, we have demonstrated that ADAR1 expression increased in LPS-stimulated macrophages. Silencing ADAR1 by using small interfering RNA in macrophages resulted in the pronounced polarization of macrophages to M1, whereas ADAR1 overexpression promoted M2 polarization, which indicated that ADAR1 can inhibit macrophage hyperpolarization and prevent immune hyperactivity. The RNA-RNP immunoprecipitation binding assay demonstrated a direct interaction between ADAR1 and miR-21 precursor. Significant up-regulation in IL-10 and down-regulation in miR-21 were observed in ADAR1-overexpressing macrophages. We evaluated miR-21 target mRNAs and macrophage polarization signaling pathways and found that forkhead box protein O1 (Foxo1) was up-regulated in cells that overexpressed ADAR1. In a mouse allogeneic skin transplantation model, grafts in the ADAR1-overexpressed group survived longer and suffered less immune cell infiltration. In ADAR1-overexpressed recipients, splenic macrophages were significantly polarized to M2, and levels of sera IL-10 were markedly higher than those in the control group. In summary, ADAR1 modulates macrophage M2 polarization via the ADAR1-miR-21-Foxo1-IL-10 axis, thereby suppressing allogeneic graft rejection.-Li, J., Xie, J., Liu, S., Li, X., Zhang, D., Wang, X., Jiang, J., Hu, W., Zhang, Y., Jin, B., Zhuang, R., Yin, W. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization.

  15. Immune Regulation by Self-Recognition

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2015-01-01

    Circulating T cells that specifically target normal self-proteins expressed by regulatory immune cells were first described in patients with cancer, but can also be detected in healthy individuals. The adaptive immune system is distinguished for its ability to differentiate between self......-antigens and foreign antigens. Thus, it was remarkable to discover T cells that apparently lacked tolerance to important self-proteins, eg, IDO, PD-L1, and FoxP3, expressed in regulatory immune cells. The ability of self-reactive T cells to react to and eliminate regulatory immune cells can influence general immune...... reactions. This suggests that they may be involved in immune homeostasis. It is here proposed that these T cells should be termed antiregulatory T cells (anti-Tregs). The role of anti-Tregs in immune-regulatory networks may be diverse. For example, pro-inflammatory self-reactive T cells that react...

  16. Vascular endothelium as a target of immune response in renal transplant rejection

    Directory of Open Access Journals (Sweden)

    Giovanni ePiotti

    2014-10-01

    Full Text Available This review of clinical and experimental studies aims at analysing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularised solid transplants. Endothelial cells express all the major sets of antigens that elicit host immune response, and therefore represent a preferential target in organ rejection.Some of the antigens expressed by endothelial cells are target of the antibody-mediated response, such as the AB0 blood group system, the HLA and MICA systems, and the endothelial cell-restricted antigens; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover the rejection process can force injured endothelial cells to expose cryptic self-antigens, toward which an auto-immune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are endothelial cells a passive target of the host immune response, but also an active player in lymphocyte activation; therefore their interaction with allogenic T-cells is analysed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells.Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of endothelial cells to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ Regulatory T-cells, that are crucial mediators of

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Ocular findings after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Tabbara, Khalid F; Al-Ghamdi, Ahmad; Al-Mohareb, Fahad; Ayas, Mouhab; Chaudhri, Naeem; Al-Sharif, Fahad; Al-Zahrani, Hazzaa; Mohammed, Said Y; Nassar, Amr; Aljurf, Mahmoud

    2009-09-01

    To study the incidence, causes, and outcome of major ocular complications in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Retrospective, noncomparative, observational clinical study. The study included a total of 620 patients who underwent allogeneic HSCT in the period from 1997 to 2007 at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Allogeneic HSCT. Patients with ocular complications were referred to the ophthalmology division for complete ophthalmologic examination, including visual acuity, tonometry, Schirmer test, biomicroscopy, and dilated ophthalmoscopy. Laboratory investigations were performed whenever indicated. The incidence and causes of major ocular complications after allogeneic HSCT were determined. Visual acuity at 1 year after allogeneic HSCT was recorded. Major ocular complications occurred in 80 (13%) of 620 patients who underwent allogeneic HSCT. There were 36 male patients (45%) and 44 female patients (55%) with a mean age of 29 years and an age range of 9 to 65 years. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate in 69 patients, and cyclosporine, methotrexate and corticosteroids, or mycophenolate mofetil in 11 patients. The most frequently encountered ocular complications were chronic GVHD, dry eye syndrome without GVHD, corneal ulcers, cataract, glaucoma, cytomegalovirus retinitis, fungal endophthalmitis, and acquisition of allergic conjunctivitis from atopic donors. There was no correlation between the pattern of ocular complications and the transplanted stem cell source. Best-corrected visual acuity (BCVA) at 1 year after transplantation was less than 20/200 in 13 patients (16%), less than 20/50 in 17 patients (21%), and better than 20/50 in 50 patients (63%). Ocular complications are common in patients undergoing allogeneic HSCT. Early recognition and prompt treatment are important. The author(s) have no proprietary or commercial

  19. Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients.

    Science.gov (United States)

    Saison, J; Ferry, T; Demaret, J; Maucort Boulch, D; Venet, F; Perpoint, T; Ader, F; Icard, V; Chidiac, C; Monneret, G

    2014-06-01

    The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort. © 2014 British Society for Immunology.

  20. Tetanus after allogeneic bone-marrow transplantation

    International Nuclear Information System (INIS)

    Kendra, J.R.; Halil, O.; Barrett, A.J.; Selwyn, S.

    1982-01-01

    A brief report is presented of a case of tetanus after allogeneic bone-marrow transplantation complicated by radiation-induced pneumonitis. A 30-year-old army sergeant received a bone-marrow transplant from his brother for the treatment of a granulocytic sarcoma after local radiotherapy to the tumour. Six years earlier he had sustained an open, compound fracture of the left tibia and fibula while on army exercise. At the time a pin and plate had been inserted and booster anti-tetanus administered. Bone-marrow transplantation was performed after total body irradiation. Cyclosporin A was given against graft-versus-host disease. Fifty four days after transplantation tetanus was diagnosed and death followed 14 days later. Necropsy disclosed radiation-induced pneumonitis, but no organisms were cultured from the lungs or the old fracture site. It is suggested that spores were incorporated into the wound site before surgery and that oxygenation around the plate became compromised after transplantation, permitting germination of dormant spores, immunosuppression allowing development of the disease. (U.K.)

  1. Amotosalen: Allogeneic Cellular Immunotherapies system, INTERCEPT Plasma System, INTERCEPT Platelet System, S 59.

    Science.gov (United States)

    2003-01-01

    validation process is currently being conducted in Denmark, France, Germany, Sweden and the UK. Marketing approval applications for the INTERCEPT Platelet System have also been submitted in Australia and Canada. In addition, the regulatory submission process has begun in the US. A phase III trial (EuroSPRITE) has been conducted in 103 patients in Europe with pooled random donor platelets. The platelets were collected using the buffy coat process. Another two 20-patient clinical trials have also been conducted in Europe, as well as a 40-patient trial using platelets collected by an apheresis collection system. Cerus has also conducted a phase III trial (SPRINT) in the US. The trial was conducted in 671 patients and used platelets collected by Baxter's apheresis collection system. INTERCEPT Plasma System: Cerus is also developing the INTERCEPT Plasma System in collaboration with Baxter Healthcare. The system also combines amotosalen, an illumination device and a compound absorption device. The two companies are currently preparing regulatory applications for the INTERCEPT Plasma System for the US. This application will be followed by a submission for CE Mark designation in Europe. Patients undergoing surgery, or transplantation, or with bleeding disorders, may require transfusions of plasma, often to control bleeding. The type of plasma is stored in frozen form and is called fresh frozen plasma (FFP). The INTERCEPT Plasma System is currently in phase IIIc development in the US. Patient enrolment in the trial is still ongoing. The trial is comparing INTERCEPT trade mark Plasma System treated versus untreated FFP in 30 patients with thrombotic thrombocytopenic purpura. Allogeneic Cellular Immunotherapies system: Cerus is also investigating the potential of its Helinx technology to improve the outcome of bone marrow transplantation procedures (used to treat leukaemia and lymphoma) through the treatmatment for many forms of leukaemia and is most effective when the donor is very

  2. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality.

    Science.gov (United States)

    Hill, Joshua A; Mayer, Bryan T; Xie, Hu; Leisenring, Wendy M; Huang, Meei-Li; Stevens-Ayers, Terry; Milano, Filippo; Delaney, Colleen; Sorror, Mohamed L; Sandmaier, Brenda M; Nichols, Garrett; Zerr, Danielle M; Jerome, Keith R; Schiffer, Joshua T; Boeckh, Michael

    2017-04-20

    Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease ( P values < .01). Absolute lymphocyte count of <200 cells/mm 3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) ( P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies. © 2017 by The American Society of Hematology.

  3. A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery

    NARCIS (Netherlands)

    van der Linden, P.; de Hert, S.; Daper, A.; Trenchant, A.; Jacobs, D.; de Boelpaepe, C.; Kimbimbi, P.; Defrance, P.; Simoens, G.

    2001-01-01

    PURPOSE: Individual and institutional practices remain an independent predictor factor for allogeneic blood transfusion. Application of a standardized multidisciplinary transfusion strategy should reduce the use of allogeneic blood transfusion in major surgical patients. METHODS: This prospective

  4. Allogeneic versus autologous derived cell sources for use in engineered bone-ligament-bone grafts in sheep anterior cruciate ligament repair.

    Science.gov (United States)

    Mahalingam, Vasudevan D; Behbahani-Nejad, Nilofar; Horine, Storm V; Olsen, Tyler J; Smietana, Michael J; Wojtys, Edward M; Wellik, Deneen M; Arruda, Ellen M; Larkin, Lisa M

    2015-03-01

    The use of autografts versus allografts for anterior cruciate ligament (ACL) reconstruction is controversial. The current popular options for ACL reconstruction are patellar tendon or hamstring autografts, yet advances in allograft technologies have made allogeneic grafts a favorable option for repair tissue. Despite this, the mismatched biomechanical properties and risk of osteoarthritis resulting from the current graft technologies have prompted the investigation of new tissue sources for ACL reconstruction. Previous work by our lab has demonstrated that tissue-engineered bone-ligament-bone (BLB) constructs generated from an allogeneic cell source develop structural and functional properties similar to those of native ACL and vascular and neural structures that exceed those of autologous patellar tendon grafts. In this study, we investigated the effectiveness of our tissue-engineered ligament constructs fabricated from autologous versus allogeneic cell sources. Our preliminary results demonstrate that 6 months postimplantation, our tissue-engineered auto- and allogeneic BLB grafts show similar histological and mechanical outcomes indicating that the autologous grafts are a viable option for ACL reconstruction. These data indicate that our tissue-engineered autologous ligament graft could be used in clinical situations where immune rejection and disease transmission may preclude allograft use.

  5. Co-Culturing of Multipotent Mesenchymal Stromal Cells with Autological and Allogenic Lymphocytes.

    Science.gov (United States)

    Kapranov, N M; Davydova, Yu O; Gal'tseva, I V; Petinati, N A; Bakshinskaitė, M V; Drize, N I; Kuz'mina, L A; Parovichnikova, E N; Savchenko, V G

    2018-03-01

    We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged. Priming of multipotent mesenchymal stromal cells with IFN did not affect these changes. In turn, lymphocytes underwent activation, expression of HLA-DR increased, subpopulation composition of lymphocytes changed towards the increase in the content of naïve T cells. These findings are important for cell therapy.

  6. Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

    Science.gov (United States)

    Khouri, I F; Sui, D; Jabbour, E J; Samuels, B I; Turturro, F; Alatrash, G; Anderlini, P; Ahmed, S; Oran, B; Ciurea, S O; Marin, D; Olson, A; Patel, K K; Popat, U R; Ledesma, C; Kadia, T M; Ferrajoli, A; Burger, J A; Jorgensen, J L; Medeiros, L J; Bassett, R L; Gulbis, A M

    2017-01-01

    Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

  7. Neural circuitry and immunity

    Science.gov (United States)

    Pavlov, Valentin A.; Tracey, Kevin J.

    2015-01-01

    Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuroimmune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases defines the emerging field of Bioelectronic Medicine. PMID:26512000

  8. Bacterial infections associated with allogenic bone transplantation

    Directory of Open Access Journals (Sweden)

    Stepanović Željko Lj.

    2015-01-01

    Full Text Available Background/Aim. Bone allografts are frequently used in orthopedic reconstructive procedures carrying a high risk for recipients. To assess the nature and frequency of allograft contamination and associated surgical infection the case records from our institutional bone bank were reviewed. Methods. We retrospectively analyzed the microbiology of discarded bone allografts and the surgical site of the recipients. A case series of patients who acquired surgical site infection after allogenic bone transplantation was presented. Swab culturing was conducted on 309 femoral heads from living donors who underwent partial and total hip arthroplasty between January 2007 and December 2013. To prevent potential bone allograft contamination we used saline solution of 2.0 mg/ml of amikacin during thawing. The overall infection rate was analyzed in 197 recipients. Results. Of the 309 donated femoral heads, 37 were discarded due to bacterial contamination, giving the overall contamination rate of 11.97%. The postoperative survey of 213 bone allotransplantations among 197 recipients showed the infection rate of 2.03%. The coagulase-negative Staphylococcus was the most commonly identified contaminant of bone allografts and recipient surgical sites. Conclusion. The allograft contamination rate and the infection rate among recipients in our institution are in accordance with the international standards. The coagulase-negative Staphylococcus was the most commonly identified contaminant of bone allografts and recipient surgical sites. There is no strong evidence that surgical site infections were associated with bone allograft utilization. We plan further improvements in allograft handling and decontamination with highly concentrated antibiotic solutions in order to reduce infection risk for recipients.

  9. Feasibility investigation of allogeneic endometrial regenerative cells

    Directory of Open Access Journals (Sweden)

    Reid Michael

    2009-02-01

    Full Text Available Abstract Endometrial Regenerative Cells (ERC are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type.

  10. Regulatory agencies and regulatory risk

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2008-01-01

    The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

  11. Patients with Multiple Myeloma Develop SOX2-Specific Autoantibodies after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Sebastian Kobold

    2011-01-01

    Full Text Available The occurrence of SOX2-specific autoantibodies seems to be associated with an improved prognosis in patients with monoclonal gammopathy of undetermined significance (MGUS. However, it is unclear if SOX2-specific antibodies also develop in established multiple myeloma (MM. Screening 1094 peripheral blood (PB sera from 196 MM patients and 100 PB sera from healthy donors, we detected SOX2-specific autoantibodies in 7.7% and 2.0% of patients and donors, respectively. We identified SOX2211–230 as an immunodominant antibody-epitope within the full protein sequence. SOX2 antigen was expressed in most healthy tissues and its expression did not correlate with the number of BM-resident plasma cells. Accordingly, anti-SOX2 immunity was not related to SOX2 expression levels or tumor burden in the patients’ BM. The only clinical factor predicting the development of anti-SOX2 immunity was application of allogeneic stem cell transplantation (alloSCT. Anti-SOX2 antibodies occurred more frequently in patients who had received alloSCT (n=74. Moreover, most SOX2-seropositive patients had only developed antibodies after alloSCT. This finding indicates that alloSCT is able to break tolerance towards this commonly expressed antigen. The questions whether SOX2-specific autoantibodies merely represent an epiphenomenon, are related to graft-versus-host effects or participate in the immune control of myeloma needs to be answered in prospective studies.

  12. Ready-made allogeneic ABO-specific serum eye drops

    DEFF Research Database (Denmark)

    Harritshøj, Lene Holm; Nielsen, Connie; Ullum, Henrik

    2014-01-01

    serum treatment. CONCLUSION: Ready-made ABO-identical allogeneic serum eye drops were straightforwardly produced, quality-assured and registered as a safe standard blood product for the treatment of certain cases of severe dry eye disease. Therapeutic efficacy was comparable to previous reports......PURPOSE: To overcome problems and delays of the preparation of autologous serum eye drops, a production line of ABO-specific allogeneic serum eye drops from male blood donors was set up in a blood bank. Feasibility, clinical routine, safety and efficacy were evaluated in a cohort of patients...

  13. Immune regulation and CNS autoimmune disease

    DEFF Research Database (Denmark)

    Antel, J P; Owens, T

    1999-01-01

    The central nervous system is a demonstrated target of both clinical and experimental immune mediated disorders. Immune regulatory mechanisms operative at the levels of the systemic immune system, the blood brain barrier, and within the CNS parenchyma are important determinants of the intensity...... and duration of the tissue directed injury. Convergence of research, involving direct manipulation of specific cells and molecular mediators in animal models and in vitro analysis of human immune and neural cells and tissues, is providing increasing insight into the role of these immune regulatory functions...

  14. Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.

    Directory of Open Access Journals (Sweden)

    Patrycja Konieczna

    Full Text Available The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1. Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses.

  15. Human Dendritic Cell DC-SIGN and TLR-2 Mediate Complementary Immune Regulatory Activities in Response to Lactobacillus rhamnosus JB-1

    Science.gov (United States)

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O’Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses. PMID:25816321

  16. Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.

    Science.gov (United States)

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O'Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses.

  17. Lyophilized allogeneic bone grafts for cystic and discontinuity defects of the jaws

    International Nuclear Information System (INIS)

    Pill Hoon Choung; Eun Seok Kim

    1999-01-01

    Allogenic bone grafts have been used after various processing in each institute was made by lyophilized allogenic bone and used for maxillofacial reconstruction. Three types of lyophilized allogenic bone grafts as powder, chip and block form were performed to reconstruct the following defects: 1) maxillectomy, 2) mandiblectomy, 3) cystectomy, 4) cleft alveolus, 5) gap in orthognathic osteotomy, 6) peri-implant defect, 7) extraction socket, and 8) facial contouring. Above defects can be classified as cystic and discontinuity defects of the maxilia and the mandible. Because discontinuity defects have more difficult problems to reconstruct considering mechanical strength of the allogenic bone. We performed allogenic bone grafts on 50 cystic defects and 12 discontinuity defects of the jaws. Among them, 3 cases were removed due to infection, and the others had no complications. In reconstruction of cystic defects, the defects were filled with allogenic chip which were made from allogenic block bone at the surgery, which later were changed to host bone. Three cases of them showed tooth eruption through the allogenic bone grafting site, changing the eruption pathway, which was interrupted by the lesion. in reconstruction of discontinuity defects, usually allogenic bone has been used as a tray, in which PMCB or demineralized bone chips were filled. But we tried to reconstruct this discontinuity defect using allogeneic bone block without inside filling of PMCB different from tray type. We will present the results of allogenic bone grafts using cranial bone, costochondral graft, and the mandible

  18. Early NK Cell Reconstitution Predicts Overall Survival in T-Cell Replete Allogeneic Hematopoietic Stem Cell Transplantation

    DEFF Research Database (Denmark)

    Minculescu, Lia; Marquart, Hanne Vibeke; Friis, Lone Smidstrups

    2016-01-01

    Early immune reconstitution plays a critical role in clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells are the first lymphocytes to recover after transplantation and are considered powerful effector cells in HSCT. We aimed to evaluate...... the clinical impact of early NK cell recovery in T-cell replete transplant recipients. Immune reconstitution was studied in 298 adult patients undergoing HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) from 2005 to 2013. In multivariate analysis NK...... cell numbers day 30 (NK30) >150cells/µL were independently associated with superior overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.95, p=0.01). Cumulative incidence analyses showed that patients with NK30 >150cells/µL had significantly less transplant related mortality (TRM), p=0...

  19. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Noerskov, K. H.; Schjødt, I.; Syrjala, K. L.

    2016-01-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction...

  20. Soluble urokinase plasminogen activator receptor during allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Haastrup, E; Andersen, J; Ostrowski, S R

    2011-01-01

    the course of allogeneic stem cell transplantation (SCT). Twenty SCT patients were included in the study. suPAR was measured by ELISA in daily taken plasma samples during the pretransplant conditioning with chemotherapy and weekly for 1 month after infusion of the graft. suPAR levels before the start...

  1. Single-centre experience of allogeneic haemopoietic stem cell ...

    African Journals Online (AJOL)

    Allogeneic haemopoietic stem cell transplant (Allo-HSCT) is used to treat a broad but well-defined range of paediatric conditions, most frequently in paediatric oncology for treatment intensification or salvage therapy for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Allo-HSCT is also indicated in.

  2. CD4 T cells mediate both positive and negative regulation of the immune response to HIV infection: complex role of T follicular helper cells and Regulatory T cells in pathogenesis

    Directory of Open Access Journals (Sweden)

    Chansavath ePhetsouphanh

    2015-01-01

    Full Text Available HIV-1 infection results in chronic activation of cells in lymphoid tissue, including T cells, B cells and myeloid lineage cells. The resulting characteristic hyperplasia is an amalgam of proliferating host immune cells in the adaptive response, increased concentrations of innate response mediators due to viral and bacterial products, and homeostatic responses to inflammation. While it is generally thought that CD4 T cells are greatly depleted, in fact, two types of CD4 T cells appear to be increased, namely regulatory T cells (Tregs and T follicular helper cells (Tfh. These cells have opposing roles, but may both be important in the pathogenic process. Whether Tregs are failing in their role to limit lymphocyte activation is unclear, but there is no doubt now that Tfh are associated with B cell hyperplasia and increased germinal centre activity. Antiretroviral therapy (ART may reduce the lymphocyte activation, but not completely, and therefore there is a need for interventions that selectively enhance normal CD4 function without exacerbating Tfh, B cell or Treg dysfunction.

  3. [Exosomes and Immune Cells].

    Science.gov (United States)

    Seo, Naohiro

    2017-05-01

    In addition to the cytokines and cytotoxic granules, exosomes have been known as the intercellular communicator and cytotoxic missile of immune cells for the past decade. It has been well known that mature dendritic cell(DC)-derived exosomes participate in the T cell and natural killer(NK)cell activation, while immature DCs secrete tolerogenic exosomes for regulatory T(Treg)cell generation. Treg cell-derived EVs act as a suppressor against pathogenic type-1 T helper(Th1)cell responses. CD8+ T cells produce tumoricidal exosomes for preventing tumor invasion and metastasis transiently after T cell receptor(TCR)-mediated stimulation. Thus, immune cells produce functional exosomes in the activation state- and/or differentiation stage-dependent manner. In this review, the role of immune cell-derived exosomes will be introduced, focusing mainly on immune reaction against tumor.

  4. Interaction between adipose tissue-derived mesenchymal stem cells and regulatory T-cells

    NARCIS (Netherlands)

    A.U. Engela (Anja); C.C. Baan (Carla); A. Peeters (Anna); W. Weimar (Willem); M.J. Hoogduijn (Martin)

    2013-01-01

    textabstractMesenchymal stem cells (MSCs) exhibit immunosuppressive capabilities, which have evoked interest in their application as cell therapy in transplant patients. So far it has been unclear whether allogeneic MSCs and host regulatory T-cells (Tregs) functionally influence each other. We

  5. Tolerance, immunocompetence, and secondary disease in fully allogeneic radiation chimeras

    International Nuclear Information System (INIS)

    Rayfield, L.S.; Brent, L.

    1983-01-01

    The aim of this study was to ascertain the extent to which secondary disease and mortality in fully allogeneic chimeras (C57BL leads to CBA) is caused (if at all) by a delayed graft-versus-host reaction. Adult CBA males were thymectomized, irradiated, and reconstituted with T-lymphocyte-depleted C57BL or CBA bone marrow cells (BMC), followed three weeks after irradiation by implantation under the kidney capsule of thymic lobes from C57BL or CBA fetal or adult donors. These mice were observed for the development of secondary disease for periods in excess of 250 days, and they were examined at 5 weeks or 4 months for T lymphocyte reactivity and tolerance to alloantigens, using the cell-mediated lympholysis assay (CML). The following results were obtained. First, removal of T lymphocytes with anti-Thy 1 antibody and complement from allogeneic bone marrow did not prevent wasting and eventual death, although it prolonged the lifespan of mice substantially. Second, T lymphocytes generated from bone marrow-derived precursor cells became tolerant of the histocompatibility antigens of the thymus donor strain but remained normally reactive to third-party antigens. Third, allogeneic radiation chimeras did not survive as well as animals reconstituted with syngeneic cells, even when they were demonstrably tolerant in CML. Fourth, C57BL BMC maturing in a CBA host equipped with a C57BL thymus graft did not become tolerant of host antigens, indicating that extra-thymic tolerance does not occur in fully allogeneic--as opposed to semiallogeneic--chimeras. It is argued that the function of B lymphocytes and/or accessory cells is impaired in fully allogeneic radiation chimeras, and that the mortality observed was directly related to the resulting immunodeficiency. The relevance of the results described in this paper to clinical bone marrow transplantation is discussed

  6. 'Mini' total body irradiation and allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Gocheva, L.; Sergieva, K.; Koleva, I.; Avramova, V.; Vassileva, V.; Georgieva, S.; Sultanov, B.

    2006-01-01

    Full text: The total body irradiation (TBI) combined with intensive chemotherapy plays an important role in the preparation of patients for bone marrow transplantation (BMT). The first autologous BMT in Bulgaria was performed in 1997 in the Specialized Pediatric Hospital for Active Treatment (SPHAT) of oncohematological diseases. The first TBI, followed by allogeneic BMT, was carried out in 2002 in the 'Queen Giovanna' University Hospital, after which its routine application as a basic form of large field radiotherapy and a main stage of the conditioning regimen for BMT was started. Fourteen allogeneic BMTs including TBI as a basic conditioning regimen have been performed till May 2006. The objective of the present report is to present the first clinical observations in the Bulgarian oncological practice on 'mini' TBI followed by allogeneic blood stem cell transplantation. During the period October 2005 - May 2006, 'mini' TBI followed by allogeneic BMT was carried out for two patients of the age 43 and 50 years. The diagnosis of both patients was acute non-lymphoblastic leukemia, in the remission stage, after one relapse, respectively. Intensive preceding chemotherapy was applied for both patients. A conditioning regimen was applied including the fludarabine purine analogue (3 x 30 mg/m 2 ) and 200 cGy TBI. It was followed by transplantation of allogeneic cell concentrate containing 2.5 x10 6 /kg CD34+ and 4.0 x10 6 /kg CD34+ blood stem cells of partially compatible family donors (a sister and a son), which were tolerable for the patients without complications. Cyclosporine and mycophelonate mofetile were applied as post-transplantation treatment. Active antibiotic, antiviral, symptomatic and substituting therapy, as well as GvHD prophylaxis was applied for both patients. Good clinical tolerance was recorded for the applied low dose conditioning regimen. The patients were discharged within 30 days in good general condition and stable draft action, with

  7. Regulatory Immunotherapy in Bone Marrow Transplantation

    Directory of Open Access Journals (Sweden)

    Vanessa Morales-Tirado

    2011-01-01

    Full Text Available Every year individuals receive hematopoietic stem cell transplantation (HSCT to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT and regulatory T cells (Treg, and their current and potential roles in tolerance induction after allogeneic HSCT.

  8. Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

    Science.gov (United States)

    Burke, Michael J; Cao, Qing; Trotz, Barb; Weigel, Brenda; Kumar, Ashish; Smith, Angela; Verneris, Michael R

    2009-12-15

    Allogeneic hematopoietic cell transplant (HCT) with best available donor for children with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allogeneic HCT is more uncertain. We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for 37 children with Ph+ ALL who received an allogeneic HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4-16.4) years. Thirteen patients received imatinib therapy pre- and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n = 23) or only post-HCT relapse (n = 1) (non-imatinib group). There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62%/15% vs. 53%/26%; P = 0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allogeneic HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in >or=CR2 (71%/16% vs. 29%/36%; P = 0.01; P = 0.05). Based on this retrospective analysis at a single institution, the use of imatinib either pre- and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allogeneic HCT with the best available donor should be encouraged in CR1.

  9. Donor-specific Anti-HLA antibodies in allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Sarah Morin-Zorman

    2016-08-01

    Full Text Available Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of Human Leukocyte Antigen (HLA incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of Primary Graft Failure (PGF, a severe complication of AHSCT that occurs in 3 to 4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 to 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect Donor Specific Antibodies (DSA in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field.

  10. Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation

    International Nuclear Information System (INIS)

    Roesler, J.; Baccarini, M.; Vogt, B.; Lohmann-Matthes, M.L.

    1989-01-01

    We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereas the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens

  11. Immune-modulatory effects of syncytiotrophoblast extracellular vesicles in pregnancy and preeclampsia

    NARCIS (Netherlands)

    Göhner, Claudia; Plösch, Torsten; Faas, Marijke M

    2017-01-01

    Unique immunologic adaptations exist to successfully establish and maintain pregnancy and to avoid an immune attack against the semi allogenic fetus. These adaptations occur both locally at the maternofetal interface and in the peripheral circulation and affect the innate as well as the adaptive

  12. A global regulatory science agenda for vaccines.

    Science.gov (United States)

    Elmgren, Lindsay; Li, Xuguang; Wilson, Carolyn; Ball, Robert; Wang, Junzhi; Cichutek, Klaus; Pfleiderer, Michael; Kato, Atsushi; Cavaleri, Marco; Southern, James; Jivapaisarnpong, Teeranart; Minor, Philip; Griffiths, Elwyn; Sohn, Yeowon; Wood, David

    2013-04-18

    The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable

  13. Regulatory activities

    International Nuclear Information System (INIS)

    2001-01-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  14. Pelvic reconstruction with allogeneic bone graft after tumor resection

    Science.gov (United States)

    Wang, Wei; Bi, Wen Zhi; Yang, Jing; Han, Gang; Jia, Jin Peng

    2013-01-01

    OBJECTIVES : Pelvic reconstruction after tumor resection is challenging. METHODS: A retrospective study had been preformed to compare the outcomes among patients who received pelvic reconstructive surgery with allogeneic bone graft after en bloc resection of pelvic tumors and patients who received en bloc resection only. RESULTS: Patients without reconstruction had significantly lower functional scores at 3 months (10 vs. 15, P = 0.001) and 6 months after surgery (18.5 vs. 22, P = 0.0024), a shorter duration of hospitalization (16 day vs. 40 days, P 0.05). CONCLUSIONS : Pelvic reconstruction with allogeneic bone graft after surgical management of pelvic tumors is associated with satisfactory surgical and functional outcomes. Further clinical studies are required to explore how to select the best reconstruction method. Level of Evidence IV, Case Series. PMID:24453659

  15. Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection.

    Science.gov (United States)

    Maric-Biresev, Jelena; Hunn, Julia P; Krut, Oleg; Helms, J Bernd; Martens, Sascha; Howard, Jonathan C

    2016-04-20

    The interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse. We show that the three regulatory IRG proteins (GMS sub-family), including Irgm1, each of which localizes to distinct sets of endocellular membranes, play an important role during the cellular response to IFN-γ, each protecting specific membranes from off-target activation of effector IRG proteins (GKS sub-family). In the absence of Irgm1, which is localized mainly at lysosomal and Golgi membranes, activated GKS proteins load onto lysosomes, and are associated with reduced lysosomal acidity and failure to process autophagosomes. Another GMS protein, Irgm3, is localized to endoplasmic reticulum (ER) membranes; in the Irgm3-deficient mouse, activated GKS proteins are found at the ER. The Irgm3-deficient mouse does not show the drastic phenotype of the Irgm1 mouse. In the Irgm1/Irgm3 double knock-out mouse, activated GKS proteins associate with lipid droplets, but not with lysosomes, and the Irgm1/Irgm3(-/-) does not have the generalized immunodeficiency phenotype expected from its Irgm1 deficiency. The membrane targeting properties of the three GMS proteins to specific endocellular membranes prevent accumulation of activated GKS protein effectors on the corresponding membranes and thus enable GKS proteins to distinguish organellar cellular membranes from the membranes of pathogen vacuoles. Our data suggest that the generalized lymphomyeloid collapse that occurs in Irgm1(-/-) mice upon infection with a variety of pathogens may be due to lysosomal damage caused by off-target activation of GKS proteins on lysosomal

  16. Financial burden in recipients of allogeneic hematopoietic cell transplantation.

    Science.gov (United States)

    Khera, Nandita; Chang, Yu-hui; Hashmi, Shahrukh; Slack, James; Beebe, Timothy; Roy, Vivek; Noel, Pierre; Fauble, Veena; Sproat, Lisa; Tilburt, Jon; Leis, Jose F; Mikhael, Joseph

    2014-09-01

    Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  18. Rabbit articular cartilage defects treated by allogenic chondrocyte transplantation

    OpenAIRE

    Boopalan, P. R. J. V. C.; Sathishkumar, Solomon; Kumar, Senthil; Chittaranjan, Samuel

    2006-01-01

    Articular cartilage defects have a poor capacity for repair. Most of the current treatment options result in the formation of fibro-cartilage, which is functionally inferior to normal hyaline articular cartilage. We studied the effectiveness of allogenic chondrocyte transplantation for focal articular cartilage defects in rabbits. Chondrocytes were cultured in vitro from cartilage harvested from the knee joints of a New Zealand White rabbit. A 3 mm defect was created in the articular cartilag...

  19. Chimeric autologous/allogeneic constructs for skin regeneration.

    Science.gov (United States)

    Rasmussen, Cathy Ann; Tam, Joshua; Steiglitz, Barry M; Bauer, Rebecca L; Peters, Noel R; Wang, Ying; Anderson, R Rox; Allen-Hoffmann, B Lynn

    2014-08-01

    The ideal treatment for severe cutaneous injuries would eliminate the need for autografts and promote fully functional, aesthetically pleasing autologous skin regeneration. NIKS progenitor cell-based skin tissues have been developed to promote healing by providing barrier function and delivering wound healing factors. Independently, a device has recently been created to "copy" skin by harvesting full-thickness microscopic tissue columns (MTCs) in lieu of autografts traditionally harvested as sheets. We evaluated the feasibility of combining these two technologies by embedding MTCs in NIKS-based skin tissues to generate chimeric autologous/allogeneic constructs. Chimeric constructs have the potential to provide immediate wound coverage, eliminate painful donor site wounds, and promote restoration of a pigmented skin tissue possessing hair follicles, sweat glands, and sebaceous glands. After MTC insertion, chimeric constructs and controls were reintroduced into air-interface culture and maintained in vitro for several weeks. Tissue viability, proliferative capacity, and morphology were evaluated after long-term culture. Our results confirmed successful MTC insertion and integration, and demonstrated the feasibility of generating chimeric autologous/allogeneic constructs that preserved the viability, proliferative capacity, and structure of autologous pigmented skin. These feasibility studies established the proof-of-principle necessary to further develop chimeric autologous/allogeneic constructs for the treatment of complex skin defects. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

  20. Clinical Allogeneic and Autologous Islet Cell Transplantation: Update

    Directory of Open Access Journals (Sweden)

    Shinichi Matsumoto

    2011-06-01

    Full Text Available Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities.

  1. Reduction in requirements for allogeneic blood products: nonpharmacologic methods.

    Science.gov (United States)

    Hardy, J F; Bélisle, S; Janvier, G; Samama, M

    1996-12-01

    Various strategies have been proposed to decrease bleeding and allogeneic transfusion requirements during and after cardiac operations. This article attempts to document the usefulness, or lack thereof, of the nonpharmacologic methods available in clinical practice. Blood conservation methods were reviewed in chronologic order, as they become available to patients during the perisurgical period. The literature in support of or against each strategy was reexamined critically. Avoidance of preoperative anemia and adherence to published guidelines for the practice of transfusion are of paramount importance. Intraoperatively, tolerance of low hemoglobin concentrations and use of autologous blood (predonated or harvested before bypass) will reduce allogeneic transfusions. The usefulness of plateletpheresis and retransfusion of shed mediastinal fluid remains controversial. Intraoperatively and postoperatively, maintenance of normothermia contributes to improved hemostasis. Several approaches have been shown to be effective. An efficient combination of methods can reduce, and sometimes abolish, the need for allogeneic blood products after cardiac operations, inasmuch as all those involved in the care of cardiac surgical patients adhere thoughtfully to existing transfusion guidelines.

  2. [Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank].

    Science.gov (United States)

    Barriga, Francisco; Wietstruck, Angélica; Rojas, Nicolás; Bertin, Pablo; Pizarro, Isabel; Carmona, Amanda; Guilof, Alejandro; Rojas, Iván; Oyarzún, Enrique

    2013-08-01

    Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

  3. A new method of prefabricated vascularized allogenic bone grafts for maxillo-mandibular reconstruction

    International Nuclear Information System (INIS)

    Pill-Hoon Choung

    1999-01-01

    Although there are various applications of allogenic bone grafts, a new technique of prevascularized lyophilized allogenic bone grafting for maxillo-mandibular reconstruction will be presented. Allogenic bone has been made by author's protocol for jaw defects as a powder, chip or block bone type. The author used lyophilized allogenic bone grafts for discontinuity defects as a block bone. In those cases, neovascularization and resorption of the allogenic bone were important factors for success of grafting. To overcome the problems, the author designed the technique of prefabricated vascularization of allogenic bone, which was lyophilized cranium, with an application of bovine BMP or not. Lyophilized cranial bone was designed for the defects and was put into the scalp. After confirming a hot spot via scintigram several months later, vascularized allogenic bone was harvested pedicled on the parietotemporal fascia based on the superficial temporal artery and vein. Vascularized allogenic cranial bone was rotated into the defect and fixed rigidly. Postoperatively, there was no severe resorption and functional disturbance of the mandible. In this technique, BMP seems to be an important role to help osteogenesis and neovascularization. Eight patients underwent prefabricated vascularization of allogenic bone grafts. Among them, four cases of reconstruction in mandibular discontinuity defects and one case of reconstruction in maxillectomy defect underwent this method, which will be presented with good results. This method may be an alternative technique of microvascular free bone graft

  4. Childhood Immunization

    Science.gov (United States)

    ... lowest levels in history, thanks to years of immunization. Children must get at least some vaccines before ... child provide protection for many years, adults need immunizations too. Centers for Disease Control and Prevention

  5. Immunizations - diabetes

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000331.htm Immunizations - diabetes To use the sharing features on this page, please enable JavaScript. Immunizations (vaccines or vaccinations) help protect you from some ...

  6. Successful Reduced Intensity Allogeneic Transplant With Full Donor Chimerism and Good Quality of Life in Adolescent Patient With Wiskott-Aldrich Syndrome.

    Science.gov (United States)

    Ali, Salah; Gacsadi, Anna; McDougall, Elizabeth; Armstrong, Christine; Krueger, Joerg; Schechter, Tal; Ali, Muhammad

    2017-07-01

    Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by microthrombocytopenia, eczema, immune deficiency, and autoimmune phenomena. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Myeloablative conditioning is the most common regimen used for HSCT in patients with WAS to avoid the risk of mixed donor chimerism and autoimmunity post-HSCT. There is limited data on the use of reduced intensity conditioning for HSCT in patients with WAS. Here, we report a case with severe phenotype of WAS transplanted successfully with reduced intensity conditioning, which is an acceptable conditioning regimen and can be considered in patients with WAS with significantly impaired organ functions.

  7. Immunization Coverage

    Science.gov (United States)

    ... room/fact-sheets/detail/immunization-coverage","@context":"http://schema.org","@type":"Article"}; العربية 中文 français русский español ... Plan Global Health Observatory (GHO) data - Immunization More information on vaccines and immunization News 1 in 10 ...

  8. Use of G-CSF-stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.

    Science.gov (United States)

    Chang, Ying-Jun; Huang, Xiao-Jun

    2011-01-01

    In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony-stimulating factor (G-CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen-matched or haploidentical transplant settings, available data have established the safety of using G-CSF-stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G-CSF-primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft-versus-host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G-CSF-stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation. © 2010 John Wiley & Sons A/S.

  9. Dominance and persistence of donor marrow in long-lived allogeneic radiation chimeras obtained with unmanipulated bone marrow

    International Nuclear Information System (INIS)

    Pierpaoli, W.; Maestroni, G.J.M.

    1983-01-01

    Allogeneic, H-2-incompatible irradiation chimeras (H-2sup(d) → H-2sup(b)) constructed with normal, unmanipulated bone marrow and with marrow-derived factors live long and do not manifest a GvH disease. Their response to primary immunization is deficient but their alloreactivity is normal. This chimeric allotolerance cannot be passively transferred from chimeric donors to normal irradiated recipients. Passive transfer of both donor- or recipient-type immuno-competent T-cells into the chimeric mice does not lead to syngeneic reconstitution, rejection of the engrafted marrow or GvH disease, and the mice maintain permanently their chimerism. This new model demonstrates that chimerism is not eradicable in long-lived chimeras reconstituted with unmanipulated bone marrow, and that the bone marrow itself plays a dominant role in maintenance of chimerism. (Auth.)

  10. Immunizing Children

    Directory of Open Access Journals (Sweden)

    Geraldine Jody Macdonald

    2014-11-01

    Full Text Available This article addresses the complex contexts within which Canadian health professionals engage in immunizing children and focuses on the Canadian practice guidelines and current scientific evidence that direct Canadian health professional competencies. The article begins by presenting two current global vaccine initiatives and links these to immunization in Canada. A selected literature review identifies current best immunization practices. With the purpose of promoting quality improvement, three key Canadian immunization competencies for health professional are highlighted: communication with parents, including those who are experiencing vaccine hesitancy; administration of immunizing agents; and documentation of immunizations. Health professionals are encouraged to reflect on immunization competencies and ensure evidence-based practices underpin vaccine delivery in their primary care settings.

  11. The clinical and pathogenetic value of Foxp3+ T regulatory cells in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    A. S. Avdeeva

    2016-01-01

    Full Text Available T regulatory cells (Tregs play a key role in the immune system due to the suppression of a hyperimmune response to autoantigens and opportunistic enteric microorganisms. In recent years, there has been evidence that Tregs can suppress various immunoinflammatory responses to a wide range of physiological and pathological stimuli, including microorganisms, tumor cells, allogeneic grafts, and fetal cells.Tregs express a broad spectrum of membrane molecules that determine their functional activity and make it possible to identify these cells; however, none has discovered a universal surface marker that would distinguish this cell subpopulation from a pool of T lymphocytes. The most specific intracellular marker for Tregs is the nuclear transcription factor Foxp3 that is of fundamental importance in the development of Tregs and their inhibitory function.The results of the vast majority of studies indicate that there are increased numbers of Tregs in the synovial fluid of patients with rheumatoid arthritis (RA; however, the data on the level of this cell population in their peripheral blood are very contradictory. The majority of investigators have observed a decrease in the percentage of circulating Tregs while other studies have revealed its increase or no differences from the corresponding value of healthy donors or patients with osteoarthritis. It is believed that a quantitative defect in CD4+CD25+Foxp3+CD127 regulatory cells is especially characteristic of early RA and associated with the risk of the latter in asymptomatic patients positive for anti-cyclic citrullinated peptide antibodies. The use of disease-modifying antirheumatic drugs and biologic agents is accompanied by a certain change in the level and functional activity of Tregs, which is responsible for the therapeutic effect of the medicaments.Thus, an important part is assigned to Tregs in the pathogenesis of autoimmune rheumatic diseases, RA in particular. The decrease in the level

  12. Mechanisms regulating skin immunity and inflammation.

    Science.gov (United States)

    Pasparakis, Manolis; Haase, Ingo; Nestle, Frank O

    2014-05-01

    Immune responses in the skin are important for host defence against pathogenic microorganisms. However, dysregulated immune reactions can cause chronic inflammatory skin diseases. Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease. In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation.

  13. Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Anthony Oyekunle

    2011-01-01

    Full Text Available In recent years, the panel of known molecular mutations in acute lymphoblastic leukemia (ALL has been continuously increased. In Philadelphia-positive ALL, deletions of the IKZF1 gene were identified as prognostically adverse factors. These improved insights in the molecular background and the clinical heterogeneity of distinct cytogenetic subgroups may allow most differentiated therapeutic decisions, for example, with respect to the indication to allogeneic HSCT within genetically defined ALL subtypes. Quantitative real-time PCR allows highly sensitive monitoring of the minimal residual disease (MRD load, either based on reciprocal gene fusions or immune gene rearrangements. Molecular diagnostics provided the basis for targeted therapy concepts, for example, combining the tyrosine kinase inhibitor imatinib with chemotherapy in patients with Philadelphia-positive ALL. Screening for BCR-ABL1 mutations in Philadelphia-positive ALL allows to identify patients who may benefit from second-generation tyrosine kinase inhibitors or from novel compounds targeting the T315I mutation. Considering the central role of the molecular techniques for the management of patients with ALL, efforts should be made to facilitate and harmonize immunophenotyping, cytogenetics, and molecular mutation screening. Furthermore, the potential of high-throughput sequencing should be evaluated for diagnosis and follow-up of patients with B-lineage ALL.

  14. RENAL ALLOGENEIC TRANSPLANTATION IN PATIENT WITH HAEMOPHILIA B

    Directory of Open Access Journals (Sweden)

    N. V. Purlo

    2014-01-01

    Full Text Available We report the case of successful renal allogeneic transplantation and treatment in a 56-year-old patient with haemophilia B at Hematology Research Center. He has received replacement therapy by factor IX since 2010. The transplant is marked with good renal function during 13 post-transplant months without episodes of rejection or bleeding complications. The complicated surgical interventions are possible in patients with haemophilia В аnd end-stage chronic renal failure in the presence of replacement therapy of IX factor for the purpose of achievement of optimum hemostasis.

  15. Unique aspects of the perinatal immune system.

    Science.gov (United States)

    Zhang, Xiaoming; Zhivaki, Dania; Lo-Man, Richard

    2017-08-01

    The early stages of life are associated with increased susceptibility to infection, which is in part due to an ineffective immune system. In the context of infection, the immune system must be stimulated to provide efficient protection while avoiding insufficient or excessive activation. Yet, in early life, age-dependent immune regulation at molecular and cellular levels contributes to a reduced immunological fitness in terms of pathogen clearance and response to vaccines. To enable microbial colonization to be tolerated at birth, epigenetic immune cell programming and early life-specific immune regulatory and effector mechanisms ensure that vital functions and organ development are supported and that tissue damage is avoided. Advancement in our understanding of age-related remodelling of immune networks and the consequent tuning of immune responsiveness will open up new possibilities for immune intervention and vaccine strategies that are designed specifically for early life.

  16. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

    Science.gov (United States)

    Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B

    2016-12-22

    Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.

  17. Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

    Science.gov (United States)

    2017-04-03

    Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL)

  18. Aberrant Pregnancy Adaptations in the Peripheral Immune Response in Type 1 Diabetes: A Rat Model.

    Directory of Open Access Journals (Sweden)

    Bart Groen

    Full Text Available Despite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune-response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications.We studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes-resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats.We observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats.This study suggests that even in the face of strict normoglycemia, pregnancy complications

  19. Indoleamine 2,3-dioxygenase 1 (IDO1 activity correlates with immune system abnormalities in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Bonanno Giuseppina

    2012-12-01

    Full Text Available Abstract Background Multiple myeloma (MM is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1 degrades tryptophan into kynurenine (KYN, which inhibits effector T cells and promote regulatory T-cell (Treg differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment. Methods We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3 or smoldering MM (SMM; n=4. IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF and with the frequency of Treg cells and NY-ESO-1-specific CD8+ T cells. Results KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4+CD25+FoxP3+ Treg cells and the contraction of NY-ESO-1-specific CD8+ T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4+ T cells into bona fide CD4+CD25hiFoxP3hi Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by d,l-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO+ myeloma disease compared with patients having IDO- MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity. Conclusions These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.

  20. The Regulatory Function of Eosinophils.

    Science.gov (United States)

    Wen, Ting; Rothenberg, Marc E

    2016-10-01

    Eosinophils are a minority circulating granulocyte classically viewed as being involved in host defense against parasites and promoting allergic reactions. However, a series of new regulatory functions for these cells have been identified in the past decade. During homeostasis, eosinophils develop in the bone marrow and migrate from the blood into target tissues following an eotaxin gradient, with interleukin-5 being a key cytokine for eosinophil proliferation, survival, and priming. In multiple target tissues, eosinophils actively regulate a variety of immune functions through their vast arsenal of granule products and cytokines, as well as direct cellular interaction with cells in proximity. The immunologic regulation of eosinophils extends from innate immunity to adaptive immunity and also involves non-immune cells. Herein, we summarize recent findings regarding novel roles of murine and human eosinophils, focusing on interactions with other hematopoietic cells. We also review new experimental tools available and remaining questions to uncover a greater understanding of this enigmatic cell.

  1. Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis.

    Science.gov (United States)

    Bergeron, A; Godet, C; Chevret, S; Lorillon, G; Peffault de Latour, R; de Revel, T; Robin, M; Ribaud, P; Socié, G; Tazi, A

    2013-06-01

    Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic SCT (HSCT) is recognized as a new-onset obstructive lung defect (OLD) in pulmonary function testing and is related to pulmonary chronic GVHD. Little is known about the different phenotypes of patients with BOS and their outcomes. We reviewed the data of all allogeneic HSCT recipients referred to our pulmonary department for a non-infectious bronchial disease between 1999 and 2010. We identified 103 patients (BOS (n=77), asthma (n=11) and chronic bronchitis (n=15)). In patients with BOS, we identified two functional phenotypes: a typical OLD, that is, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 (n=53), and an atypical OLD with a concomitant decrease in the FEV1 <80% and FVC <80% predicted with a normal total lung capacity (n=24). The typical OLD was characterized by more severe FEV1 and fewer centrilobular nodules on the computed tomography scan. The FEV1 was not significantly affected during the follow-up, regardless of the phenotype. In addition to acute and extensive chronic GVHD, only the occurrence of BOS soon after transplantation and the intentional treatment of BOS with steroids were associated with a poor survival. The determination of patient subgroups should be explored to improve the management of this condition.

  2. Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Hanajiri, Ryo; Kobayashi, Takeshi; Yoshioka, Kosuke; Watanabe, Daisuke; Watakabe, Kyoko; Murata, Yutaka; Hagino, Takeshi; Seno, Yasushi; Najima, Yuho; Igarashi, Aiko; Doki, Noriko; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2017-03-01

    Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04). Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  3. Response to intravenous allogeneic equine cord-blood-derived mesenchymal stromal cells administered from chilled or frozen state in serum and protein free media

    Directory of Open Access Journals (Sweden)

    Lynn Brandon Williams

    2016-07-01

    following hypothermic or frozen simulated transport, respectively. CB-MSC do not elicit clinical abnormalities, but allogeneic stimulation of CD4+ and CD8+ lymphocyte populations may occur. Future studies should include in vitro or in vivo evaluation of cell mediated or adaptive immunity to autologous, identical allogeneic, or MSC originating from additional unrelated individuals in order to better characterize this response.□

  4. The mechanism of humoral immune response to allogeneic organ transplantation

    Directory of Open Access Journals (Sweden)

    A. S. Berkos

    2017-01-01

    Full Text Available The problem of antibody-mediated rejection of donor organ remains extremely relevant. The main targets of the antibodies are mainly donor HLA-antigens (Human Leucocyte Antigens, expressed, in particular, by the cells of graft vascular endothelium. This review describes the mechanisms of the development of humoral alloimmunity which are based on B-cell recognition of epitopes of donor HLA-molecules and affinity maturation of B-cell receptors in the germinal centers of peripheral lymphatic system. Monitoring of epitope load and cross-reactivity indicators to evaluate HLA-compatibility of donor and recipient plays an important role in the prevention of allograft humoral rejection.

  5. Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors

    DEFF Research Database (Denmark)

    Saito, Fumiji; Hirayasu, Kouyuki; Satoh, Takeshi

    2017-01-01

    , but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150-200 genes per parasite genome...

  6. Plasma-mediated immune suppression : a neonatal perspective

    NARCIS (Netherlands)

    Belderbos, Mirjam E.; Levy, Ofer; Meyaard, Linde; Bont, Louis

    Plasma is a rich mixture of immune regulatory factors that shape immune cell function. This immunomodulatory role of plasma is especially important in neonates. To maintain in utero feto-maternal tolerance and to allow for microbial colonization after birth, the neonatal immune system is biased

  7. Immune System

    Science.gov (United States)

    A properly functioning immune system is essential to good health. It defends the body against infectious agents and in some cases tumor cells. Individuals with immune deficiencies resulting from genetic defects, diseases (e.g., AIDS, leukemia), or drug therapies are more suscepti...

  8. Skin Immunization Obviates Alcohol-Related Immune Dysfunction

    Directory of Open Access Journals (Sweden)

    Rhonda M. Brand

    2015-11-01

    Full Text Available Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results in lower alcohol levels in skin than blood, we hypothesized that the skin immune network may be relatively preserved, enabling skin-targeted immunizations to obviate the immune inhibitory effects of alcohol consumption on conventional vaccines. We employed the two most common chronic EtOH mouse feeding models, the liver-damaging Lieber-DeCarli (LD and liver-sparing Meadows-Cook (MC diets, to examine the roles of EtOH and/or EtOH-induced liver dysfunction on alcohol related immunosuppression. Pair-fed mice were immunized against the model antigen ovalbumin (OVA by DNA immunization or against flu by administering the protein-based influenza vaccine either systemically (IV, IM, directly to liver (hydrodynamic, or cutaneously (biolistic, ID. We measured resulting tissue EtOH levels, liver stress, regulatory T cell (Treg, and myeloid-derived suppressor cell (MDSC populations. We compared immune responsiveness by measuring delayed-type hypersensitivity (DTH, antigen-specific cytotoxic T lymphocyte (CTL, and antibody induction as a function of delivery route and feeding model. We found that, as expected, and independent of the feeding model, EtOH ingestion inhibits DTH, CTL lysis, and antigen-specific total IgG induced by traditional systemic vaccines. On the other hand, skin-targeted vaccines were equally immunogenic in alcohol-exposed and non-exposed subjects, suggesting that cutaneous immunization may result in more efficacious vaccination in alcohol-ingesting subjects.

  9. Allogenic blood transfusion following total hip arthroplasty: results from the nationwide inpatient sample, 2000 to 2009.

    Science.gov (United States)

    Saleh, Anas; Small, Travis; Chandran Pillai, Aiswarya Lekshmi Pillai; Schiltz, Nicholas K; Klika, Alison K; Barsoum, Wael K

    2014-09-17

    The large-scale utilization of allogenic blood transfusion and its associated outcomes have been described in critically ill patients and those undergoing high-risk cardiac surgery but not in patients undergoing elective total hip arthroplasty. The objective of this study was to determine the trends in utilization and outcomes of allogenic blood transfusion in patients undergoing primary total hip arthroplasty in the United States from 2000 to 2009. An observational cohort of 2,087,423 patients who underwent primary total hip arthroplasty from 2000 to 2009 was identified in the Nationwide Inpatient Sample. International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes 99.03 and 99.04 were used to identify patients who received allogenic blood products during their hospital stay. Risk factors for allogenic transfusions were identified with use of multivariable logistic regression models. We used propensity score matching to estimate the adjusted association between transfusion and surgical outcomes. The rate of allogenic blood transfusion increased from 11.8% in 2000 to 19.0% in 2009. Patient-related risk factors for receiving an allogenic blood transfusion include an older age, female sex, black race, and Medicaid insurance. Hospital-related risk factors include rural location, smaller size, and non-academic status. After adjusting for confounders, allogenic blood transfusion was associated with a longer hospital stay (0.58 ± 0.02 day; p conservation methods. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.

  10. FOXP3-specific immunity

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2013-01-01

    Forkhead box P3 (FOXP3)-specific cytotoxic CD8(+) T cells are present among human peripheral blood mononuclear cells (PBMCs), especially in cancer patients. Such T lymphocytes are able not only to specifically recognize dendritic cells (DCs) that have been exposed to recombinant FOXP3 and regulat...... and regulatory T cells, but also to kill FOXP3(+) malignant T cells. The natural occurrence of FOXP3-specific cytotoxic T lymphocytes among human PBMCs suggests a general role for these cells in the complex network of immune regulation....

  11. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies.

    Science.gov (United States)

    Liu, Jun; Zhong, Jiang F; Zhang, Xi; Zhang, Cheng

    2017-01-31

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the cornerstone in treatment of hematological malignancies. However, relapse of the hematological disease after allo-HSCT remains a challenge and is associated with poor long-term survival. Chimeric antigen receptor redirected T cells (CAR-T cells) can lead to disease remission in patients with relapsed/refractory hematological malignancies. However, the therapeutic window for infusion of CAR-T cells post allo-HSCT and its efficacy are debatable. In this review, we first discuss the use of CAR-T cells for relapsed cases after allo-HSCT. We then review the toxicities and the occurrence of graft-versus-host disease in relapsed patients who received CAR-T cells post allo-HSCT. Finally, we review clinical trial registrations and the therapeutic time window for infusion of CAR-T cells post allo-HSCT. The treatment of allogeneic CAR-T cells is beneficial for patients with relapsed B cell malignancies after allo-HSCT with low toxicities and complications. However, multicenter clinical trials with larger sample sizes should be performed to select the optimal therapeutic window and confirm its efficacy.

  12. Immunomodulator, immunosuppression of radiation and immune reconstruction

    International Nuclear Information System (INIS)

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

    2010-01-01

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

  13. Immunity booster

    International Nuclear Information System (INIS)

    Stefanescu, Ioan; Titescu, Gheorghe; Tamaian, Radu; Haulica, Ion; Bild, Walther

    2002-01-01

    The immunity booster is, according to its patent description, microbiologically pure water with an D/(D+H) isotopic concentration of 100 ppm, with physical-chemical characteristics similar to those of distilled water. It is obtained by sterilization of a mixture of deuterium depleted water, with a 25 ppm isotopic concentration, with distilled water in a volume ratio of 4:6. Unlike natural immunity boosters (bacterial agents as Bacillus Chalmette-Guerin, Corynebacterium parvum; lipopolysaccharides; human immunoglobulin) or synthetical products (levamysol; isoprinosyne with immunostimulating action), which cause hypersensitivity and shocks, thrill, fever, sickness and the immunity complex disease, the water of 100 ppm D/(D + H) isotopic concentration is a toxicity free product. The testing for immune reaction of the immunity booster led to the following results: - an increase of cell action capacity in the first immunity shielding stage (macrophages), as evidenced by stimulation of a number of essential characterizing parameters, as well as of the phagocytosis capacity, bactericide capacity, and opsonic capacity of serum; - an increase of the number of leucocyte particularly of the granulocyte in peripheral blood, produced especially when medullar toxic agents like caryolysine are used; - it hinders the effect of lowering the number of erythrocytes in peripheral blood produced by experimentally induced chronic inflammation; - an increase of nonspecific immunity defence capacity against specific bacterial aggression of both Gram-positive bacteria (Streptococcus pneumoniae 558 ) and of the Gram-negative ones (Klebsiella pneumoniae 507 ); - an increase of immunity - stimulating activity (proinflamatory), like that of levamisole as evidenced by the test of stimulation of experimentally induced inflammation by means of carrageenan. The following advantages of the immunity booster are stressed: - it is toxicity free and side effect free; - can be orally administrated as

  14. 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.

  15. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, le...... they arise. In short, I expose the regulatory anatomy of the policy landscape....

  16. Regulatory Governance

    DEFF Research Database (Denmark)

    Kjær, Poul F.; Vetterlein, Antje

    2018-01-01

    Regulatory governance frameworks have become essential building blocks of world society. From supply chains to the regimes surrounding international organizations, extensive governance frameworks have emerged which structure and channel a variety of social exchanges, including economic, political...... by the International Transitional Administrations (ITAs) in Kosovo and Iraq as well as global supply chains and their impact on the garment industry in Bangladesh....

  17. Protection of lethally irradiated mice with allogeneic fetal liver cells: influence of irradiation dose on immunologic reconstitution

    International Nuclear Information System (INIS)

    Tulunay, O.; Good, R.A.; Yunis, E.J.

    1975-01-01

    After lethal irradiation long-lived, immunologically vigorous C3Hf mice were produced by treatment with syngeneic fetal liver cells or syngeneic newborn or adult spleen cells. Treatment of lethally irradiated mice with syngeneic or allogeneic newborn thymus cells or allogeneic newborn or adult spleen cells regularly led to fatal secondary disease or graft-versus-host reactions. Treatment of the lethally irradiated mice with fetal liver cells regularly yielded long-lived, immunologically vigorous chimeras. The introduction of the fetal liver cells into the irradiated mice appeared to be followed by development of immunological tolerance of the donor cells. The findings suggest that T-cells at an early stage of differentiation are more susceptible to tolerance induction than are T-lymphocytes at later stages of differentiation. These investigations turned up a perplexing paradox which suggests that high doses of irradiation may injure the thymic stroma, rendering it less capable of supporting certain T-cell populations in the peripheral lymphoid tissue. Alternatively, the higher and not the lower dose of irradiation may have eliminated a host cell not readily derived from fetal liver precursors which represents an important helper cell in certain cell-mediated immune functions, e.g., graft-versus-host reactions, but which is not important in others, e.g., allograft rejections. The higher dose of lethal irradiation did not permit development or maintenance of a population of spleen cells that could initiate graft-versus-host reactions but did permit the development of a population of donor cells capable of achieving vigorous allograft rejection

  18. Umbilical cord-derived mesenchymal stem cells reversed the suppressive deficiency of T regulatory cells from peripheral blood of patients with multiple sclerosis in a co-culture – a preliminary study

    Science.gov (United States)

    Yang, Hongna; Sun, Jinhua; Wang, Feng; Li, Yan; Bi, Jianzhong; Qu, Tingyu

    2016-01-01

    The immunoregulatory function of T regulatory cells (Tregs) is impaired in multiple sclerosis (MS). Recent studies have shown that umbilical cord-derived mesenchymal stem cells (UC-MSCs) exert regulatory effect on the functions of immune cells. Thus, we investigated whether UC-MSCs could improve the impaired function of Tregs from MS patients. Co-cultures of UC-MSCs with PBMCs of MS patients were performed for 3 days. Flow cytometry was used to determine the frequency of Tregs. A cell proliferation assay was used to evaluate the suppressive capacity of Tregs. ELISA was conducted for cytokine analysis in the co-cultures. Our results showed that UC-MSCs significantly increased the frequency of CD4+CD25+CD127low/− Tregs in resting CD4+ T cells (pUC-MSC-primed Tregs of MS patients significantly inhibited the proliferation of PHA-stimulated autologous and allogeneic CD4+CD25− T effector cells (Teffs) from MS patients and healthy individuals compared to non-UC-MSC-primed (naïve) Tregs from the same MS patients (pUC-MSC-primed Tregs from MS patients and naïve Tregs from healthy subjects. The impaired suppressive function of Tregs from MS can be completely reversed in a co-culture by UC-MSC modulation. This report is the first to demonstrate that functional defects of Tregs in MS can be repaired in vitro using a simple UC-MSC priming approach. PMID:27705922

  19. How and when I do allogeneic transplant in CLL.

    Science.gov (United States)

    Gribben, John G

    2018-05-11

    Allogenic stem cell transplantation (allo-SCT) has been considered the treatment of choice for high-risk patients with chronic lymphocytic leukemia (CLL) and the only approach offered with curative intent in this disease. The availability novel agents including the B cell receptor inhibitors (BCRi) ibrutinib, acalabrutinib and idelalisib, as well as venetoclax which targets the BCL2 pathway and the success of these agents in treating high-risk disease patients has made it more difficult to assess who and when in their treatment course allo-SCT should be considered. In this review, I will discuss the different treatment options available for the treatment of high-risk CLL and how allo-SCT fits into the treatment algorithm in the era of novel agents. Copyright © 2018 American Society of Hematology.

  20. Interaction between adipose tissue-derived mesenchymal stem cells and regulatory T-cells

    OpenAIRE

    Engela, Anja; Baan, Carla; Peeters, Anna; Weimar, Willem; Hoogduijn, Martin

    2013-01-01

    textabstractMesenchymal stem cells (MSCs) exhibit immunosuppressive capabilities, which have evoked interest in their application as cell therapy in transplant patients. So far it has been unclear whether allogeneic MSCs and host regulatory T-cells (Tregs) functionally influence each other. We investigated the interaction between both cell types using perirenal adipose tissue-derived MSCs (ASCs) from kidney donors and Tregs from blood bank donors or kidney recipients 6 months after transplant...

  1. Innate immunity

    African Journals Online (AJOL)

    Ronnie Anderson is Director of the Medical Research Council Unit for Inflammation and Immunity. ... field have included macrophage, T cell, cytokine and cytokine activated killer cell interactions .... monocytes, mast cells, lymphocytes, eccrine.

  2. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas

    2014-02-01

    Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (PEpstein-Barr virus mismatch recipient-/donor+ (Pdisease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (Pdisease after transplantation in need of pre-emptive measures.

  3. THE ROLE OF AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANTATION IN FOLLICULAR LYMPHOMA IN THE NEW DRUGS ERA.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    2016-09-01

    Full Text Available Follicular lymphoma (FL is the second most common histotype of non-Hodgkin’s lymphoma and it is generally characterized by a heterogeneous clinical course. Despite recent therapeutic and diagnostic improvements, a significant fraction of FL patients still relapsed. In younger and/or fit FL relapsed patients bone marrow transplant (BMT has represented the main salvage therapy for many years. Thanks to the ability of high dose chemotherapy to overcome the lymphoma resistance and refractoriness, autologous stem cell transplantation (ASCT is able to achieve a high complete remission rate (CR and favourable outcome in terms of progression free survival (PFS and overall survival (OS. Allogeneic stem cell transplantation (alloSCT combines the high dose chemotherapy effect together with the immune reaction of the donor immune system against lymphoma, the so called ‘graft versus lymphoma’ (GVL effect. Considering the generally higher transplant related mortality (TRM, alloSCT is mostly indicated for FL relapsed after ASCT. During the last years there has been a great spread of novel effective and feasible drugs Although these and future novel drugs will probably change our current approach to FL, the OS post-BMT (ASCT and alloSCT has never been reproduced by any novel combination. In this scenario, it is important to correctly evaluate the disease status, the relapse risk and the comorbidity profile of the relapsed FL patients in order to provide the best salvage therapy and eventually transplant consolidation.

  4. Childhood immunization

    Science.gov (United States)

    Romain, Sandra; Schillaci, Michael A.

    2009-01-01

    ABSTRACT OBJECTIVE To examine childhood immunization levels relative to the number of family physicians, pediatricians, and public health nurses in Ontario. DESIGN Retrospective comparative analysis of publicly available data on immunization coverage levels and the relative number of family physicians, pediatricians, and public health nurses. SETTING Ontario. PARTICIPANTS Seven-year-old children, family physicians, pediatricians, and public health nurses in Ontario. MAIN OUTCOME MEASURES The association between immunization coverage levels and the relative number of family physicians, pediatricians, and public health nurses. RESULTS We found correlations between immunization coverage levels and the relative number (ie, per 1000 Ontario residents) of family physicians (ρ = 0.60) and pediatricians (ρ = 0.70) and a lower correlation with the relative number of public health nurses (ρ = 0.40), although none of these correlations was significant. A comparison of temporal trends illustrated that variation in the relative number of family physicians and pediatricians in Ontario was associated with similar variation in immunization coverage levels. CONCLUSION Increasing the number of family physicians and pediatricians might help to boost access to immunizations and perhaps other components of cost-saving childhood preventive care. PMID:19910599

  5. Immune regulation by microbiome metabolites.

    Science.gov (United States)

    Kim, Chang H

    2018-03-22

    Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X 7 , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article. © 2018 John Wiley & Sons Ltd.

  6. Allogeneic epidermal substitutes in the treatment of chronic diabetic leg and foot ulcers

    Directory of Open Access Journals (Sweden)

    Andrea Marchesi

    2014-09-01

    Full Text Available Aim: Diabetic foot ulcers are the most common cause of nontraumatic lower extremity amputations in the industrialized world. Tissue-engineering products offer a lower extremity salvage strategy when healing does not proceed according to the standard of care. New allogeneic sheets are available for the management of diabetic leg and foot ulcers. Methods: The endpoints of this case series study regard preliminary outcomes of the application of allogeneic keratinocytes composed of benzyl ester of hyaluronic acid to 16 diabetic foot and leg ulcers in 11 patients with type 2 diabetes mellitus. Results: Between 21 and 70 days after cellular therapy, 6 out of 16 lesions were completely healed, reducing the wound dimension by 70% and improving the wound bed score by 52%. Conclusion: The clinical results of the new allogeneic sheets indicate that allogeneic keratinocytes may represent an effective and safe therapy for diabetic foot and leg ulcers in the multidisciplinary approach to this diabetes-related complication.

  7. Current status of grafts and implants in rhinoplasty: Part II. Homologous grafts and allogenic implants.

    Science.gov (United States)

    Sajjadian, Ali; Naghshineh, Nima; Rubinstein, Roee

    2010-03-01

    After reading this article, the participant should be able to: 1. Understand the challenges in restoring volume and structural integrity in rhinoplasty. 2. Identify the appropriate uses of various homologous grafts and allogenic implants in reconstruction, including: (a) freeze-dried acellular allogenic cadaveric dermis grafts, (b) irradiated cartilage grafts, (c) hydroxyapatite mineral matrix, (d) silicone implants, (e) high-density polyethylene implants, (f) polytetrafluoroethylene implants, and (g) injectable filler materials. 3. Identify the advantages and disadvantages of each of these biomaterials. 4. Understand the specific techniques that may aid in the use these grafts or implants. This review specifically addresses the use of homologous grafts and allogenic implants in rhinoplasty. It is important to stress that autologous materials remain the preferred graft material for use in rhinoplasty, owing to their high biocompatibility and low risk of infection and extrusion. However, concerns of donor-site morbidity, graft availability, and graft resorption have motivated the development and use of homologous and allogenic implants.

  8. Alternative allogeneic donor sources for transplantation for childhood diseases: unrelated cord blood and haploidentical family donors.

    Science.gov (United States)

    Cairo, Mitchell S; Rocha, Vanderson; Gluckman, Eliane; Hale, Gregory; Wagner, John

    2008-01-01

    Allogeneic stem cell transplantation has been demonstrated to be curative in a wide variety of pediatric malignant and nonmalignant diseases, and can be traced back over 50 years ago to the original report of Thomas et al. HLA matched sibling donors have been the gold standard for pediatric recipients requiring allogeneic donors for both nonmalignant and malignant conditions. However, only 25% of potential pediatric recipients possesses an HLA-matched sibling donor, and the frequency is even less in those with genetic nonmalignant conditions because of genetically affected other siblings within the family. Therefore, 75% to 90% of potential pediatric recipients require alternative allogeneic donor cells for treatment of their underlying conditions. Potential alternative allogeneic donor sources include unrelated cord blood donors, unrelated adult donors, and haploidentical family donors. In this article we review the experience of both unrelated cord blood donor and haploidentical family donor transplants in selected pediatric malignant and nonmalignant conditions.

  9. Socially disadvantaged parents of children treated with allogeneic haematopoietic stem cell transplantation (HSCT)

    DEFF Research Database (Denmark)

    Larsen, Hanne Bækgaard; Heilmann, Carsten; Johansen, Christoffer

    2013-01-01

    PURPOSE: This study was undertaken to test a daily Family Navigator Nurse (FNN) conducted intervention program, to support parents during the distressful experience of their child's Allogeneic Haematopoietic Stem Cell Transplantation (HSCT). METHODS: A qualitative analysis of the supportive...

  10. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

    NARCIS (Netherlands)

    Choi, S.W.; Gatza, E.; Hou, G.; Sun, Y; Whitfield, J.; Song, Y.; Oravecz-Wilson, K.; Tawara, I.; Dinarello, C.A.; Reddy, P.

    2015-01-01

    We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from

  11. Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT.

    Science.gov (United States)

    Konuma, Takaaki; Ooi, Jun; Takahashi, Satoshi; Tomonari, Akira; Tsukada, Nobuhiro; Kato, Seiko; Sato, Aki; Monma, Fumihiko; Kasahara, Senji; Uchimaru, Kaoru; Iseki, Tohru; Tojo, Arinobu; Asano, Shigetaka

    2009-06-01

    There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

  12. Comparative analysis of autologous blood transfusion and allogeneic blood transfusion in surgical patients

    OpenAIRE

    Long, Miao-Yun; Liu, Zhong-Han; Zhu, Jian-Guang

    2014-01-01

    Objective: To investigate application effects of autologous blood transfusion and allogeneic blood transfusion in surgically treated patients receiving spine surgery, abdomen surgery and ectopic pregnancy surgery. Methods: 130 patients who would undergo selective operations were divided into autologous transfusion group and allogeneic transfusion group. Both groups received the same anesthesia, and there was no significant difference in transfusion volume or fluid infusion volume. Results: Th...

  13. Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model

    OpenAIRE

    Saso, Srdjan; Petts, Gemma; David, Anna L.; Thum, Meen-Yau; Chatterjee, Jayanta; Vicente Antón, José Salvador; Marco Jiménez, Francisco; Corless, David; Boyd, Michael; Noakes, David; Lindsay, Iain; Del Priorei, Giuseppe; Ghaem-Maghami, Sadaf; Smith, J. Richard

    2015-01-01

    [EN] Objective: Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI). The goal of UTx remains achieving pregnancy and live birth of a healthy neonate following allogeneic UTx. Our aim was to assess whether fertility was possible following allogeneic uterine transplantation (UTx), when the recipient had demonstrated long-term survival and had been administered immunosuppression. Study desig...

  14. Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0234 TITLE: Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion PRINCIPAL...14/2017 4. TITLE AND SUBTITLE Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion 5a. CONTRACT NUMBER 5b. GRANT...tolerance induction of all types of allografts. In this study, we investigate whether co-infusion of amnion- derived multipotent progenitor (AMP) cells

  15. TREATMENT OF SEVERE AUTOIMMUNE CYTOPENIAS AFTER ALLOGENEIC STEM CELL TRANSPLANTATION – REPORT OF TWO CASES

    Directory of Open Access Journals (Sweden)

    Irena Preložnik Zupan

    2004-12-01

    Full Text Available Background. Autoimmune cytopenias, thrombocytopenia, anemia and neutropenia, are rare but serious complications after stem cell transplantation (SCT. There are only a few reports concerning their treatment. We performed splenectomy in two patients with severe autoimmune cytopenias after allogeneic SCT resistant to immunosuppressive treatment.Patients, methods and results. First patient had unrelated alloSCT at Royal Free Hospital London for chronic granulocytic leukemia (CGL in July 2000. Post-transplant period was complicated with cytomegalovirus reactivation and septicemia. Seven months later RBC and platelet counts went down. Direct Coomb’s test was intermittently positive. She was resistant to steroids and high dose immunoglobulin. Splenectomy was performed in February 2001. After splenectomy hemoglobin concentration and platelet count improved. Her blood counts remained stable with hemoglobin about 110 g/L and platelets over 100 x109/L. She continued therapy with Itraconazol, Valacyclovir and Penicillin. Three months later she was readmitted for E. Coli fulminated septic infection with fatal outcome.Second patient had related alloSCT at University Medical Centre Ljubljana for CGL in January 2003. Post-transplant course was uneventful. Seven months later he was readmitted for retinal bleeding with severe thrombocytopenia with positive anti-platelet antibodies. He was resistant to steroids and high dose immunoglobulin. Splenectomy was performed in September 2003. His platelet count normalized and remains stable so far. He continues therapy with Itraconazol, Valacyclovir and Penicillin and didn’t experience any serious infection.Conclusions. We assume that splenectomy is an efficient treatment for resistant immune cytopenias after alloSCT. However, severe late infections may compromise the outcome.

  16. Expression of antigens coded in murine leukemia viruses on thymocytes of allogeneic donor origin in AKR mice following syngeneic or allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Wustrow, T.P.; Good, R.A.

    1985-01-01

    Removal of T-lymphocytes from marrow inoculum with monoclonal antibody plus complement permitted establishment of long-lived allogeneic chimeras between C57BL/6 and AKR/J mice. Development of leukemia was prevented for 15 mo. Protection from leukemia occurred with both young (4 wk) and older (4 mo) recipients. AKR mice reconstituted with syngeneic marrow or control AKR mice all developed leukemia-lymphoma before 1 yr of age. During spontaneous lymphomagenesis in AKR mice, amplified expression of gag or env gene-coded virus antigens on the surface of thymocytes preceded leukemia development and evidence for amplification of other virus genes. These changes generally appeared before 6 mo. Similar viral gene expression and viral gene amplification occurred in the thymus and spleen cells of leukemia-resistant chimeric mice. Using monoclonal antibodies to Mr 70,000 glycoprotein epitopes characteristic of ecotropic, xenotropic, or dualtropic viruses, antigens marking each virus form were found on thymocytes of allogeneic 4-wk and 4-mo chimeras as well as on the cells of AKR mice and of AKR mice reconstituted with syngeneic marrow. Flow cytometric analysis showed amplification of the virus genes in mice protected from leukemia-lymphoma by allogeneic bone marrow transplantation from leukemia-resistant mice. Allogeneic chimeras and syngeneically transplanted mice both showed evidence of accelerated viremia and of recombinant virus formation. The findings suggest that an event essential to leukemogenesis which occurs within the AKR lymphoid cells or their environment is lacking in the allogeneic chimeras. The nature of this influence of a resistance gene or genes introduced into AKR mice by allogeneic bone marrow transplantation deserves further study

  17. Selective T-cell Ablation with Bismuth-213 Labeled Anti-TCR Alpha Beta as Nonmyeloablative Conditioning for Allogeneic Canine Marrow Transplantion

    International Nuclear Information System (INIS)

    Bethge, W. A.; Wilbur, D. Scott; Storb, R.; Hamlin, Donald K.; Santos, E. B.; Brechbiel, M. W.; Fisher, Darrell R.; Sandmaier, B. M.

    2003-01-01

    Two major immunological barriers, the host versus graft (HVG) and the graft versus host (GVH) reaction, must be overcome for successful allogeneic hematopoietic stem cell transplantation. T-cells are involved in these barriers in the major histocompatibility complex-identical settings. We hypothesized that selective ablation of T-cells using radioimmunotherapy, together with postgrafting immunosuppression, would ensure stable allogeneic engraftment. We developed a canine model of nonmyeloablative marrow transplantation in which host immune reactions are impaired by a single dose of 2 Gy total body irradiation (TBI), and where both GVH and residual HVG reactions are controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We substituted the alpha-emitter bismuth-213 linked to a monoclonal antibody against TCR(alpha,beta)using the metal-binding chelate CHX-A-DTPA, for 2 Gy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen and liver. In a dosimetry study, 4 dogs were treated with 0.13-0.46 mg/kg TCR mAb labeled with 3.7-5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantion of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Therapy was well tolerated except for elevations of transaminases, which were transient in all but one dog. No other organ toxicities or signs of graft-versus-host-disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5-55 % with >30 weeks follow up

  18. Selective T-cell Ablation with Bismuth-213 Labeled Anti-TCR Alpha Beta as Nonmyeloablative Conditionaing for Allogeneic Canine Marrow Transplantion

    Energy Technology Data Exchange (ETDEWEB)

    Bethge, W. A.; Wilbur, D. Scott; Storb, R.; Hamlin, Donald K.; Santos, E. B.; Brechbiel, M. W.; Fisher, Darrell R.; Sandmaier, B. M.

    2003-06-15

    Two major immunological barriers, the host versus graft (HVG) and the graft versus host (GVH) reaction, must be overcome for successful allogeneic hematopoietic stem cell transplantation. T-cells are involved in these barriers in the major histocompatibility complex-identical settings. We hypothesized that selective ablation of T-cells using radioimmunotherapy, together with postgrafting immunosuppression, would ensure stable allogeneic engraftment. We developed a canine model of nonmyeloablative marrow transplantation in which host immune reactions are impaired by a single dose of 2 Gy total body irradiation (TBI), and where both GVH and residual HVG reactions are controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We substituted the alpha-emitter bismuth-213 linked to a monoclonal antibody against TCR(alpha,beta)using the metal-binding chelate CHX-A”-DTPA, for 2 Gy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen and liver. In a dosimetry study, 4 dogs were treated with 0.13-0.46 mg/kg TCR mAb labeled with 3.7-5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantion of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Therapy was well tolerated except for elevations of transaminases, which were transient in all but one dog. No other organ toxicities or signs of graft-versus-host-disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5-55 % with >30 weeks follow up.

  19. 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.

  20. Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice.

    Science.gov (United States)

    David, Anu; Day, James Ronald; Cichon, Alexa Leigh; Lefferts, Adam; Cascalho, Marilia; Shikanov, Ariella

    2017-07-01

    Premature ovarian insufficiency (POI) is a major complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. In pediatric cancer patients modern therapy has improved the long-term survival to over 80% in the United States. However, these cancer survivors face long-term health problems related to treatment toxicity. In female cancer survivors POI leads to sterility, along with the consequences of estrogen deficiency such as premature osteopenia, muscle wasting, accelerated cardiovascular diseases and a vast array of other health and developmental problems. These long-lasting effects are particularly significant for young girls reaching puberty. As such, restoring ovarian endocrine function is paramount in this population. In the present study, we evaluated the feasibility of restoring ovarian endocrine function in ovariectomized mice by transplanting syngeneic and allogeneic ovarian tissue encapsulated in alginate capsules or TheraCyte ® . Histological analysis of the implants retrieved after 7 and 30 days' post implantation showed follicular development up to the secondary and antral stages in both syngeneic and allogeneic implants. Implantation of syngeneic and allogeneic ovarian grafts encapsulated in TheraCyte devices restored ovarian endocrine function, which was confirmed by decreased serum FSH levels from 60 to 70 ng/mL in ovariectomized mice to 30-40 ng/mL 30 days after implantation. Absence of allo-MHC-specific IgG and IgM antibodies in the sera of implanted mice with allogeneic ovarian tissue encapsulated in TheraCyte indicate that the implants did not evoke an allo-immune response, while the allogeneic controls were rejected 21 days after implantation. Our results show that TheraCyte effectively isolates the graft from immune recognition but also supports follicular growth.

  1. Cross-sensitization between xeno- and allo-antigens on subsequent allogeneic and xenogeneic pancreatic islet transplantation in a murine model.

    Science.gov (United States)

    Kim, Hyun-Je; Byun, Nari; Kwon, Ohsang; Park, Chung-Gyu

    2016-11-18

    The number of patients in need of organ transplantation is continuously on the rise. However, because of organ donor shortage, xenotransplantation has been highlighted as an alternative. Among the various porcine organs and tissues, porcine islets are considered to be the best-matching implantable candidates for clinical application based on recent progress in nonhuman primate pre-clinical studies. Nevertheless, before initiation of clinical trials, it should be confirmed whether the requisite xeno-antigen sensitization would have a deleterious effect on subsequent allo-transplantation or vice versa. Therefore, in the present study, the survival rate of islets grafted in naïve recipients was compared with that in cross-sensitized recipients. Enzyme-linked immunosorbent spot, fluorescence-activated cell sorting, and immunohistochemistry were conducted to assess the cellular and humoral immune responses. The survival days of Balb/c mouse islets transplanted into B6 mice that had been previously sensitized with porcine cells (i.e., xeno-sensitized) showed no significant difference from that of naïve B6 mice. Moreover, the survival days of porcine islets transplanted into allo-antigen (Balb/c)-sensitized B6 recipients was not significantly different from that in naïve B6 mice. Furthermore, our data provide the first demonstration that the cellular xenogeneic immune response (against porcine antigen) measured by an enzyme-linked immunosorbent spot assay is not cross-reactive to the allogeneic immune responses in a murine islet transplantation model. These results suggest that clinical application of islet xenotransplantation is not likely to have a deleterious effect on subsequent allogeneic islet transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Incomplete immune recovery in HIV infection

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Hartling, Hans J; Gerstoft, Jan

    2012-01-01

    -infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic...... tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution....... Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution...

  3. The role of NK cells in HIV-1 protection: autologous, allogeneic or both?

    Science.gov (United States)

    Hens, Jef; Jennes, Wim; Kestens, Luc

    2016-01-01

    Natural killer (NK) cells specialize in killing virally infected- or tumor cells and are part of the innate immune system. The activational state of NK cells is determined by the balance of incoming activating and inhibitory signals mediated by receptor-ligand binding with the target cell. These receptor-ligand bonds mainly consist of the killer immunoglobulin-like receptors (KIR), which are expressed at the cell surface of NK cells, and their ligands: the highly variable human leukocyte antigen -class I molecules (HLA). Absence of an inhibitory receptor-ligand bond lowers the NK cell activation threshold, whereas an activating receptor-ligand bond stimulates the cell, potentially overcoming this threshold and triggering NK cell activation. NK cells influence the course of infection as well as the acquisition of HIV-1. Several lines of evidence relate the activating NK cell receptor KIR3DS1, in the presence or absence of its putative ligand HLA-Bw4, with slower disease progression as well as resistance to HIV-1 infection. Overall, resistance to HIV-1 infection predominantly correlates with activating KIR/HLA profiles, consisting of e.g. activating KIRs, group B haplotypes, or inhibitory KIRs in absence of their ligands. Such a conclusion is less evident for studies of HIV-1 disease progression, with studies reporting beneficial as well as detrimental effects of activating KIR/HLA genotypes. It is likely that KIR/HLA association studies are complicated by the complexity of the KIR and HLA loci and their mutual interactions, as well as by additional factors like route of HIV exposure, immune activation, presence of co-infections, and the effect of anti-HIV-1 antibodies. One newly discovered NK cell activation pathway associated with resistance to HIV-1 infection involves the presence of an iKIR/HLA mismatch between partners. The absence of such an iKIR/HLA bond renders donor-derived allogeneic HIV-1 infected cells vulnerable to NK cell responses during HIV-1

  4. Roles of Toll-like receptors in allogeneic islet transplantation.

    Science.gov (United States)

    Ro, Han; Hong, Juho; Kim, Beom Seok; Lee, Eun Won; Kim, Myung-Gyu; Han, Kyu Hyun; Yeom, Hye-Jung; Lee, Eun Mi; Jeong, Jong Cheol; Oh, Kook-Hwan; Ahn, Curie; Yang, Jaeseok

    2012-11-27

    Toll-like receptors (TLRs) are involved in the rejection of solid organ allografts. However, the roles of TLRs in islets are still controversial. We investigated the roles of TLRs in donor islets together with those in recipients in allogeneic islet transplantation. To assess the roles of TLRs in either donor islets or recipients, allogeneic islet transplantation was performed using myeloid differentiation factor 88 (MyD88)-knockout (KO), TLR4-KO, or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-KO mice. Both polyriboinosinic polyribocytidylic acid and lipopolysaccharide (LPS) stimulation induced the mRNA expression of regulated and normal T cell expressed and secreted, interferon-γ-inducible protein-10, monocyte chemotactic protein-1, interleukin-8, and inducible nitric oxide synthase in murine islets, whereas the induction was attenuated in TRIF-KO, interferon-β promoter stimulator-1-KO, and TLR4-KO mice. When islets from MyD88-KO, TLR4-KO, or TRIF-KO C57BL/6 mice were transplanted to BALB/c recipients, graft survival was not better than that of wild-type (WT) islets. However, the survival of the MyD88-KO islet allograft was significantly prolonged when combined with anti-CD40L. In parallel, LPS stimulation in donor islets interfered with anti-CD40L blockade-mediated long-term survival of islet allografts in TLR4-KO recipients. LPS stimulation increased the perigraft infiltration of both T cells and macrophages. Then again, when islets from WT BALB/c mice were transplanted to MyD88-KO, TRIF-KO, or WT C57BL/6 mice, there was no difference in graft survival, although some of the MyD88-KO recipients obtained long-term graft survival. However, anti-CD40L prolonged graft survival significantly in MyD88-KO recipients. The absence of MyD88 in either donors or recipients decreased the perigraft infiltration of inflammatory cells when combined with anti-CD40L. TLRs in both donor islets and recipients are involved in islet allograft

  5. Altered Immune Regulation in Type 1 Diabetes

    Science.gov (United States)

    Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

    2013-01-01

    Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

  6. Altered Immune Regulation in Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    András Zóka

    2013-01-01

    Full Text Available Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

  7. Immune System

    Science.gov (United States)

    ... of the Immune System Print en español El sistema inmunitario Whether you're stomping through the showers ... of Use Notice of Nondiscrimination Visit the Nemours Web site. Note: All information on TeensHealth® is for ...

  8. Immunizing Adults

    Centers for Disease Control (CDC) Podcasts

    Vaccines aren’t just for kids; adults also need to get immunized. Overall, far too many people 19 years and older aren’t getting the vaccines they need and remain unprotected. In this podcast, Dr. Walter Williams discuss the importance of adults being fully vaccinated.

  9. Vaccines (immunizations) - overview

    Science.gov (United States)

    Vaccinations; Immunizations; Immunize; Vaccine shots; Prevention - vaccine ... of the vaccine. VACCINE SCHEDULE The recommended vaccination (immunization) schedule is updated every 12 months by the ...

  10. [Allogeneic vascularized transplantation in cases of bone and joint defects].

    Science.gov (United States)

    Hofmann, G O; Kirschner, M H; Gonschorek, O; Bühren, V

    1999-06-01

    This paper presents preliminary results of allogeneic vascularized transplantations of three femoral diaphyses and four total human knee joints. Grafts were harvested from multi-organ-donors and immediately transplanted. Osteosyntheses were performed employing intramedullary nails. Vascular pedicles of the grafts were anastomosed in end-to-side technique. Immunosuppression mainly based on Cyclosporine and Azathioprine. Grafts' perfusion was demonstrated by DSA and Duplex-sonograms, bone metabolism by SPECT-scintigraphy. Five months following transplantation osteotomies demonstrated consolidation in conventional X-rays. Biopsies of the grafted bone revealed intact osteocytes and arthroscopy demonstrated intact synovial, chondral and ligamentous structures. From the technical aspect vascularized transplantation of the femoral diaphyses and total knee joints is feasible. The main problems are of immunologic nature. Transplantations were performed respecting the ABO-compatibility but with a large HLA-mismatch. Acute and chronic rejection crises may damage the grafts. At least in synovial joints live-long immunosuppression of the recipients seems to be unavoidable.

  11. EXPERIENCE OF USING ALLOGENIC BIOIMPLANTS IN LARYNGEAL RESECTION

    Directory of Open Access Journals (Sweden)

    E. N. Novozhilova

    2017-01-01

    Full Text Available Introduction. Currently, a great importance is being attached to improvement of the surgical component of combination treatment of locally advanced laryngeal cancer. New technological capabilities (transoral microsurgery of the larynx and robotic surgery offer great opportunities for early cancer stages. However, in some cases capabilities of endoscopic laser intervention are limited. Therefore, open laryngeal resection is still relevant as it serves as the only type of radical organ preservation treatment for stages Т2–Т3. But major laryngeal resection is associated with a problem of tissue defect closure.The article describes data on the use of biocompatible materials, their advantages and disadvantages. The study objective is to present experience of using a Russian allogenic bioimplant for plastic reconstruction of the opening of the larynx after laryngeal resection.Materials and methods. The authors present their experience of using a Russian bioimplant produced in collaboration with the Samara Tissue Bank of the Research Institute of Experimental Medicine and Biotechnology of the Samara State Medical University. The material was tested in anterolateral laryngeal resection with simultaneous reconstruction in 5 patients with stages Т2–Т3 laryngeal cancer and in a patient with chondrosarcoma.Conclusion. The Russian biocompatible implant served as a reliable, simple, cheap, and effective variant of plastic material for reconstruction of the larynx.

  12. T cell reconstitution in allogeneic haematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kielsen, K; Jordan, K K; Uhlving, H H

    2015-01-01

    Infections and acute graft-versus-host disease (aGVHD) are major causes of treatment-related mortality and morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). Both complications depend on reconstitution of the T-lymphocyte population based on donor T cells. Although...... it is well established that Interleukin-7 (IL-7) is a cytokine essential for de novo T cell development in the thymus and homoeostatic peripheral expansion of T cells, associations between circulating levels of IL-7 and T cell reconstitution following HSCT have not been investigated previously. We...... in patients treated with anti-thymocyte globulin (ATG) compared with those not treated with ATG (P = 0.0079). IL-7 levels at day +7 were negatively associated with T cell counts at day +30 to +60 (at day +60: CD3(+) : β = -10.6 × 10(6) cells/l, P = 0.0030; CD8(+) : β = -8.4 × 10(6) cells/l, P = 0.061; CD4...

  13. Pneumatosis intestinalis in children after allogeneic bone marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Yeager, A M; Kanof, M E; Lake, A M; Kramer, S S; Jones, B; Saral, R; Santos, G W

    1987-01-01

    Four children, ages 3 to 8 years, developed pneumatosis intestinalis (PI) after allogeneic bone marrow transplantation (BMT) for acute leukemia or severe aplastic anemia. PI was detected at a median of 48 days (range, 10-63 days) after BMT and was associated with abdominal symptoms and clinical signs. All patients had severe systemic and/or highgrade cutaneous acute graft-versus-host disease (AGVHD) at some time after BMT and were receiving corticosteroids at the time of development of PI; however, PI was associated with concomitant severe AGVHD in only one patient. One patient with PI had Hafnia alvei bacteremia and another patient had gastroenteritis due to rotavirus and adenovirus. All patients were treated with supportive care and systemic broad-spectrum antibiotics, and PI resolved 2-16 days after onset. Two patients died with BMT-associated complications unrelated to PI. Multiple factors contribute to the development of PI after BMT, and the prognosis for recovery from PI is good with medical management alone. Overall survival in these patients is dependent on the frequency and severity of other conditions, such as AGVHD and opportunistic infections, after BMT.

  14. Allogenic banking of dental pulp stem cells for innovative therapeutics.

    Science.gov (United States)

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-08-26

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

  15. Pneumatosis intestinalis in children after allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Yeager, A.M.; Kanof, M.E.; Lake, A.M.; Kramer, S.S.; Jones, B.; Saral, R.; Santos, G.W.

    1987-01-01

    Four children, ages 3 to 8 years, developed pneumatosis intestinalis (PI) after allogeneic bone marrow transplantation (BMT) for acute leukemia or severe aplastic anemia. PI was detected at a median of 48 days (range, 10-63 days) after BMT and was associated with abdominal symptoms and clinical signs. All patients had severe systemic and/or highgrade cutaneous acute graft-versus-host disease (AGVHD) at some time after BMT and were receiving corticosteroids at the time of development of PI; however, PI was associated with concomitant severe AGVHD in only one patient. One patient with PI had Hafnia alvei bacteremia and another patient had gastroenteritis due to rotavirus and adenovirus. All patients were treated with supportive care and systemic broad-spectrum antibiotics, and PI resolved 2-16 days after onset. Two patients died with BMT-associated complications unrelated to PI. Multiple factors contribute to the development of PI after BMT, and the prognosis for recovery from PI is good with medical management alone. Overall survival in these patients is dependent on the frequency and severity of other conditions, such as AGVHD and opportunistic infections, after BMT. (orig.)

  16. Regulatory T-cells and autoimmunity.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

  17. The expanding universe of regulatory T cell subsets in cancer.

    Science.gov (United States)

    Gajewski, Thomas F

    2007-08-01

    Evidence has indicated that failed antitumor immunity is dominated by immunosuppressive mechanisms within the tumor microenvironment. In this issue of Immunity, Peng et al. (2007) add to this list by describing tumor-infiltrating gammadelta T cells that have regulatory function.

  18. Local and systemic tumor immune dynamics

    Science.gov (United States)

    Enderling, Heiko

    Tumor-associated antigens, stress proteins, and danger-associated molecular patterns are endogenous immune adjuvants that can both initiate and continually stimulate an immune response against a tumor. In retaliation, tumors can hijack intrinsic immune regulatory programs that are intended to prevent autoimmune disease, thereby facilitating continued growth despite the activated antitumor immune response. In metastatic disease, this ongoing tumor-immune battle occurs at each site. Adding an additional layer of complexity, T cells activated at one tumor site can cycle through the blood circulation system and extravasate in a different anatomic location to surveil a distant metastasis. We propose a mathematical modeling framework that incorporates the trafficking of activated T cells between metastatic sites. We extend an ordinary differential equation model of tumor-immune system interactions to multiple metastatic sites. Immune cells are activated in response to tumor burden and tumor cell death, and are recruited from tumor sites elsewhere in the body. A model of T cell trafficking throughout the circulatory system can inform the tumor-immune interaction model about the systemic distribution and arrival of T cells at specific tumor sites. Model simulations suggest that metastases not only contribute to immune surveillance, but also that this contribution varies between metastatic sites. Such information may ultimately help harness the synergy of focal therapy with the immune system to control metastatic disease.

  19. Regulatory Myeloid Cells in Transplantation

    Science.gov (United States)

    Rosborough, Brian R.; Raïch-Regué, Dàlia; Turnquist, Heth R.; Thomson, Angus W.

    2013-01-01

    Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin. PMID:24092382

  20. Regulatory Physiology

    Science.gov (United States)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  1. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of bench-marking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  2. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  3. A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery.

    Science.gov (United States)

    Van der Linden, P; De Hert, S; Daper, A; Trenchant, A; Jacobs, D; De Boelpaepe, C; Kimbimbi, P; Defrance, P; Simoens, G

    2001-10-01

    Individual and institutional practices remain an independent predictor factor for allogeneic blood transfusion. Application of a standardized multidisciplinary transfusion strategy should reduce the use of allogeneic blood transfusion in major surgical patients. This prospective non randomized observational study evaluated the effects of a standardized multidisciplinary transfusion strategy on allogeneic blood products exposure in patients undergoing non-emergent cardiac surgery. The developed strategy involved a standardized blood conservation program and a multidisciplinary allogeneic blood transfusion policy based mainly on clinical judgement, not only on a specific hemoglobin concentration. Data obtained in a first group including patients operated from September 1997 to August 1998 (Group pre: n=321), when the transfusion strategy was progressively developed, were compared to those obtained in a second group, including patients operated from September 1998 to August 1999 (Group post: n=315) when the transfusion strategy was applied uniformly. Patient populations and surgical procedures were similar. Patients in Group post underwent acute normovolemic hemodilution more frequently, had a higher core temperature at arrival in the intensive care unit and presented lower postoperative blood losses at day one. Three hundred forty units of packed red blood cells were transfused in 33% of the patients in Group pre whereas 161 units were transfused in 18% of the patients in Group post (P <0.001). Pre- and postoperative hemoglobin concentrations, mortality and morbidity were not different among groups. Development of a standardized multidisciplinary transfusion strategy markedly reduced the exposure of cardiac surgery patients to allogeneic blood.

  4. Platelet transfusion refractoriness attributable to HLA antibodies produced by donor-derived cells after allogeneic bone marrow transplantation from one HLA-antigen-mismatched mother.

    Science.gov (United States)

    Hatakeyama, Naoki; Hori, Tsukasa; Yamamoto, Masaki; Inazawa, Natsuko; Iesato, Kotoe; Miyazaki, Toru; Ikeda, Hisami; Tsutsumi, Hiroyuki; Suzuki, Nobuhiro

    2011-12-01

    PTR is a serious problem in patients being treated for hematologic disorders. Two patients with acute leukemia developed PTR after allogeneic BMT from one HLA-antigen-mismatched mother attributable to HLA antibodies, which could not be detected in their serum before BMT. HLA antibodies, whose specificity resembled that of each patient, were detected in each donor's serum. Each donor had probably been immunized during pregnancy by their partner's HLA antigens expressed by the fetus, consequently, transplanted donor-derived cells provoked HLA antibodies in each recipient early after BMT, and those HLA antibodies induced PTR. If the mothers are selected as donors for their children, they should be tested for the presence of HLA antibodies. © 2010 John Wiley & Sons A/S.

  5. Adult Immunization

    Directory of Open Access Journals (Sweden)

    Omer Coskun

    2008-04-01

    Full Text Available Despite the many advances in modern medicine, each year thousands of people in the world die from diseases that are easily prevented by safe and effective vaccines. Few measures in preventive medicine are of such proven value and as easy to implement as routine immunization against infectious diseases. Prevention of infection by immunization is a lifelong process. There are a number of vaccines that all adults (¡I18 years require. There are also other vaccines that need to be tailored to meet individual variations in risk resulting from occupation, foreign travel, underlying illness, lifestyle and age. In this study, we tried to review this important subject. [TAF Prev Med Bull 2008; 7(2.000: 159-166

  6. Immune response and histology of humoral rejection in kidney transplantation.

    Science.gov (United States)

    González-Molina, Miguel; Ruiz-Esteban, Pedro; Caballero, Abelardo; Burgos, Dolores; Cabello, Mercedes; Leon, Miriam; Fuentes, Laura; Hernandez, Domingo

    2016-01-01

    The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  7. Immunizations for Preterm Babies

    Science.gov (United States)

    ... Issues Health Issues Health Issues Conditions Injuries & Emergencies Vaccine Preventable Diseases ... Children > Safety & Prevention > Immunizations > Immunizations For Preterm Babies Safety & ...

  8. Weakened Immune Systems

    Science.gov (United States)

    ... Issues Health Issues Health Issues Conditions Injuries & Emergencies Vaccine Preventable Diseases ... Children > Safety & Prevention > Immunizations > Weakened Immune Systems Safety & Prevention ...

  9. Immunizations: Active vs. Passive

    Science.gov (United States)

    ... Issues Health Issues Health Issues Conditions Injuries & Emergencies Vaccine Preventable Diseases ... Children > Safety & Prevention > Immunizations > Immunizations: Active vs. Passive Safety & ...

  10. Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells.

    NARCIS (Netherlands)

    Jedema, I.; Meent, M. van de; Pots, J.M.; Kester, M.G.; Beek, M.T. van der; Falkenburg, J.H.F.

    2011-01-01

    BACKGROUND: One of the major challenges in allogeneic stem cell transplantation is to find a balance between the harmful induction of graft-versus-host disease and the beneficial graft-versus-leukemia and pathogen-specific immune responses. Adoptive transfer of in-vitro generated donor T cells with

  11. Organ procurement organization compliance with 21 CFR 1271: a challenge for allogeneic pancreatic islet cell transplantation programs.

    Science.gov (United States)

    Winters, J L; Tran, S A; Gastineau, D A; Padley, D J; Dean, P G; Kudva, Y C

    2009-06-01

    In order to protect tissue recipients, the Food and Drug Administration drafted Title 21, Section 1271 of the Code of Federal Regulations 1271 (21 CFR 1271) to address infectious disease risk. These regulations apply to tissues but not vascularized organs. Pancreatic islet cells are regulated under 21 CFR 1271. These regulations require qualification of suppliers of critical materials and services with regard to 21 CFR 1271 compliance. As part of supplier qualification, all organ procurement organizations (OPOs) in the United States were sent a questionnaire covering the key components of these regulations. Of the 57 OPOs, 29 (51%) were in compliance based upon survey results. Twelve (21%) were not compliant in one or more areas. All indicated plans to become compliant. The remaining 15 (27%) either failed or refused to complete the survey, some indicating 21 CFR 1271 did not apply to OPOs. Using 2006 data, OPOs compliant with 21 CFR 1271 recovered 50% of the organs procured in the United States. These findings represent a challenge for allogeneic islet cell transplant programs whose raw material must comply with 21 CFR 1271. OPOs should work toward understanding and complying with 21 CFR 1271. Regulatory agencies should work toward enhancing safety of the pancreas supply by facilitating compliance through harmonization of requirements.

  12. Analysis of the results of allogeneic hematopoietic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair

    Directory of Open Access Journals (Sweden)

    Ye. V. Kuzmich

    2015-01-01

    Full Text Available HLA matching of the donor / recipient pair is a major factor associated with the outcome of allogeneic stem cell transplantation. In the presentstudy we analyzed the risk of severe acute graft-versus-host disease, graft failure, 2.year overall survival of the patients after allogeneic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair.

  13. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies

    DEFF Research Database (Denmark)

    Sorror, Mohamed L; Sandmaier, Brenda M; Storer, Barry E

    2011-01-01

    A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions.......A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions....

  14. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation

    Directory of Open Access Journals (Sweden)

    B. Dhakal

    2016-01-01

    Full Text Available Parainfluenza virus (PIV may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure.

  15. Regulatory dendritic cell therapy: from rodents to clinical application

    OpenAIRE

    Raïch-Regué, Dalia; Glancy, Megan; Thomson, Angus W.

    2013-01-01

    Dendritic cells (DC) are highly-specialized, bone marrow-derived antigen-presenting cells that induce or regulate innate and adaptive immunity. Regulatory or “tolerogenic” DC play a crucial role in maintaining self tolerance in the healthy steady-state. These regulatory innate immune cells subvert naïve or memory T cell responses by various mechanisms. Regulatory DC (DCreg) also exhibit the ability to induce or restore T cell tolerance in many animal models of autoimmune disease or transplant...

  16. In search of the optimal platform for Post-Allogeneic SCT immunotherapy in relapsed multiple myeloma: a systematic review.

    Science.gov (United States)

    Oostvogels, R; Uniken Venema, S M; de Witte, M; Raymakers, R; Kuball, J; Kröger, N; Minnema, M C

    2017-09-01

    Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients. Eleven studies were included. Median PFS ranged from 5.2 to 36.8 months and OS was 13.0 to 63.0 months. The relapse related mortality at 1 year varied between 0 and 50% and TRM between 8 and 40%. Lowest GvHD incidences were reported for conditioning regimens with T-cell depletion using ATG or graft CD34+ selection. Similar strategies could lay the foundation for a post-transplant immune platform, this should be further evaluated in prospective clinical trials.

  17. Estimating demand and unmet need for allogeneic hematopoietic cell transplantation in the United States using geographic information systems.

    Science.gov (United States)

    Besse, Kelsey L; Preussler, Jaime M; Murphy, Elizabeth A; Denzen, Ellen M; Lill, Michael C; Chell, Jeffrey W; Senneka, Mary K; Majhail, Navneet S; Williams, Eric P

    2015-03-01

    Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used therapy for many patients with hematologic malignancies and other marrow failure or immune system disorders. The purpose of this study was to quantify and visualize both the demand and unmet need for HCT. HCT use for 2012 was described using the Center for International Blood and Marrow Transplant Research registry. Potential demand for HCT was calculated using 2012 SEER data and published literature for HCT-treatable conditions. Point locations of transplant centers were geocoded using geographic information system (GIS) software; Thiessen polygons were created to establish adult (age 20 to 74 years) and pediatric (age 0 to 19 years) market areas. Market-area population estimates were calculated using 2012 population estimates by age aggregated by census block. US market areas for HCTs were identified separately for transplant centers treating adult (n = 62) and pediatric patients (n = 52). Overall HCT demand among adults was 16,096, with an unmet need for HCTs of 10,276 patients. For pediatric patients, the total demand was 4,561, with an unmet need of 3,213 potential recipients. Evaluation of adult and pediatric market areas indicated that the largest unmet needs tended to be in areas with large populations. Market-area maps and statistics developed using GIS will help communicate the unmet need for HCT, inform policy, and assist transplant centers in planning for the anticipated growth in HCT use. Copyright © 2015 by American Society of Clinical Oncology.

  18. Allogenic sedimentary components of Bear Lake, Utah and Idaho

    Science.gov (United States)

    Rosenbaum, J.G.; Dean, W.E.; Reynolds, R.L.; Reheis, M.C.

    2009-01-01

    Bear Lake is a long-lived lake filling a tectonic depression between the Bear River Range to the west and the Bear River Plateau to the east, and straddling the border between Utah and Idaho. Mineralogy, elemental geochemistry, and magnetic properties provide information about variations in provenance of allogenic lithic material in last-glacial-age, quartz-rich sediment in Bear Lake. Grain-size data from the siliciclastic fraction of late-glacial to Holocene carbonate-rich sediments provide information about variations in lake level. For the quartz-rich lower unit, which was deposited while the Bear River fl owed into and out of the lake, four source areas are recognized on the basis of modern fluvial samples with contrasting properties that reflect differences in bedrock geology and in magnetite content from dust. One of these areas is underlain by hematite-rich Uinta Mountain Group rocks in the headwaters of the Bear River. Although Uinta Mountain Group rocks make up a small fraction of the catchment, hematite-rich material from this area is an important component of the lower unit. This material is interpreted to be glacial fl our. Variations in the input of glacial flour are interpreted as having caused quasi-cyclical variations in mineralogical and elemental concentrations, and in magnetic properties within the lower unit. The carbonate-rich younger unit was deposited under conditions similar to those of the modern lake, with the Bear River largely bypassing the lake. For two cores taken in more than 30 m of water, median grain sizes in this unit range from ???6 ??m to more than 30 ??m, with the coarsest grain sizes associated with beach or shallow-water deposits. Similar grain-size variations are observed as a function of water depth in the modern lake and provide the basis for interpreting the core grain-size data in terms of lake level. Copyright ?? 2009 The Geological Society of America.

  19. Intravenous Tranexamic Acid Decreases Allogeneic Transfusion Requirements in Periacetabular Osteotomy.

    Science.gov (United States)

    Bryan, Andrew J; Sanders, Thomas L; Trousdale, Robert T; Sierra, Rafael J

    2016-01-01

    Bernese (Ganz) periacetabular osteotomy is associated with significant blood loss and the need for perioperative transfusion. Tranexamic acid decreases blood loss and minimizes transfusion rates in total joint arthroplasty. However, no reports have described its use in patients undergoing Bernese periacetabular osteotomy. This study reports the use of intravenous tranexamic acid in these patients. The study included 137 patients (150 hips) who underwent isolated periacetabular osteotomy at a single institution between 2003 and 2014. Of these, 68 patients (75 hips) received intravenous tranexamic acid 1 g at the time of incision and 1 g at the time of closure. A group of 69 patients (75 hips) served as control subjects who underwent periacetabular osteotomy without administration of intravenous tranexamic acid. Thromboembolic disease was defined as deep venous thrombosis or pulmonary embolism occurring within 6 weeks of surgery. Outcomes measured included transfusion requirements, pre- and postoperative hemoglobin values, operative times, and thromboembolic disease rates. Aspirin was used as the thromboembolic prophylactic regimen in 95% of patients. The rate of allogeneic transfusion was 0 in the tranexamic acid group compared with 21% in the control group (P=.0001). No significant difference was found in the autologous cell salvage requirement (.96 vs 1.01; P=.43) or the thromboembolic disease rate between the tranexamic acid group and the control group (2.67% vs 1.33%; P=.31). The use of intravenous tranexamic acid led to a decreased transfusion requirement with no increased risk of thromboembolic disease in this contemporary cohort of patients undergoing periacetabular osteotomy. Copyright 2016, SLACK Incorporated.

  20. Nonspecific suppressor elements in murine allogeneic radiation chimeras

    International Nuclear Information System (INIS)

    Urso, P.; Gengozian, N.

    1979-01-01

    Spleen cells from long-term mouse allogeneic radiation chimeras were tested for their ability to modulate the graft-versus-host (GVH) or plaque-forming cell (PFC) response of normal lymphocytes transplanted in lethally x-irradiated recipients. In vivo GVH proliferation of normal lymphocytes (syngeneic to donor cells of the chimera) against antigens of host-type in which the chimeric state had been established was reduced by chimera cells. Inhibition varied, some chimeras suppressing GVH more than others and a few not suppressing at all. The suppressive effect was abrogated if the chimera cells were treated with anti-THETA; treatment with anti-IgM did not eliminate this activity. When mixtures of normal donor lymphocytes and chimera cells were given to irradiated recipients genetically different from host or donor, reduction of donor cell GVH also occurred. Further, chimera cells reduced the GVH activity of normal host cells in irradiated recipients differing from the host at one H-2 locus and from the donor at minor histocompatibility loci. The modulating effect of spleen cells from chimeras on the PFC response by normal lymphocytes also varied. Six chimeras induced a 25 to 90% suppression, two enhanced the response, and one showed no effect. Where suppression occurred, treatment of chimera cells with anti-THETA most often, but not always, restored PFC production. Our results show that the suppressive action of splenic lymphoid cells by chimeras is highly nonspecific and variable in expression. We suggest that tolerance in chimeras may be mediated by nonspecific suppressor elements leading to unresponsiveness to a variety of antigens including SRBC

  1. A protocol avoiding allogeneic transfusion in joint arthroplasties.

    Science.gov (United States)

    Suh, You-Sung; Nho, Jae-Hwi; Choi, Hyung-Suk; Ha, Yong-Chan; Park, Jong-Seok; Koo, Kyung-Hoi

    2016-09-01

    Arthroplasties of hip and knee are associated with blood loss, which may lead to adverse patient outcome. Performing arthroplasties in Jehovah's Witness patients who do not accept transfusion has been a matter of concern. We developed a protocol, which avoids transfusion in arthroplasties of Jehovah's Witness patients, and evaluated the feasibility and safety of the protocol. The target of preoperative hemoglobin was more than 10 g/dL. When preoperative hemoglobin was lower than 10 g/dL, 4000 U erythropoietin (3 times a week) and 100 mg iron supplement (every day) were administered until the hemoglobin reached 10 g/dL. When the preoperative hemoglobin was higher than 10 g/dL, 4000 U erythropoietin and 100 mg iron supplement were administered once, before operation. During the operation, cell saver was used. Postoperatively, erythropoietin and iron supplements were administered until the hemoglobin reached 10 g/dL, similar to the preoperative protocol. We evaluated the feasibility of our protocol, perioperative complications and hematologic changes. From 2002 to 2014, 186 Witness patients visited our department. In 179 patients (96.2 %), 77 total knee arthroplasties, 69 bipolar hemiarthroplasties and 33 total hip arthroplasties were performed. The mean hemoglobin level was 12.3 g/dL preoperatively, 9.4 g/dL on postoperative day 3 and 10.3 g/dL on postoperative day 7. One patient died immediately after the arthroplasty and the remaining 178 patients survived. Total joint arthroplasty could be done without transfusion using this protocol in most of our patients. The rates of infection and mortality were similar with known infection and mortality rates of arthroplasties. In patients who do not want allogeneic transfusions, our protocol is a safe alternative to perform joint arthroplasties.

  2. Allogeneic stem cell transplantation for thalassemia major in India

    Directory of Open Access Journals (Sweden)

    Vikram Mathews

    2017-12-01

    Full Text Available Allogeneic stem cell transplantation (allo-SCT is the only currently available curative treatment for thalassemia major. Since it was first done in 1981, several thousand patients have benefited from it and it is now possible to offer this treatment in different parts of the world with good results. With better risk stratification and supportive care, the results of allo-SCT are now very good even in high risk patients who have significant iron overload related organ dysfunction. The improvements have mainly been in the conditioning strategies with less toxic myeloablation and management of the complications of SCT. However, several challenges remain. Transplant related complications still cause significant morbidity and mortality. There is data to show that the results of transplantation as best if done in well transfused and chelated patients <7 years of age. As only a third of the patients will have a matched related donor, there is need for investigating SCT with alternative donors. Experience with SCT for thalassemia major from matched unrelated donors or haplo-identical donors is still limited but needs further exploration. Adequate management needs to be provided post-SCT for all pre-existing complications particularly iron chelation to prevent further organ dysfunction. Systematic follow-up is needed to measure long term outcomes. The biggest challenges in India are the cost of this treatment and access to centres capable of providing this treatment. With greater support from the government, health insurance and philanthropic programs, there has been a rapid increase in the number of SCTs for thalassemia major in India. The number centres providing this treatment are also increasing making this curative treatment more widely available in India.

  3. Alternative procedures for reducing allogeneic blood transfusion in elective orthopedic surgery.

    Science.gov (United States)

    Kleinert, Kathrin; Theusinger, Oliver M; Nuernberg, Johannes; Werner, Clément M L

    2010-09-01

    Perioperative blood loss is a major problem in elective orthopedic surgery. Allogeneic transfusion is the standard treatment for perioperative blood loss resulting in low postoperative hemoglobin, but it has a number of well-recognized risks, complications, and costs. Alternatives to allogeneic blood transfusion include preoperative autologous donation and intraoperative salvage with postoperative autotransfusion. Orthopedic surgeons are often unaware of the different pre- and intraoperative possibilities of reducing blood loss and leave the management of coagulation and use of blood products completely to the anesthesiologists. The goal of this review is to compare alternatives to allogeneic blood transfusion from an orthopedic and anesthesia point of view focusing on estimated costs and acceptance by both parties.

  4. Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges.

    Science.gov (United States)

    Jossen, Valentin; van den Bos, Christian; Eibl, Regine; Eibl, Dieter

    2018-05-01

    Human mesenchymal stem cell (hMSC)-based therapies are of increasing interest in the field of regenerative medicine. As economic considerations have shown, allogeneic therapy seems to be the most cost-effective method. Standardized procedures based on instrumented single-use bioreactors have been shown to provide billion of cells with consistent product quality and to be superior to traditional expansions in planar cultivation systems. Furthermore, under consideration of the complex nature and requirements of allogeneic hMSC-therapeutics, a new equipment for downstream processing (DSP) was successfully evaluated. This mini-review summarizes both the current state of the hMSC production process and the challenges which have to be taken into account when efficiently producing hMSCs for the clinical scale. Special emphasis is placed on the upstream processing (USP) and DSP operations which cover expansion, harvesting, detachment, separation, washing and concentration steps, and the regulatory demands.

  5. Regulation of TGFβ in the immune system: An emerging role for integrins and dendritic cells

    OpenAIRE

    Worthington, John J.; Fenton, Thomas M.; Czajkowska, Beata I.; Klementowicz, Joanna E.; Travis, Mark A.

    2012-01-01

    Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell?cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-? (TGF-?). TGF-? is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells ...

  6. Allogeneic human dermal fibroblasts are viable in peripheral blood mononuclear co-culture

    Directory of Open Access Journals (Sweden)

    Restu Syamsul Hadi

    2014-08-01

    Full Text Available Background Transplanted allogeneic dermal fibroblasts retain stem cell subpopulations, and are easily isolated, expanded and stored using standard techniques. Their potential for regenerative therapy of chronic wounds should be evaluated. The aim of this study was to determine allogeneic fibroblast viability in the presence of peripheral blood mononuclear cells (PBMC. Methods In this experimental study, fibroblasts were isolated from foreskin explants, expanded in the presence of serum, and stored using slow-freezing. We used one intervention group of allogeneic fibroblasts co-cultured with PBMC and 2 control groups of separate fibroblast and PBMC cultures.Fibroblasts were characterized by their collagen secretion and octamer-binding transcription factor 4 (OCT4 expression. Viability was evaluated using water soluble tetrazolium-1 (WST-1 proliferation assay. Absorbances were measured at 450 nm. Data analysis was performed by student’s paired t-test. Results Dermal fibroblasts were shown to secrete collagen, express OCT4, be recoverable after cryopreservation, and become attached to the culture dish in a co-culture with PBMC. Co-cultured and control fibroblasts had no significantly different cell viabilities (p>0.05. Calculated viable cell numbers increased 1.8 and 5.1-fold, respectively, at days 2 and 4 in vitro. Both groups showed comparable doubling times at days 2 and 4 in vitro. PBMC did not interfere with allogeneic fibroblast viability and proliferative capacity Conclusions Allogeneic fibroblasts remain viable and proliferate in the presence of host PBMC. Future research should evaluate allogeneic human dermal fibroblast competency in clinical settings. Dermal fibroblasts are a potential source for cell therapy in chronic wound management.

  7. Immature dendritic cells generated from cryopreserved human monocytes show impaired ability to respond to LPS and to induce allogeneic lymphocyte proliferation.

    Directory of Open Access Journals (Sweden)

    Guilherme Ferreira Silveira

    Full Text Available Dendritic cells play a key role in the immune system, in the sensing of foreign antigens and triggering of an adaptive immune response. Cryopreservation of human monocytes was investigated to understand its effect on differentiation into immature monocyte-derived dendritic cells (imdDCs, the response to inflammatory stimuli and the ability to induce allogeneic lymphocyte proliferation. Cryopreserved (crp-monocytes were able to differentiate into imdDCs, albeit to a lesser extent than freshly (frh-obtained monocytes. Furthermore, crp-imdDCs had lower rates of maturation and cytokine/chemokine secretion in response to LPS than frh-imdDCs. Lower expression of Toll-like receptor 4 (at 24 and 48 h and higher susceptibility to apoptosis in crp-imdDCs than in fresh cells would account for the impaired maturation and cytokine/chemokine secretion observed. A mixed leukocyte reaction showed that lymphocyte proliferation was lower with crp-imdDCs than with frh-imdDCs. These findings suggested that the source of monocytes used to generate human imdDCs could influence the accuracy of results observed in studies of the immune response to pathogens, lymphocyte activation, vaccination and antigen sensing. It is not always possible to work with freshly isolated monocytes but the possible effects of freezing/thawing on the biology and responsiveness of imdDCs should be taken into account.

  8. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    DEFF Research Database (Denmark)

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona

    2011-01-01

    T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow......) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors....

  9. Decellularized allogeneic heart valves demonstrate self-regeneration potential after a long-term preclinical evaluation.

    Directory of Open Access Journals (Sweden)

    Laura Iop

    Full Text Available Tissue-engineered heart valves are proposed as novel viable replacements granting longer durability and growth potential. However, they require extensive in vitro cell-conditioning in bioreactor before implantation. Here, the propensity of non-preconditioned decellularized heart valves to spontaneous in body self-regeneration was investigated in a large animal model. Decellularized porcine aortic valves were evaluated for right ventricular outflow tract (RVOT reconstruction in Vietnamese Pigs (n = 11 with 6 (n = 5 and 15 (n = 6 follow-up months. Repositioned native valves (n = 2 for each time were considered as control. Tissue and cell components from explanted valves were investigated by histology, immunohistochemistry, electron microscopy, and gene expression. Most substitutes constantly demonstrated in vivo adequate hemodynamic performances and ex vivo progressive repopulation during the 15 implantation months without signs of calcifications, fibrosis and/or thrombosis, as revealed by histological, immunohistochemical, ultrastructural, metabolic and transcriptomic profiles. Colonizing cells displayed native-like phenotypes and actively synthesized novel extracellular matrix elements, as collagen and elastin fibers. New mature blood vessels, i.e. capillaries and vasa vasorum, were identified in repopulated valves especially in the medial and adventitial tunicae of regenerated arterial walls. Such findings correlated to the up-regulated vascular gene transcription. Neoinnervation hallmarks were appreciated at histological and ultrastructural levels. Macrophage populations with reparative M2 phenotype were highly represented in repopulated valves. Indeed, no aspects of adverse/immune reaction were revealed in immunohistochemical and transcriptomic patterns. Among differentiated elements, several cells were identified expressing typical stem cell markers of embryonic, hematopoietic, neural and mesenchymal lineages in significantly

  10. Beneficial effects of non-matched allogeneic cord blood mononuclear cells upon patients with idiopathic osteoporosis

    Directory of Open Access Journals (Sweden)

    Li Jun

    2012-05-01

    Full Text Available Abstract Background Immunological arguments and historical examples have shown that treatment with cord blood for non-hematopoietic activities, such as growth factor production and stimulation of angiogenesis, may not require matching or immune suppression. Methods To study the benefit of blood mononuclear cell therapy, 8 patients with idiopathic osteoporosis were given intermittent treatments with non-matched allogeneic cord blood mononuclear cells for 3 months. Morning fasting samples were collected for measuring urine N telopeptide of type-1 collagen, serum bone-specific alkaline phosphatase, and insulin-like growth factor 1 during one-year study. Results Clinical response was striking. Serum insulin-like growth factor 1 significantly increased in all patients at 3 months compared with baseline values, from 264.1 ± 107.0 to 384.4 ± 63.1 ng/mL (P = 0.002, with a tendency to return to baseline values at 12 months (312.9 ± 75.5 ng/mL, P = 0.083. In contrast, differences in serum bone-specific alkaline phosphatase and urine N telopeptide of type-1 collagen were not significant at 3 (P = 0.765, P = 0.057 or 12 months (P = 0.889, P = 0.122. A beneficial effect on bone density was observed in all patients at the lumbar spine. The mean bone mineral density calculated during therapy (0.6811 ± 0.1442 g/cm2 tended higher than baseline values (0.6239 ± 0.1362 g/cm2, P  Conclusions The findings indicate that for these patients with idiopathic osteoporosis, treatment with cord blood mononuclear cells led to a significant increase in insulin-like growth factor 1 levels, which favors the increase in bone mineral density.

  11. Adoptive transfer of natural antibodies to non-immunized chickens affects subsequent antigen-specific humoral and cellular immune responses

    NARCIS (Netherlands)

    Lammers, A.; Klomp, M.E.V.; Nieuwland, M.G.B.; Savelkoul, H.F.J.; Parmentier, H.K.

    2004-01-01

    To determine a regulatory function of natural antibodies in the immune response of chickens, pooled plasma obtained from non-immunized (naive) 15 months old hens was subjected to keyhole limpet hemocyanin (KLH) antigen-affinity chromatography. Purified KLH-binding antibodies were adoptively

  12. Ação dos linfócitos T regulatórios em transplantes T regulatory lymphocytes action in transplants

    Directory of Open Access Journals (Sweden)

    Bruno A. Faria

    2008-08-01

    Full Text Available O sistema imunológico humano possui um significado comum de proteção contra antígenos estranhos com potencialidade patogênica ou não, ativando uma ação coletiva e coordenada entre células e moléculas. Embora sendo um sistema benéfico, deve ser controlado para evitar que auto-antígenos sejam alvejados. Recentemente, por meio de novas técnicas, tem-se observado uma corrente de estudo para as células T CD4+CD25+ Foxp3 como células reguladoras que controlam ativamente a função de outras células imunes impedindo sua atividade e, conseqüentemente, o desenvolvimento de doenças auto-imunes, rejeição de enxerto e combate a células tumorais. Em pacientes submetidos ao transplante alogênico, os mecanismos que levam a hiporresponsividade, assim como os mecanismos que permitem uma maior sobrevida do enxerto ainda são pouco conhecidos. Este artigo aborda uma revisão da literatura sobre as células T regulatórias, vislumbrando uma nova possibilidade de terapia imunomoduladora para pacientes transplantados.The human immune system mounts specific responses against a vast array of foreign antigens, pathogenic or otherwise, activating a coordinated action between cells and molecules. Although this is beneficial, it must be carefully controlled to ensure that normal self antigens are not targeted. Recently, with the development of new techniques, it has been observed that T CD4+CD25+Foxp3 act as regulatory cells which actively control the properties of other immune cells by suppressing their functional activity to prevent autoimmunity and transplant rejection as well as to trigger the immune system against tumor cells. In patients submitted to allogeneic transplantation, specific unresponsive mechanisms and mechanisms that induce and maintain graft tolerance are little understood. This article reviews what is currently known about these so-called regulatory T cells and discusses the potential use of these cells in transplantation

  13. Integrated Circuit Immunity

    Science.gov (United States)

    Sketoe, J. G.; Clark, Anthony

    2000-01-01

    This paper presents a DOD E3 program overview on integrated circuit immunity. The topics include: 1) EMI Immunity Testing; 2) Threshold Definition; 3) Bias Tee Function; 4) Bias Tee Calibration Set-Up; 5) EDM Test Figure; 6) EMI Immunity Levels; 7) NAND vs. and Gate Immunity; 8) TTL vs. LS Immunity Levels; 9) TP vs. OC Immunity Levels; 10) 7805 Volt Reg Immunity; and 11) Seventies Chip Set. This paper is presented in viewgraph form.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems.

    Science.gov (United States)

    Buchwald, Zachary S; Aurora, Rajeev

    2013-01-01

    There are a number of dynamic regulatory loops that maintain homeostasis of the immune and skeletal systems. In this review, we highlight a number of these regulatory interactions that contribute to maintaining homeostasis. In addition, we review data on a negative regulatory feedback loop between osteoclasts and CD8 T cells that contributes to homeostasis of both the skeletal and immune systems.

  16. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

    2009-01-01

    OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International......, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early...

  17. Donor Vδ1+ γδ T cells expand after allogeneic hematopoietic stem cell transplantation and show reactivity against CMV-infected cells but not against progressing B-CLL.

    Science.gov (United States)

    Prinz, Immo; Thamm, Kristina; Port, Matthias; Weissinger, Eva M; Stadler, Michael; Gabaev, Ildar; Jacobs, Roland; Ganser, Arnold; Koenecke, Christian

    2013-05-11

    γδ T lymphocytes play an important role in immune reactions towards infections and malignancies. In particular, Vγ9-Vδ1+ T lymphocytes are thought to play protective antiviral roles in human CMV infection. Recently, Vδ1+ T lymphocytes were proposed to also have anti- B-CLL reactivity. Here we report a case of 48-year-old man who received allogeneic stem cell transplantation for progressive B-CLL. Within one year after transplantation, lymphoma relapsed despite a dramatic increase of Vδ1+ T cells in the patient's blood. In vitro killing assays revealed activity of patient's γδ cells against CMV target cells, but not against the relapsing lymphoma-cells. This argues for a contribution of Vδ1+ cells in the immune reaction against CMV reactivation, but does not support a strong correlation of expanded Vδ1+ T cells and favorable disease outcome in B-CLL patients.

  18. Adaptive immunity in autoimmune hepatitis.

    Science.gov (United States)

    Longhi, Maria Serena; Ma, Yun; Mieli-Vergani, Giorgina; Vergani, Diego

    2010-01-01

    The histological lesion of interface hepatitis, with its dense portal cell infiltrate consisting of lymphocytes, monocytes/macrophages and plasma cells, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of autoimmune hepatitis (AIH). Immunohistochemical studies, focused on the phenotype of inflammatory cells infiltrating the liver parenchyma, have shown a predominance of alphabeta-T cells. Amongst these cells, the majority have been CD4 helper/inducers, while a sizeable minority have consisted of CD8 cytotoxic/suppressors. Lymphocytes on non-T cell lineage included natural killer cells, monocytes/macrophages and B lymphocytes. For autoimmunity to arise, the self-antigenic peptide, embraced by an human leukocyte antigen (HLA) class II molecule, must be presented to an uncommitted T helper (T(H)0) lymphocyte by professional antigen-presenting cells. Once activated and according to the presence in the milieu of interleukin 12 (IL-12) or IL-4, T(H)0 lymphocytes can differentiate into T(H)1 cells, which are pivotal to macrophage activation; enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack; and induce HLA class II expression on hepatocytes; or they can differentiate into T(H)2 cells, which produce IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25(high) regulatory T cells. Numerical and functional regulatory T cell impairment characterises AIH and permits the perpetuation of effector immune responses with ensuing persistent liver destruction. Advances in the study of autoreactive T cells stem mostly from AIH type 2, where the main autoantigen, cytochrome P450IID6 (CYP2D6), is known to enable characterisation of antigen-specific immune responses. Copyright 2010 S. Karger AG, Basel.

  19. Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview.

    Science.gov (United States)

    Singh, Anurag K; McGuirk, Joseph P

    2016-11-15

    The field of hematopoietic stem cell transplant (HSCT) has made ground-breaking progress in the treatment of many malignant and nonmalignant conditions. It has also pioneered the concepts of stem cell therapy and immunotherapy as a tool against cancer. The success of transplant for hematologic malignancies derives both from the ability to treat patients with intensive chemoradiotherapy and from potent graft-versus-leukemia (GVL) effects mediated by donor immunity. Additionally, HSCT has been a curative therapy for several nonmalignant hematologic disorders through the provision of donor-derived hematopoiesis and immunity. Preclinical and clinical research in the field has contributed to an advanced understanding of histocompatibility, graft-versus-host disease (GVHD), GVL effect, and immune reconstitution after transplant. Improved donor selection, tailored conditioning regimens, and better supportive care have helped reduce transplant-related morbidity and mortality and expanded access. The development of unrelated donor registries and increased utilization of cord blood and partially matched related donor transplants have ensured a donor for essentially everyone who needs a transplant. However, significant barriers still remain in the form of disease relapse, GVHD infectious complications, and regimen-related toxicities. Recent developments in the field of cellular therapy are expected to further improve the efficacy of transplant. In this review, we discuss the current science of HSCT from a historical perspective, highlighting major discoveries. We also speculate on future directions in this field. Cancer Res; 76(22); 6445-51. ©2016 AACR. ©2016 American Association for Cancer Research.

  20. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission

    DEFF Research Database (Denmark)

    Nagler, Arnon; Rocha, Vanderson; Labopin, Myriam

    2013-01-01

    Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable...

  1. Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

    Science.gov (United States)

    Westerdahl, Daniel E; Chang, David H; Hamilton, Michele A; Nakamura, Mamoo; Henry, Timothy D

    2016-09-01

    Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

  2. On the Feasibility of Utilizing Allogeneic Bone Blocks for Atrophic Maxillary Augmentation

    Directory of Open Access Journals (Sweden)

    Alberto Monje

    2014-01-01

    Full Text Available Purpose. This systematic review was aimed at assessing the feasibility by means of survival rate, histologic analysis, and causes of failure of allogeneic block grafts for augmenting the atrophic maxilla. Material and Methods. A literature search was conducted by one reviewer in several databases. Articles were included in this systematic review if they were human clinical trials in which outcomes of allogeneic bone block grafts were studied by means of survival rate. In addition other factors were extracted in order to assess their influence upon graft failure. Results. Fifteen articles fulfilled the inclusion criteria and subsequently were analyzed in this systematic review. A total of 361 block grafts could be followed 4 to 9 months after the surgery, of which 9 (2.4% failed within 1 month to 2 months after the surgery. Additionally, a weighed mean 4.79 mm (95% CI: 4.51–5.08 horizontal bone gain was computed from 119 grafted sites in 5 studies. Regarding implant cumulative survival rate, the weighed mean was 96.9% (95% CI: 92.8–98.7%, computed from 228 implants over a mean follow-up period of 23.9 months. Histologic analysis showed that allogeneic block grafts behave differently in the early stages of healing when compared to autogenous block grafts. Conclusion. Atrophied maxillary reconstruction with allogeneic bone block grafts represents a reliable option as shown by low block graft failure rate, minimal resorption, and high implant survival rate.

  3. Specific Factors Influence the Success of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Thissiane L. Gonçalves

    2009-01-01

    Full Text Available Successful hematopoietic stem cell transplantation (HSCT, both autologous and allogeneic, requires a rapid and durable engraftment, with neutrophil (>500/µL and platelet (>20,000/µL reconstitution. Factors influencing engraftment after autologous or allogeneic HSCT were investigated in 65 patients: 25 autologous peripheral stem cell transplantation (PBSCT and 40 allogeneic bone marrow transplantation (BMT patients. The major factor affecting engraftment was the graft source for HSCT. Neutrophil and platelet recovery were more rapid in autologous PBSCT than in allogeneic BMT [neutrophil occurring in median on day 10.00 (09.00/11.00 and 19.00 (16.00/23.00 and platelet on day 11.00 (10.00/13.00 and 21.00 (18.00/25.00, respectively; p < 0.0001]. The type of disease also affected engraftment, where multiple myeloma (MM and lymphoma showed faster engraftment when compared with leukemia, syndrome myelodysplastic (SMD and aplastic anemia (AA and MM presented the best overall survival (OS in a period of 12 months. Other factors included the drug used in the conditioning regimen (CR, where CBV, melphalan (M-200 and FluCy showed faster engraftment and M-200 presented the best OS, in a period of 12 months and age, where 50–59 years demonstrated faster engraftment. Sex did not influence neutrophil and platelet recovery.

  4. Novel therapies and their integration into allogeneic stem cell transplant for chronic lymphocytic leukemia.

    Science.gov (United States)

    Jaglowski, Samantha M; Byrd, John C

    2012-01-01

    Over the past decade, numerous advances have been made in elucidating the biology of and improving treatment for chronic lymphocytic leukemia (CLL). These studies have led to identification of select CLL patient groups that generally have short survival dating from time of treatment or initial disease relapse who benefit from more aggressive therapeutic interventions. Allogeneic transplantation represents the only potentially curative option for CLL, but fully ablative regimens applied in the past have been associated with significant morbidity and mortality. Reduced-intensity preparative regimens has made application of allogeneic transplant to CLL patients much more feasible and increased the number of patients proceeding to this modality. Arising from this has been establishment of guidelines where allogeneic stem cell transplantation should be considered in CLL. Introduction of new targeted therapies with less morbidity, which can produce durable remissions has the potential to redefine where transplantation is initiated in CLL. This review briefly summarizes the field of allogeneic stem cell transplant in CLL and the interface of new therapeutics with this modality. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  5. Blood management in total hip replacement: an analysis of factors associated with allogenic blood transfusion.

    Science.gov (United States)

    Wong, Samuel; Tang, Howard; de Steiger, Richard

    2015-06-01

    The aim of this study was to audit the blood transfusion practice throughout the Epworth Healthcare Hospitals for patients undergoing primary total hip replacement (THR). We determined if blood-saving techniques were having an impact on the risk of allogenic blood transfusion and which patients were at risk of receiving allogenic blood transfusion. This study uses a retrospective audit of 787 patients who had undergone primary THR surgery at three Melbourne hospitals: Epworth Richmond, Epworth Eastern and Epworth Freemasons in 2010. Patient demographics, transfusion requirements and blood-conserving techniques were recorded. One hundred and eighty (23%) patients received allogenic blood transfusion and 18 (2.3%) patients received autologous blood transfusion. On multivariate analysis, preoperative anaemia (odds ratio (OR) 4.7, P blood transfusion. Use of spinal anaesthetic was found to be associated with lower risk of transfusion (OR 0.6, P = 0.0180) compared with general anaesthetic alone. Cell saver, acute normovolaemic haemodilution and re-infusion drain tube usage did not have a significant impact on reducing the risk of allogenic blood transfusion. Identification of patients at risk of blood transfusion, correction of preoperative anaemia and a restrictive transfusion policy are important factors to consider in effective perioperative blood management. © 2015 Royal Australasian College of Surgeons.

  6. Preoperative Acute Normovolemic Hemodilution for Minimizing Allogeneic Blood Transfusion: A Meta-Analysis.

    Science.gov (United States)

    Zhou, Xuelong; Zhang, Chenjing; Wang, Yin; Yu, Lina; Yan, Min

    2015-12-01

    Previous studies have evaluated the efficacy of preoperative acute normovolemic hemodilution (PANH) in reducing the need for allogeneic blood transfusion. However, the results to date have been controversial. In this study, we sought to reassess the efficacy and safety of PANH based on newly emerging evidence. Medline, EMBASE, ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials databases were searched using the key words "hemodilution," "autotransfusion," or "hemorrhage" to retrieve all randomized controlled trials examining the benefits of PANH compared with control patients not undergoing PANH in any type of surgery. Sixty-three studies involving 3819 patients were identified. The risk of requiring an allogeneic blood transfusion and the overall volume of allogeneic red blood cell transfused during the perioperative period were reduced in the PANH group compared with the control group (relative risk, 0.74; 95% confidence interval, 0.63 to 0.88; P = 0.0006; weighted mean difference, -0.94 units; 95% confidence interval, -1.27 to -0.61 units; P transfusion. Perioperative blood loss, adverse events, and the length of hospitalization were comparable between these groups. Although these results suggest that PANH is effective in reducing allogeneic blood transfusion, we identified significant heterogeneity and publication bias, which raises concerns about the true efficacy of PANH.

  7. Differential diagnosis of skin lesions after allogeneic haematopoietic stem cell transplantation

    NARCIS (Netherlands)

    Canninga-van Dijk, MR; Sanders, CJ; Verdonck, LF; Fijnheer, R; van den Tweel, JG

    Allogeneic haematopoietic stem cell transplantation (i.e. bone marrow or peripheral blood stem cell transplantation) is a common procedure in the treatment of various haematological disorders such as aplastic anaemia, (pre)leukaemias, some malignant lymphomas, multiple myeloma and immunodeficiency

  8. Unrelated allogeneic stem-cell transplantation in adult patients – 10-year experience

    Directory of Open Access Journals (Sweden)

    Jožef Pretnar

    2012-12-01

    Conclusion: Unrelated allogeneic stem-cell transplantation is suitable for acute myeloblastic leukemias with unfavorable risk factors. However, results in acute lymphoblastic leukemia are worse. Unrelated transplantation is not efficient as salvage treatment for patients with recurrent disease after autologous transplantation or chemotherapy- resistant relapse.

  9. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E

    2013-01-01

    We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the pures...

  10. Titanium implant insertion into dog alveolar ridges augmented by allogenic material

    DEFF Research Database (Denmark)

    Pinholt, E M; Haanaes, H R; Donath, K

    1994-01-01

    The purpose of this investigation was to evaluate whether titanium endosseous implants would osseointegrate in dog alveolar ridges augmented by allogenic material. In 8 dogs en bloc resection, including 2 pre-molars, was performed bilaterally in the maxilla and the mandible. After a healing period...

  11. Prolonged Survival of Subcutaneous Allogeneic Islet Graft by Donor Chimerism without Immunosuppressive Treatment

    Directory of Open Access Journals (Sweden)

    Brend Ray-Sea Hsu

    2017-01-01

    Full Text Available The aim of this study was to investigate whether tolerance-induced protection of islets in the renal subcapsular space can also prevent subcutaneous allogeneic islets from being rejected. We used bone marrow stem cells from C57BL/6 (H2b mice to construct donor chimerism in conditioned diabetic BALB/c (H2d mice and investigated the effect of donor chimerism on engraftment and survival of subcutaneously transplanted allogeneic islets in streptozotocin-induced diabetic mice. We also studied the anti-inflammatory effect of mesenchymal stem cell on islet engraftment. Full but not low-grade or no donor chimerism was associated with successful engraftment of allogeneic islets and restoration of normoglycemia in the treated diabetic mice. The temporary hyperglycemia was 11 ± 1 versus 19 ± 5 days (p<0.05 for the mice with full donor chimerism with transplanted islets in the renal subcapsular space versus the subcutaneous space, respectively. Cotransplantation of mesenchymal stem cell did not enhance alloislet engraftment. Full multilineage donor chimerism was associated with a higher transient expansion of CD11b+ and Gr-1+ myeloid progenitor cells and effector memory CD4 and CD8 T cells. In conclusion, full donor chimerism protected both renal subcapsular and subcutaneous allogeneic islets in this rodent transplantation model.

  12. The effect of allogenic versus autologue mesenchymal stem cells in bone reconstructio

    DEFF Research Database (Denmark)

    Jensen, Stefan; Overgaard, Søren; Ding, Ming

    2008-01-01

    with allogenic MSC (group#3) proved to have a significant higher mean SFE (Fisher's LSD-test). The other groups (#1 and #2) had a slightly higher mean SFE (Table 2). Discussion and Conclusion: There are shown two interesting things in this minor pilot-study. There is a trend showing, that the use of MSC has...

  13. Treg cell-IgA axis in maintenance of host immune homeostasis with microbiota

    OpenAIRE

    Feng, Ting; Elson, Charles O.; Cong, Yingzi

    2010-01-01

    The intestine is the home to a vast diversity of microbiota and a complex of mucosal immune system. Multiple regulatory mechanisms control host immune responses to microbiota and maintain intestinal immune homeostasis. This mini review will provide evidence indicating a Treg cell-IgA axis and such axis playing a major role in maintenance of intestinal homeostasis.

  14. Intergovernmental Immunities in Litigation, Taxation, and Regulation: Separation of Powers Issues in Controversies About Federalism

    Science.gov (United States)

    Tribe, Laurence H.

    1976-01-01

    The author argues that attention to the question of who should decide an intergovernmental immunity issue--the states, the federal courts, the federal executive, or Congress--illuminates the law of eleventh amendment immunities and intergovernmental tax and regulatory immunities and supports all but a handful of the results courts have reached.…

  15. Maintenance of systemic immune functions prevents accelerated presbycusis.

    Science.gov (United States)

    Iwai, Hiroshi; Baba, Susumu; Omae, Mariko; Lee, Shinryu; Yamashita, Toshio; Ikehara, Susumu

    2008-05-07

    There is no effective therapy for progressive hearing loss such as presbycusis, the causes of which remain poorly understood because of the difficulty of separating genetic and environmental contributions. In the present study, we show that the age-related dysfunctions of the systemic immune system in an animal model of accelerated presbycusis (SAMP1, senescence-accelerated mouse P1) can be corrected by allogeneic bone marrow transplantation (BMT). We also demonstrate that this presbycusis can be prevented; BMT protects the recipients from age-related hearing impairment and the degeneration of spiral ganglion cells (SGCs) as well as the dysfunctions of T lymphocytes, which have a close relation to immune senescence. No donor cells are infiltrated to the spiral ganglia, confirming that this experimental system using BMT is connected to the systemic immune system and does not contribute to transdifferentiation or fusion by donor hematopoietic stem cells (HSCs), or to the direct maintenance of ganglion cells by locally infiltrated donor immunocompetent cells. Therefore, another procedure which attempts to prevent the age-related dysfunctions of the recipient immune system is the inoculation of syngeneic splenocytes from young donors. These mice show no development of hearing loss, compared with the recipient mice with inoculation of saline or splenocytes from old donors. Our studies on the relationship between age-related systemic immune dysfunctions and neurodegeneration mechanisms open up new avenues of treatment for presbycusis, for which there is no effective therapy.

  16. Immune reactivity after high-dose irradiation

    International Nuclear Information System (INIS)

    Gassmann, W.; Wottge, H.U.; von Kolzynski, M.; Mueller-Ruchholtz, W.

    1986-01-01

    Immune reactivity after total-body irradiation was investigated in rats using skin graft rejection as the indicator system. After sublethal irradiation with 10.5 Gy (approximately 50% lethality/6 weeks) the rejection of major histocompatibility complex allogeneic skin grafts was delayed significantly compared with nonirradiated control animals (28 versus 6.5 days). In contrast, skin grafts were rejected after 7.5 days in sublethally irradiated animals and 7 days in lethally irradiated animals if additional skin donor type alloantigens--namely, irradiated bone marrow cells--were given i.v. either simultaneously or with a delay of not more than 24 hr after the above conditioning regimen. These reactions were alloantigen-specific. They were observed in six different strain combinations with varying donors and recipients. Starting on day 2 after irradiation, i.v. injection of bone marrow gradually lost its effectivity and skin grafts were no longer rejected with uniform rapidity; skin donor marrow given on days 4 or 8 did not accelerate skin graft rejection at all. These data show that for approximately 1-2 days after high-dose total-body irradiation rats are still capable of starting a vigorous immune reaction against i.v.-injected alloantigens. The phenomenon of impaired rejection of skin grafted immediately after high-dose irradiation appears to result from the poor accessibility of skin graft alloantigens during the early postirradiation phase when vascularization of the grafted skin is insufficient

  17. IL-35, a hallmark of immune-regulation in cancer progression, chronic infections and inflammatory diseases.

    Science.gov (United States)

    Teymouri, Manouchehr; Pirro, Matteo; Fallarino, Francesca; Gargaro, Marco; Sahebkar, Amirhosein

    2018-03-25

    Cytokine members of the IL-12 family have attracted enormous attention in the last few years, with IL-35 being the one of the most attractive-suppressive cytokine. IL-35 is an important mediator of regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal-maternal tolerance, maintenance of self-tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune-homoeostasis on the aforementioned issues, taking IL-35 as the hallmark of regulatory responses. The dilemma between immune-mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL-35 requires additional immune-regulatory cytokines, such as IL-10 and TGF-β, to induce effective and maximal anti-inflammatory effects suggest that immune-regulation requires multi-factorial analysis of many immune playmakers rather than a specific immune target. © 2018 UICC.

  18. Innate immune system and preeclampsia

    Directory of Open Access Journals (Sweden)

    Alejandra ePerez-Sepulveda

    2014-05-01

    Full Text Available Normal pregnancy is considered as a Th2 type immunological state that favors an immune-tolerance environment in order to prevent fetal rejection. PE has been classically described as a Th1/Th2 imbalance; however, the Th1/Th2 paradigm has proven insufficient to fully explain the functional and molecular changes observed during normal/pathological pregnancies. Recent studies have expanded the Th1/Th2 into a Th1⁄Th2⁄Th17 and regulatory T (Treg cells paradigm and where dendritic cells could have a crucial role. Recently, some evidence has emerged supporting the idea that mesenchymal stem cells might be part of the feto-maternal tolerance environment. This review will discuss the involvement of the innate immune system in the establishment of a physiological environment that favors pregnancy and possible alterations related to the development of preeclampsia.

  19. Platelet-rich-plasmapheresis for minimising peri-operative allogeneic blood transfusion.

    Science.gov (United States)

    Carless, Paul A; Rubens, Fraser D; Anthony, Danielle M; O'Connell, Dianne; Henry, David A

    2011-03-16

    Concerns regarding the safety of transfused blood have generated considerable enthusiasm for the use of technologies intended to reduce the use of allogeneic blood (blood from an unrelated donor). Platelet-rich plasmapheresis (PRP) offers an alternative approach to blood conservation. To examine the evidence for the efficacy of PRP in reducing peri-operative allogeneic red blood cell (RBC) transfusion, and the evidence for any effect on clinical outcomes such as mortality and re-operation rates. We identified studies by searching MEDLINE (1950 to 2009), EMBASE (1980 to 2009), The Cochrane Library (Issue 1, 2009), the Internet (to March 2009) and the reference lists of published articles, reports, and reviews. Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to PRP, or to a control group which did not receive the intervention. Primary outcomes measured were: the number of patients exposed to allogeneic RBC transfusion, and the amount of RBC transfused. Other outcomes measured were: the number of patients exposed to allogeneic platelet transfusions, fresh frozen plasma, and cryoprecipitate, blood loss, re-operation for bleeding, post-operative complications (thrombosis), mortality, and length of hospital stay. Treatment effects were pooled using a random-effects model. Trial quality was assessed using criteria proposed by Schulz et al (Schulz 1995). Twenty-two trials of PRP were identified that reported data for the number of patients exposed to allogeneic RBC transfusion. These trials evaluated a total of 1589 patients. The relative risk (RR) of exposure to allogeneic blood transfusion in those patients randomised to PRP was 0.73 (95%CI 0.59 to 0.90), equating to a relative risk reduction (RRR) of 27% and a risk difference (RD) of 19% (95%CI 10% to 29%). However, significant heterogeneity of treatment effect was observed (p transfused (weighted mean difference [WMD] -0.69, 95%CI -1.93 to 0.56 units). Trials

  20. Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model.

    Science.gov (United States)

    Saso, Srdjan; Petts, Gemma; David, Anna L; Thum, Meen-Yau; Chatterjee, Jayanta; Vicente, Jose S; Marco-Jimenez, Francisco; Corless, David; Boyd, Michael; Noakes, David; Lindsay, Iain; Del Priore, Giuseppe; Ghaem-Maghami, Sadaf; Smith, J Richard

    2015-02-01

    Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI). The goal of UTx remains achieving pregnancy and live birth of a healthy neonate following allogeneic UTx. Our aim was to assess whether fertility was possible following allogeneic uterine transplantation (UTx), when the recipient had demonstrated long-term survival and had been administered immunosuppression. Nine allogeneic UTx in New Zealand White rabbits were performed using a pre-determined protocol. Tacrolimus was the immunosuppressant selected. Embryos were transferred into both cornua of the sole living recipient via a mini-midline laparotomy. The pregnancy was monitored with regular reproductive profiles and serial trans-abdominal ultrasound to measure conceptus growth (gestation sac and crown rump length (CRL)). In the sole surviving doe a gestation sac was visualised on ultrasound from Day 9 (D9) after embryo transfer. Gestation sac diameter and CRL increased from D9 to D16 but by D18 the gestation sac had reduced in size. The fetus was no longer visible, suggesting fetal resorption had occurred. Subsequent scans on D22 and D25 did not demonstrate a gestation sac. Scheduled necropsy on D27 and histopathology confirmed evidence of a gravid uterus and presence of a gestational sac. A single episode of acute rejection occurred on D13. Pregnancy was achieved after rabbit allogeneic UTx but serial ultrasound suggested that fetal demise occurred prior to scheduled necropsy. The study represents only the third example of conception and pregnancy following an animal allogeneic UTx. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Outcomes of allogeneic hematopoietic stem cell transplantation for lymphomas: a single-institution experience

    Directory of Open Access Journals (Sweden)

    Mira Romany Massoud

    Full Text Available ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes. Methods: All patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied. Results: Forty-one patients were reviewed: 10 (24% had Hodgkin's and 31 (76% had non-Hodgkin lymphomas. The median age was 50 years and 23 (56% were male. The majority of patients (68% had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43% patients were in complete and seven (17% were in partial remission. Most (95% patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival. Conclusions: Allogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.

  2. Effect of allogenic thymic cells on radioleukaemogenesis in AKR-T1ALD mice

    International Nuclear Information System (INIS)

    Legrand, E.; Sankar-Mistry, P.; Kressmann, M.C.

    1975-01-01

    When AKR mice are irradiated with a sub-lethal dose (4 times 175 R), thymic lymphosarcomas (L.S.) occur earlier than in controls. This accelerated leukaemogenesis is not inhibited by syngenic restoration with bone marrows cells (BM). Using the AKR/T1ALD substrain which bears 38 chromosomes with 1 metacentric markers, it has been shown that AKR radio-chimaeras restored by T1ALD BM developed two kinds of L.S.: early (radiation-induced) L.S. originating mainly from host cells surviving irradiation and late L.S. from donor cells. The experiments were to investigate the potential influence of normal allogenic thymic cells, with or without syngenic B.M., on the incidence, latency and origin of LS appearing in irradiated AKR recipients. Adding C3H allogenic thymic cells to syngenic B.M. increases the percentage of early L.S. whose latencies are unchanged. Besides, when C3H thymic cells are injected to irradiated controls without syngenic B.M. cells, L.S. are seen to occur significantly earlier than in just the irradiated animals alone. In radio-chimaeras restored by allogenic thymic cells and syngenic B.M., except in one case, all the L.S. were seen to originate from B.M. cells. The interpretation of these results depends on the possible role of allogenic thymic cells on host cells surviving the irradiation, or the exogeneous B.M. In the first case, allogenic thymocytes could induce a graft versus host reaction increasing the post-irradiation depletion of lymphoid system and hastening thymic endoregeneration which is supposed to be the first step towards leukaemogenesis. The second hypothesis, which seems the most likely, would be that C1H thymic cells could selectively act on host cells surviving irradiation and enhance the differenciation of haemopoietic precursors at the expense of the lymphoid cells [fr

  3. Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human.

    Science.gov (United States)

    Aerts, Joachim G J V; de Goeje, Pauline L; Cornelissen, Robin; Kaijen-Lambers, Margaretha E H; Bezemer, Koen; van der Leest, Cor H; Mahaweni, Niken M; Kunert, André; Eskens, Ferry A L M; Waasdorp, Cynthia; Braakman, Eric; van der Holt, Bronno; Vulto, Arnold G; Hendriks, Rudi W; Hegmans, Joost P J J; Hoogsteden, Henk C

    2018-02-15

    Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans. Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines. Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months). Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766-76. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. As to achieve regulatory action, regulatory approaches

    International Nuclear Information System (INIS)

    Cid, R.; Encinas, D.

    2014-01-01

    The achievement of the effectiveness in the performance of a nuclear regulatory body has been a permanent challenge in the recent history of nuclear regulation. In the post-Fukushima era this challenge is even more important. This article addresses the subject from two complementary points of view: the characteristics of an effective regulatory body and the regulatory approaches. This work is based on the most recent studies carried out by the Committee on Nuclear Regulatory Activities, CNRA (OECD/NEA), as well as on the experience of the Consejo de Seguridad Nuclear, CSN, the Spanish regulatory body. Rafael Cid is the representative of CSN in these project: Diego Encinas has participated in the study on regulatory approaches. (Author)

  5. Regulatory T Cells in Human Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Dong-Jun Peng

    2012-01-01

    Full Text Available Multiple layers of suppressive components including regulatory T (TReg cells, suppressive antigen-presenting cells, and inhibitory cytokines form suppressive networks in the ovarian cancer microenvironment. It has been demonstrated that as a major suppressive element, TReg cells infiltrate tumor, interact with several types of immune cells, and mediate immune suppression through different molecular and cellular mechanisms. In this paper, we focus on human ovarian cancer and will discuss the nature of TReg cells including their subsets, trafficking, expansion, and function. We will briefly review the development of manipulation of TReg cells in preclinical and clinical settings.

  6. Immune System Quiz

    Science.gov (United States)

    ... Safe Videos for Educators Search English Español Quiz: Immune System KidsHealth / For Kids / Quiz: Immune System Print How much do you know about your immune system? Find out by taking this quiz! About Us ...

  7. Immunization Schedules for Adults

    Science.gov (United States)

    ... ACIP Vaccination Recommendations Why Immunize? Vaccines: The Basics Immunization Schedule for Adults (19 Years of Age and ... diseases that can be prevented by vaccines . 2018 Immunization Schedule Recommended Vaccinations for Adults by Age and ...

  8. Immunizations and African Americans

    Science.gov (United States)

    ... Data > Minority Population Profiles > Black/African American > Immunizations Immunizations and African Americans African American adults are less ... 19 to 35 months had comparable rates of immunization. African American women are as likely to have ...

  9. Instant Childhood Immunization Schedule

    Science.gov (United States)

    ... Recommendations Why Immunize? Vaccines: The Basics Instant Childhood Immunization Schedule Recommend on Facebook Tweet Share Compartir Get ... date. See Disclaimer for additional details. Based on Immunization Schedule for Children 0 through 6 Years of ...

  10. Interleukin-2 and STAT5 in regulatory T cell development and function

    OpenAIRE

    Mahmud, Shawn A.; Manlove, Luke S.; Farrar, Michael A.

    2013-01-01

    Interleukin-2 and its downstream target STAT5 have effects on many aspects of immune function. This has been perhaps best documented in regulatory T cells. In this review we summarize the initial findings supporting a role for IL2 and STAT5 in regulatory T cell development and outline more recent studies describing how this critical signaling pathway entrains regulatory T cell differentiation and affects regulatory T cell function.

  11. Future targets for immune therapy in colitis?

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Claesson, M H

    2008-01-01

    Crohn's disease and Ulcerative Colitis, collectively termed inflammatory bowel disease (IBD), are chronic inflammatory disorders of the bowel. It is generally accepted that the pathology associated with IBD is characterized by a hyper-reactive immune response in the gut wall directed against...... the commensal intestinal bacterial flora, and that the CD4+ T cells dominate the adaptive immune response. Chemokines are small proteins involved in the guidance of migration of immune cells during normal homeostasis and inflammation. Chemokines have been shown to play a central role in recruiting inflammatory...... cells from congenic normal mice are transplanted into immune deficient mice, which in turn develop a chronic lethal colitis within 1-2 months. By simultaneous transplantation of CD4+CD25+ regulatory T cells (Tregs) it is possible to hinder development of colitis. Thus the model is well suited...

  12. RNA-Binding Proteins in Plant Immunity

    Directory of Open Access Journals (Sweden)

    Virginia Woloshen

    2011-01-01

    Full Text Available Plant defence responses against pathogen infection are crucial to plant survival. The high degree of regulation of plant immunity occurs both transcriptionally and posttranscriptionally. Once transcribed, target gene RNA must be processed prior to translation. This includes polyadenylation, 5′capping, editing, splicing, and mRNA export. RNA-binding proteins (RBPs have been implicated at each level of RNA processing. Previous research has primarily focused on structural RNA-binding proteins of yeast and mammals; however, more recent work has characterized a number of plant RBPs and revealed their roles in plant immune responses. This paper provides an update on the known functions of RBPs in plant immune response regulation. Future in-depth analysis of RBPs and other related players will unveil the sophisticated regulatory mechanisms of RNA processing during plant immune responses.

  13. Immunization Action Coalition

    Science.gov (United States)

    ... IAC | Contact | A-Z Index | Donate | Shop | SUBSCRIBE Immunization Action Coalition Favorites ACIP Recommendations Package Inserts Additional Immunization Resources Photos Adult Vaccination Screening Checklists Ask the ...

  14. Allogeneic transplantation of programmable cells of monocytic origin (PCMO) improves angiogenesis and tissue recovery in critical limb ischemia (CLI): a translational approach.

    Science.gov (United States)

    Berndt, Rouven; Hummitzsch, Lars; Heß, Katharina; Albrecht, Martin; Zitta, Karina; Rusch, Rene; Sarras, Beke; Bayer, Andreas; Cremer, Jochen; Faendrich, Fred; Groß, Justus

    2018-04-27

    Employing growth factor-induced partial reprogramming in vitro, peripheral human blood monocytes can acquire a state of plasticity along with expression of various markers of pluripotency. These so-called programmable cells of monocytic origin (PCMO) hold great promise in regenerative therapies. The aim of this translational study was to explore and exploit the functional properties of PCMO for allogeneic cell transplantation therapy in critical limb ischemia (CLI). Using our previously described differentiation protocol, murine and human monocytes were differentiated into PCMO. We examined paracrine secretion of pro-angiogenic and tissue recovery-associated proteins under hypoxia and induction of angiogenesis by PCMO in vitro. Allogeneic cell transplantation of PCMO was performed in a hind limb ischemia mouse model in comparison to cell transplantation of native monocytes and a placebo group. Moreover, we analyzed retrospectively four healing attempts with PCMO in patients with peripheral artery disease (PAD; Rutherford classification, stage 5 and 6). Statistical analysis was performed by using one-way ANOVA, Tukey's test or the Student's t test, p < 0.05. Cell culture experiments revealed good resilience of PCMO under hypoxia, enhanced paracrine release of pro-angiogenic and tissue recovery-associated proteins and induction of angiogenesis in vitro by PCMO. Animal experiments demonstrated significantly enhanced SO 2 saturation, blood flow, neoangiogenesis and tissue recovery after treatment with PCMO compared to treatment with native monocytes and placebo. Finally, first therapeutic application of PCMO in humans demonstrated increased vascular collaterals and improved wound healing in patients with chronic CLI without exaggerated immune response, malignant processes or extended infection after 12 months. In all patients minor and/or major amputations of the lower extremity could be avoided. In summary, PCMO improve angiogenesis and tissue recovery in chronic

  15. Transient hemolysis due to anti-D and anti-A1 produced by engrafted donor's lymphocytes after allogeneic unmanipulated haploidentical hematopoietic stem cell transplantation.

    Science.gov (United States)

    Bailén, Rebeca; Kwon, Mi; Pérez-Corral, Ana María; Pascual, Cristina; Buño, Ismael; Balsalobre, Pascual; Serrano, David; Gayoso, Jorge; Díez-Martín, José Luis; Anguita, Javier

    2017-10-01

    Development of de novo alloantibodies against recipient's red blood cell (RBC) antigens by engrafted donor's lymphocytes is a known phenomenon in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). This situation is usually clinically insignificant. We report a case of early clinically relevant hemolytic anemia in a blood group A 1 D+ patient, due to a limited production of anti-D and anti-A 1 produced by nonpreviously sensitized newly engrafted donor's immune system. A 31-year-old Caucasian woman, blood group A 1 , D+, with Hodgkin's lymphoma, received an unmanipulated haploidentical allogeneic peripheral blood HSCT after a nonmyeloablative conditioning regimen. Donor blood group was A 2 B, D-. The patient had an uneventful course until Day +34, when she developed clinically significant hemolytic anemia with a positive direct antiglobulin test. Anti-D and anti-A 1 produced by the donor-engrafted lymphocytes were detected both in serum and in eluate. The hemolysis produced an accelerated group change, turning the patient's ABO group into A 2 B 2 weeks after the detection of the alloantibodies. As the residual patient's RBCs progressively disappeared, anti-D and anti-A 1 production decreased and were not detected in serum by Day +41. This case illustrates that de novo alloantibody production against ABO and D antigens by the newly engrafted donor's lymphocytes can occasionally cause clinically significant anemia. To our knowledge, this is the first case reported of clinically significant hemolytic anemia due to a transient anti-D anti-A 1 alloimmunization after T-cell-repleted haploidentical HSCT. © 2017 AABB.

  16. Regulatory T Cells: Potential Target in Anticancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Chi-Mou Juang

    2007-09-01

    Full Text Available The concept of regulatory T cells was first described in the early 1970s, and regulatory T cells were called suppressive T cells at that time. Studies that followed have demonstrated that these suppressive T cells negatively regulated tumor immunity and contributed to tumor growth in mice. Despite the importance of these studies, there was extensive skepticism about the existence of these cells, and the concept of suppressive T cells left the center stage of immunologic research for decades. Interleukin-2 receptor α-chain, CD25, was first demonstrated in 1995 to serve as a phenotypic marker for CD4+ regulatory cells. Henceforth, research of regulatory T cells boomed. Regulatory T cells are involved in the pathogenesis of cancer, autoimmune disease, transplantation immunology, and immune tolerance in pregnancy. Recent evidence has demonstrated that regulatory T cellmediated immunosuppression is one of the crucial tumor immune evasion mechanisms and the main obstacle of successful cancer immunotherapy. The mechanism and the potential clinical application of regulatory T cells in cancer immunotherapy are discussed.

  17. Regulatory dendritic cells in autoimmunity: A comprehensive review.

    Science.gov (United States)

    Liu, Juan; Cao, Xuetao

    2015-09-01

    Dendritic cells (DCs) are professional antigen-presenting cells (APC) with significant phenotypic heterogeneity and functional plasticity. DCs play crucial roles in initiating effective adaptive immune responses for elimination of invading pathogens and also in inducing immune tolerance toward harmless components to maintain immune homeostasis. The regulatory capacity of DCs depends on their immature state and distinct subsets, yet not restricted to the immature state and one specialized subset. The tolerogenicity of DC is controlled by a complex network of environmental signals and cellular intrinsic mechanisms. Regulatory DCs play an important role in the maintenance of immunological tolerance via the induction of T cell unresponsiveness or apoptosis, and generation of regulatory T cells. DCs play essential roles in driving autoimmunity via promoting the activation of effector T cells such as T helper 1 and T helper 17 cells, and/or suppressing the generation of regulatory T cells. Besides, a breakdown of DCs-mediated tolerance due to abnormal environmental signals or breakdown of intrinsic regulatory mechanisms is closely linked with the pathogenesis of autoimmune diseases. Novel immunotherapy taking advantage of the tolerogenic potential of regulatory DCs is being developed for treatment of autoimmune diseases. In this review, we will describe the current understanding on the generation of regulatory DC and the role of regulatory DCs in promoting tolerogenic immune responses and suppressing autoimmune responses. The emerging roles of DCs dysfunction in the pathogenesis of autoimmune diseases and the potential application of regulatory DCs in the treatment of autoimmune diseases will also be discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. The Balance of Th1/Th2 and LAP+Tregs/Th17 Cells Is Crucial for Graft Survival in Allogeneic Corneal Transplantation

    Directory of Open Access Journals (Sweden)

    Shang Li

    2018-01-01

    Full Text Available Purpose. CD4+LAP+ T cells are newly discovered regulatory T cells (Tregs. The aim of this study is to investigate the balance of Th1/Th2 and LAP+Tregs/Th17 in mice after allogeneic corneal transplantation. Methods. A total of 65 mice received orthotopic penetrating transplantation. According to the survival scores of the grafts, the mice were divided into the rejection group and the survival group 3 weeks after transplantation. Th1, Th2, Th17, and regulatory T cells in the ipsilateral drainage lymph nodes and spleens were measured with flow cytometry. The related cytokines in aqueous humor were also analyzed. Results. The frequencies of Foxp3+Tregs, GARP+Tregs, and LAP+Tregs in the survival group were significantly higher than those in the rejection group. And the expression trend of CD4+LAP+ T cells and CD4+GARP+ T cells was consistent. The level of IFN-γ, TNF, IL-6, and IL-17A markedly increased in aqueous humor during corneal allograft rejection. The ratio of Th1/Th2 and Th17/LAP+Tregs significantly increased in the rejection group at the 3rd week after corneal transplantation. Conclusion. LAP+Tregs might be regarded as substitute for Foxp3+Tregs. The balance of Th1/Th2 and LAP+Tregs/Th17 is crucial for corneal allograft survival.

  19. The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

    DEFF Research Database (Denmark)

    Kishimoto, K; Dong, V M; Issazadeh-Navikas, Shohreh

    2000-01-01

    We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have...... impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT....... Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation...

  20. [Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].

    Science.gov (United States)

    Kuhlmann-Gottke, Johanna; Duchow, Karin

    2015-11-01

    At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.

  1. The Fourth Nagoya International Blood and Marrow Transplantation Symposium: new horizons in allogeneic hematopoietic cell transplantation--2001 revolution.

    Science.gov (United States)

    Sao, Hiroshi; Morishita, Yoshihisa

    2002-02-01

    In this symposium, we saw new horizons in allogeneic transplantation. Are these truly revolutionary? We do not yet know the answer. However, there is no question about the importance of allogeneic T cells. T cells are much more powerful than any pharmacological drug man has ever generated. The question is, how do we take the most advantage of their potential. Every participant was encouraged to search for good answers to this question until the next meeting.

  2. Inhibition of erythroid cell growth by allogeneic murine lymphocytes. Evidence for a synergism between lymph node cells and thymocytes

    International Nuclear Information System (INIS)

    Blomgren, H.; Jacobsson, H.

    1974-01-01

    Murine lymphoid cells from thymus and lymph nodes were tested for synergistic response in a graft-vs-host test. The test is based on the principle that allogeneic lymphocytes inhibit erythroid cell proliferation in the spleens of irradiated mice infused with syngeneic bone marrow cells. Mixtures of thymocytes and lymph node cells from the same parental strain yielded graft-vs-host responses in irradiated F 1 -hybrids higher than expected by summing the responses of the two cell populations tested separately. A similar synergistic response was obtained using mixtures of thymocytes and lymph node cells obtained from the two parental strains of the hybrid, whereas such an effect was not detected using mixtures of lymph node cells or mixtures of thymocytes from the two parental strains. Nor could synergy be demonstrated between parental strain lymph node cells and thymocytes syngeneic with the bone marrow target cells. Thymocytes obtained from one parental strain which was injected into its irradiated F 1 -hybrid transformed into a population of sensitized cells in the spleens of the recipients. This transformation was suppressed by the simultaneous injection of lymph node cells from the second parental strain. Since there is a synergistic immune response by such cell mixtures it is concluded that thymocytes may enhance the graft-vs-host response of lymph node cells. Parental strain thymocytes and lymph node cells, the latter being specifically immunologically tolerant to the bone marrow target cells, failed to give a synergistic response indicating that thymocytes do not transform unresponsive lymphocytes into responsive, but rather enhance the reactivity of existing, specifically responsive cells. The results thus show that thymocytes may enhance the response of lymph node cells in this specific graft-vs-host assay

  3. Myeloid Sarcoma after Allogenic Stem Cell Transplantation for Acute Myeloid Leukemia: Successful Consolidation Treatment Approaches in Two Patients

    Directory of Open Access Journals (Sweden)

    Silje Johansen

    2018-01-01

    Full Text Available Myeloid sarcoma is an extramedullary (EM manifestation (i.e., manifestation outside the bone marrow of acute myeloid leukemia (AML; it is assumed to be relatively uncommon and can be the only manifestation of leukemia relapse after allogenic stem cell transplantation (allo-SCT. An EM sarcoma can manifest in any part of the body, although preferentially manifesting in immunological sanctuary sites as a single or multiple tumors. The development of myeloid sarcoma after allo-SCT is associated with certain cytogenetic abnormalities, developing of graft versus host disease (GVHD, and treatment with donor lymphocytes infusion (DLI. It is believed that posttransplant myeloid sarcomas develop because the EM sites evade immune surveillance. We present two patients with EM myeloid sarcoma in the breast and epipharynx, respectively, as the only manifestation of leukemia relapse. Both patients were treated with a combination of local and systemic therapy, with successfully longtime disease-free survival. Based on these two case reports, we give an updated review of the literature and discuss the pathogenesis, diagnosis, and treatment of EM sarcoma as the only manifestation of AML relapse after allo-SCT. There are no standard guidelines for the treatment of myeloid sarcomas in allotransplant recipients. In our opinion, the treatment of these patients needs to be individualized and should include local treatment (i.e., radiotherapy combined with systemic therapy (i.e., chemotherapy, immunotherapy, DLI, or retransplantation. The treatment has to consider both the need for sufficient antileukemic efficiency versus the risk of severe complications due to cumulative toxicity.

  4. Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT.

    Science.gov (United States)

    Gartlan, Kate H; Varelias, Antiopi; Koyama, Motoko; Robb, Renee J; Markey, Kate A; Chang, Karshing; Wilkinson, Andrew N; Smith, David; Ullah, Md Ashik; Kuns, Rachel D; Raffelt, Neil C; Olver, Stuart D; Lineburg, Katie E; Teal, Bianca E; Cheong, Melody; Teng, Michele W L; Smyth, Mark J; Tey, Siok-Keen; MacDonald, Kelli P A; Hill, Geoffrey R

    2017-02-14

    T-helper 17 (Th17) cells have been widely implicated as drivers of autoimmune disease. In particular, Th17 cytokine plasticity and acquisition of an interleukin-17A + (IL-17A + )interferon γ(IFNγ) + cytokine profile is associated with increased pathogenic capacity. Donor Th17 polarization is known to exacerbate graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT); however, donor Th17 cytokine coexpression and plasticity have not been fully characterized. Using IL-17 "fate-mapping" mice, we identified IL-6-dependent Th17 cells early after allo-SCT, characterized by elevated expression of proinflammatory cytokines, IL-17A, IL-22, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor. This population did not maintain lineage fidelity, with a marked loss of IL-17A and IL-22 expression late posttransplant. Th17 cells were further segregated based on IFNγ coexpression, and IL-17A + IFNγ + Th17 displayed an enhanced proinflammatory phenotype. Th17 cytokine plasticity and IFNγ production were critically dependent upon donor-derived IL-12p40, and cyclosporine (CsA) treatment regulated this differentiation pathway. This observation was highly concordant with clinical samples from allo-SCT recipients receiving CsA-based immune suppression where although the IFNγ-negative-Th17 subset predominated, IFNγ + -Th17 cells were also present. In sum, Th17 polarization and ensuing differentiation are mediated by sequential inflammatory signals, which are modulated by immunosuppressive therapy, leading to distinct phenotypes within this lineage.

  5. Cyclosporine suppression of lymphocyte recruitment, regional blood flow, and vascular permeability at sites of allogeneic cellular interactions

    International Nuclear Information System (INIS)

    Hanto, D.W.; Harty, J.T.; Hoffman, R.; Simmons, R.L.

    1983-01-01

    Although cyclosporine (CsA) has been thought to act primarily on the afferent phase of the immune response, we can demonstrate that it also acts at the efferent phase. The effect of CsA on lymphocyte recruitment (LR), regional blood flow (RBF), and vascular permeability (VP) was studied in paired, healed, subcutaneously placed urethane sponge grafts inoculated with specifically sensitized lymphocytes (SSLs) and allogeneic target cells. Intravenous injection of 111 In-labelled unsensitized lymphocytes, 86 RbCl and 125 I-labelled albumin were used to assess LR, RBF, and VP, respectively. Suspensions of SSL and targets in CsA at 10 and 1 microgram/ml prior to graft inoculation markedly reduce the preferential increase in LR to the site of interaction between SSLs and targets bearing the sensitizing alloantigen (P less than 0.002 for both). Similarly, CsA blocks the preferential increase in RBF (P . 0.017) and VP (P less than 0.002) to the graft site. These effects persist for at least 24 hours. If SSLs and targets are washed after incubation with CsA, LR is still reduced. These results are consistent with the idea that cell-bound CsA blocks the elaboration of lymphokines which results from the interaction between SSLs and specific alloantigen in vivo. These lymphokines increase RBF and VP and are accompanied by an increase in LR. Inhibition of these vascular effects may prevent the recruitment of additional lymphocytes to the graft site. CsA may, therefore, prevent or interrupt allograft rejection by blocking amplification of the rejection mechanism at the graft site

  6. Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Inazawa, Natsuko; Hori, Tsukasa; Hatakeyama, Naoki; Yamamoto, Masaki; Yoto, Yuko; Nojima, Masanori; Suzuki, Nobuhiro; Shimizu, Norio; Tsutsumi, Hiroyuki

    2015-08-01

    Viral reactivations following hematopoietic stem cell transplantation are thought to result from the breakdown of both cell-mediated and humoral immunity. As a result, many viruses could be reactivated individually or simultaneously. Using a multiplex polymerase chain reaction (PCR), we prospectively examined many kinds of viral DNAs at a time in 105 patients who underwent allogeneic hematopoietic stem cell transplantation. In total, 591 whole blood samples were collected weekly from pre- to 42 days post-transplantation and the following 13 viruses were tested; herpes simplex virus 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, HHV-8, adenovirus, BK virus (BKV), JC virus (JCV), parvovirus B19, and hepatitis B virus (HBV). Several viral DNAs were detected in 12 patients before hematopoietic stem cell transplantation. The detection rate gradually increased after transplantation and peaked at 21 days. The most frequently detected virus was HHV-6 (n = 63; 60.0%), followed by EBV (n = 11; 10.5%), CMV (n = 11; 10.5%), and HHV-7 (n = 9; 8.6%). Adenovirus and HBV were each detected in one patient (1.0%). Detection of HHV-6 DNA was significantly more common among patients undergoing cord blood transplantation or with steroid treatment. EBV DNA tended to be more common in patients treated with anti-thymocyte globulin. Multiplex PCR was useful for detecting many viral reactivations after hematopoietic stem cell transplantation, simultaneously. Cord blood transplantation, steroid treatment, or anti-thymocyte globulin use was confirmed to be risk factors after transplantation. © 2015 Wiley Periodicals, Inc.

  7. Professional and Regulatory Search

    Science.gov (United States)

    Professional and Regulatory search are designed for people who use EPA web resources to do their job. You will be searching collections where information that is not relevant to Environmental and Regulatory professionals.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Efficient natural defense mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer

    International Nuclear Information System (INIS)

    Roesler, J.; Groettrup, E.B.; Baccarini, M.; Lohmann-Mattes, M.L.

    1989-01-01

    Radiation chimeras in the early phase after bone marrow transplantation are a good model to study the efficiency of the body's nonspecific defense system represented by macrophages (M phi), polymorphonuclear cells (PMN), and NK cells. These cell types are present in large numbers in spleen and liver at that time, whereas the specific immune system represented by T and B cells is functionally deficient. We previously reported enhanced activities in vitro of M phi (and PMN) from recipient animals in an early phase after allogeneic bone marrow transfer. We here demonstrate that these activities result in enhanced spontaneous resistance against Listeria monocytogenes in vivo: CFU of L. monocytogenes in spleen and liver 48 h after infection were about 1 or 2 to 4 log steps less than in untreated control mice of donor or host haplotype. This enhanced resistance decreased over the 4-mo period after marrow transfer. Preactivated M phi were identified as the most important effector cells. Isolated from spleen and peritoneal cavity, they performed enhanced killing of phagocytosed Listeria. Such preactivated M phi occurred in recipient animals after transfer of allogeneic but not of syngeneic bone marrow. The precise mechanism of M phi activation in the allogeneic radiation chimera in the complete absence of any detectable T cell function is not clear at present. However, these preactivated M phi display an important protective effect against L. monocytogenes: chimeras could eliminate Listeria without acquisition of positive delayed-type sensitivity when infected with 10(3) bacteria. An inoculum of 5 . 10(3) L. monocytogenes resulted either in prolonged survival compared with normal mice of the recipient haplotype or in definitive survival accompanied by a positive delayed-type sensitivity

  10. Recipient micro-environment does not dictate the Igh-V restriction specificity of T cell suppressor inducer factor (TsiF) from allogeneic bone marrow chimera in mice

    International Nuclear Information System (INIS)

    Noguchi, M.; Ogasawara, M.; Iwabuchi, K.; Osgasawara, K.; Ishihara, T.; Good, R.A.; Morikawa, K.; Onoe, K.

    1985-01-01

    The authors have ascertained previously from a study of fully allogeneic irradiation chimeras in mice that the H-2 restriction of the suppressor factor (Ly-2 T suppressor factor) is determined by the post-thymic environment protected by the donor cells, rather than by the thymic environment of the recipient. In the present study, the author analyzed differentiation influences that determine the Igh restriction specificities of the suppressor inducer T cell factor(s) (TsiF) that are produced by Ly-1+ splenic T cells in fully allogeneic bone marrow chimeras in mice. AKR mice that had been lethally irradiated and reconstituted with B10 marrow cells, [B10----AKR] chimeras, produced Ly-1 TsiF after hyper-immunization with sheep erythrocytes (SRBC) which suppressed antigen--specifically the primary antibody responses to SRBC that were generated in cells of the same Igh-Vb haplotype of donor strain and not those generated in cells of the recipient Igh-Va type. Similar results were obtained when Ly-1 TsiF from [B6----BALB/c] and [BALB/c----B6] chimeras were analyzed. Furthermore, the Ly-1 TsiF from [BALB/c----B6] chimeras suppressed the primary antibody responses of both BALB/c [H-2d, Igh-Va, Igh-Ca] and BAB-14 (H-2d, Igh-Va, Igh-Cb), but not those of CAL-20 (H-2d, Igh-Vd, Igh-Cd). These results demonstrate clearly that the Ly-1 TsiF from allogeneic bone marrow chimeras are donor Igh-V-restricted and are not influenced by the recipient micro-environment, presumably that were provided by the thymuses of the recipient mice

  11. Our Immune System

    Science.gov (United States)

    Our Immune System A story for children with primary immunodeficiency diseases Written by Sara LeBien IMMUNE DEFICIENCY FOUNDATION A note ... who are immune deficient to better understand their immune system. What is a “ B-cell, ” a “ T-cell, ” ...

  12. Friends and foes of tuberculosis: modulation of protective immunity.

    Science.gov (United States)

    Brighenti, Susanna; Joosten, Simone A

    2018-05-27

    Protective immunity in tuberculosis (TB) is subject of debate in the TB research community, as this is key to fully understand TB pathogenesis and to develop new promising tools for TB diagnosis and prognosis as well as a more efficient TB vaccine. IFN-γ producing CD4 + T cells are key in TB control, but may not be sufficient to provide protection. Additional subsets have been identified that contribute to protection such as multifunctional and cytolytic T cell subsets, including classical and non-classical T cells as well as novel innate immune cell subsets resulting from trained immunity. However, to define protective immune responses against TB, the complexity of balancing TB immunity also has to be considered. In this review, insights in effector cell immunity and how this is modulated by regulatory cells, associated comorbidities and the host microbiome is discussed. We systematically map how different suppressive immune cell subsets may affect effector cell responses at the local site of infection. We also dissect how common co-morbidities such as HIV, helminthes and diabetes may bias protective TB immunity towards pathogenic and regulatory responses. Finally, also the composition and diversity of the microbiome in the lung and gut could affect host TB immunity. Understanding these various aspects of the immunological balance in the human host is fundamental to prevent TB infection and disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion

    Science.gov (United States)

    Henry, David A; Carless, Paul A; Moxey, Annette J; O’Connell, Dianne; Stokes, Barrie J; Fergusson, Dean A; Ker, Katharine

    2014-01-01

    a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1.50). Most of the data contributing to this added risk came from a single study - the BART trial (2008). Authors’ conclusions Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects. PMID:21412876

  14. Targeting regulatory T cells in cancer.

    LENUS (Irish Health Repository)

    Byrne, William L

    2012-01-31

    Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-kappaB (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity. Problems with these strategies include a lack of specificity, resulting in depletion of antitumor effector T cells or global interruption of regulatory T cells, which may predispose to autoimmune diseases. Emerging technologies, such as RNA interference and tetramer-based targeting, may have the potential to improve selectivity and efficacy.

  15. Future nuclear regulatory challenges

    International Nuclear Information System (INIS)

    Royen, J.

    1998-01-01

    In December 1996, the NEA Committee on Nuclear Regulatory Activities concluded that changes resulting from economic deregulation and other recent developments affecting nuclear power programmes have consequences both for licensees and regulatory authorities. A number of potential problems and issues which will present a challenge to nuclear regulatory bodies over the next ten years have been identified in a report just released. (author)

  16. Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations.

    Science.gov (United States)

    Bradford, Kathryn L; Moretti, Federico A; Carbonaro-Sarracino, Denise A; Gaspar, Hubert B; Kohn, Donald B

    2017-10-01

    Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T - B - NK - ), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.

  17. Fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Mori, T; Nakamura, Y; Kato, J; Sugita, K; Murata, M; Kamei, K; Okamoto, S

    2012-02-01

    Rhodotorula species have been increasingly recognized as emerging pathogens, particularly in immunocompromised patients. We herein report on a patient with myelodysplastic syndrome who developed fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. He developed severe acute graft-versus-host disease requiring high-dose steroids, and had serially been administered fluconazole and micafungin for the prophylaxis of fungal infection. Although several cases of Rhodotorula infection after HSCT have been reported, all of them were recipients of autologous HSCT, not allogeneic HSCT. A review of all the reported cases of Rhodotorula infection after HSCT revealed that all patients had received fluconazole or echinocandins before the onset of infection. The findings suggest that Rhodotorula species could be causative yeasts, particularly in patients receiving fluconazole or echinocandins, both of which are inactive against the species. © 2011 John Wiley & Sons A/S.

  18. Lichen striatus occurring after allogenic peripheral blood stem cell transplantation in an adult with aplastic anemia.

    Science.gov (United States)

    Mun, Je-Ho; Park, Hyun-Je; Kim, Hoon-Soo; Kim, Su-Han; Ko, Hyun-Chang; Kim, Byung-Soo; Kim, Moon-Bum

    2012-02-01

    Lichens striatus (LS) is an acquired, self-limiting inflammatory dermatosis that follows the lines of Blaschko. The etiology of the eruption is unknown, but several theories have been proposed with focus on environmental factors, viral infection, cutaneous injury, hypersensitivity, and genetic predisposition. We describe a 19-year-old woman who developed a unilateral linear eruption 17 months after allogenic peripheral blood stem cell transplantation. Histopathology revealed features, which were consistent with LS. To the best of our knowledge, our patient is the first case describing the appearance of LS occurring after allogenic stem cell transplantation. We speculate that this condition represents an unusual form of localized, chronic graft-versus-host disease.

  19. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma

    DEFF Research Database (Denmark)

    Nysom, K; Holm, K; Hesse, B

    1996-01-01

    Longitudinal data were analysed on the lung function of 25 of 29 survivors of childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide and total body irradiation before allogeneic bone marrow transplantation, to test whether children are particularly vulnerable to pulmonary...... damage after transplantation. None developed chronic graft-versus-host disease. Transfer factor and lung volumes were reduced immediately after bone marrow transplantation, but increased during the following years. However, at the last follow up, 4-13 years (median 8) after transplantation, patients had...... to their age at bone marrow transplantation. In conclusion, patients had subclinical restrictive pulmonary disease at a median of eight years after total body irradiation and allogeneic bone marrow transplantation....

  20. Allogeneic bone marrow transplantation in adults after fractionated body irradiation and high dose cyclophosphamide

    International Nuclear Information System (INIS)

    Brinch, L.; Evensen, S.A.; Albrechtsen, D.; Egeland, T.; Solheim, B.G.; Rollag, H.; Naalsund, A.; Jacobsen, A.B.

    1991-01-01

    The authors present short and long-term results of allogeneic bone marrow transplantation after hyper-fractionated total body irradiation and high dose cyclophosphamide in ten patients treated for leukaemia during th period 1985-89. Three patients died from complications connected to the transplantation, while seven are living free from leukaemia 18 to 59 months after transplantation. Two patients need treatment for chronic graft versus host disease. Allogeneic bone marrow transplantation is expensive and risky. Close cooperation between clinicians and laboratory specialists is essential. The treatment increases long term survival and probably cures certain patients with leukaemia. Some of the patients will need treatment for chronic graft versus host disease and other late sequelae. 19 refs., 2 tabs

  1. Neutrophils in Homeostasis, Immunity, and Cancer.

    Science.gov (United States)

    Nicolás-Ávila, José Ángel; Adrover, José M; Hidalgo, Andrés

    2017-01-17

    Neutrophils were among the first leukocytes described and visualized by early immunologists. Prominent effector functions during infection and sterile inflammation classically placed them low in the immune tree as rapid, mindless aggressors with poor regulatory functions. This view is currently under reassessment as we uncover new aspects of their life cycle and identify transcriptional and phenotypic diversity that endows them with regulatory properties that extend beyond their lifetime in the circulation. These properties are revealing unanticipated roles for neutrophils in supporting homeostasis, as well as complex disease states such as cancer. We focus this review on these emerging functions in order to define the true roles of neutrophils in homeostasis, immunity, and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Lichen Striatus Occurring after Allogenic Peripheral Blood Stem Cell Transplantation in an Adult with Aplastic Anemia

    OpenAIRE

    Mun, Je-Ho; Park, Hyun-Je; Kim, Hoon-Soo; Kim, Su-Han; Ko, Hyun-Chang; Kim, Byung-Soo; Kim, Moon-Bum

    2012-01-01

    Lichens striatus (LS) is an acquired, self-limiting inflammatory dermatosis that follows the lines of Blaschko. The etiology of the eruption is unknown, but several theories have been proposed with focus on environmental factors, viral infection, cutaneous injury, hypersensitivity, and genetic predisposition. We describe a 19-year-old woman who developed a unilateral linear eruption 17 months after allogenic peripheral blood stem cell transplantation. Histopathology revealed features, which w...

  3. Activated allogeneic NK cells preferentially kill poor prognosis B-cell chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Diego Sanchez-Martinez

    2016-10-01

    Full Text Available Mutational status of TP53 together with expression of wild type (wt IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL patients. Adoptive cell therapy using allogeneic HLA mismatched Natural Killer (NK cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs the most effective stimulus to activate NK cells. Here we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell activating receptors (NKG2D and NCRs and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.□

  4. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    Science.gov (United States)

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV ) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  5. Informed consent: cultural and religious issues associated with the use of allogeneic and xenogeneic mesh products.

    Science.gov (United States)

    Jenkins, Eric D; Yip, Michael; Melman, Lora; Frisella, Margaret M; Matthews, Brent D

    2010-04-01

    Our aim was to investigate the views of major religions and cultural groups regarding the use of allogeneic and xenogeneic mesh for soft tissue repair. We contacted representatives from Judaism, Islam, Buddhism, Hinduism, Scientology, and Christianity (Baptists, Methodists, Seventh-Day Adventists, Catholics, Lutherans, Church of Jesus Christ of Latter-Day Saints, Evangelical, and Jehovah's Witnesses). We also contacted American Vegan and People for the Ethical Treatment of Animals (PETA). Standardized questionnaires were distributed to the religious and cultural authorities. Questions solicited views on the consumption of beef and pork products and the acceptability of human-, bovine-, or porcine-derived acellular grafts. Dietary restrictions among Jews and Muslims do not translate to tissue implantation restriction. Approximately 50% of Seventh-day Adventists and 40% of Buddhists practice vegetarianism, which may translate into a refusal of the use of xenogeneic tissue. Some Hindus categorically prohibit the use of human tissue and animal products; others allow the donation and receipt of human organs and tissues. PETA is opposed to all uses of animals, but not to human acellular grafts or organ transplantation. Some vegans prefer allogeneic to xenogeneic tissue. Allogeneic and xenogeneic acellular grafts are acceptable among Scientologists, Baptists, Lutherans, Evangelicals, and Catholics. Methodists, Jehovah's Witnesses, and The Church of Jesus Christ of Latter-Day Saints leave the decision up to the individual. Knowledge of religious and cultural preferences regarding biologic mesh assists the surgeon in obtaining a culturally sensitive informed consent for procedures involving acellular allogeneic or xenogeneic grafts. Copyright (c) 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  6. Aerobic exercise capacity at long-term follow-up after paediatric allogeneic haematopoietic SCT

    DEFF Research Database (Denmark)

    Mathiesen, S; Uhlving, H H; Buchvald, F

    2014-01-01

    Peak oxygen uptake (VO2peak), a measure of aerobic exercise capacity, predicts mortality and morbidity in healthy and diseased individuals. Our aim was to determine VO2peak years after paediatric allogeneic haematopoietic SCT (HSCT) and to identify associations with baseline patient and donor...... type or GvHD were found. Although causes for reduced VO2peak may be multiple, our findings stress the need to focus on physical activity post HSCT to prevent lifestyle diseases and improve quality of life....

  7. Clinical and Surgical Strategies for Avoiding or Reducing Allogeneic Blood Transfusions

    OpenAIRE

    dos Santos, Antonio Alceu; Baumgratz, Jose Francisco; Vila, Jose Henrique Andrade; Castro, Rodrigo Moreira; Bezerra, Rodrigo Freire

    2016-01-01

    Blood transfusions have still been used as a standard therapy to treat severe anemia. Current evidences point to both excessive allogeneic blood consumption and decreased donations, which result in reduced stocks in blood banks. Several studies have increasingly suggested a more restrictive transfusion practice for blood products. Currently, a number of autologous blood conservation protocols in surgeries have been noted. We report a case of severe anemia with 2.9 g/dL hemoglobin, which was s...

  8. Regulatory activities; Actividades regulatorias

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information.

  9. Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients.

    Science.gov (United States)

    Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu; Stednick, Zach; Callais, Cheryl; Leisenring, Wendy M; Englund, Janet A; Chien, Jason W; Boeckh, Michael

    2016-05-01

    Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction. Copyright © 2016 American Society for Blood and Marrow Transplantation. All rights reserved.

  10. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

    Science.gov (United States)

    Ramadan, Safaa M.; Di Veroli, Ambra; Camboni, Agnese; Breccia, Massimo; Iori, Anna Paola; Aversa, Franco; Cupelli, Luca; Papayannidis, Cristina; Bacigalupo, Andrea; Arcese, William; Lo-Coco, Francesco

    2012-01-01

    The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed. PMID:22689684

  11. Allogeneic BMT and patient eligibility based on psychosocial criteria: a survey of BMT professionals.

    Science.gov (United States)

    Foster, L W; McLellan, L J; Rybicki, L A; Dabney, J; Welsh, E; Bolwell, B J

    2006-01-01

    BMT professionals were compared regarding their willingness to proceed with allogeneic BMT given select psychosocial issues. A questionnaire was sent to 660 physician members of ASBMT, 92 social work members of BMT Special Interest Group, Association of Oncology Social Work, and 626 nurse members of BMT Special Interest Group, Oncology Nursing Society; 597 responded with a response rate of 43.5%. Items included background information, followed by 17 case vignettes; each represented a different psychosocial issue to which respondents indicated whether or not they would recommend proceeding with allogeneic BMT. In every vignette, at least 10% of respondents indicated they would not proceed. In six vignettes, at least 64% indicated do not proceed: suicidal ideation (86.8%), uses addictive illicit drugs (81.7%), history of noncompliance (80.5%), no lay caregiver (69.3%), alcoholic (64.8%), and mild dementia/Alzheimer's (64.4%). In 10 vignettes, at least 73% indicated proceed. On four vignettes, professional subgroups differed in their recommendation on whether or not to proceed with allogeneic BMT. Qualitative data suggest that this decision is contingent on the perceived acuity, severity, and currency of the psychosocial issue, patient ability to comply with treatment given the issue, and its manageability as a risk factor for treatment related vulnerability and outcomes.

  12. Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

    Directory of Open Access Journals (Sweden)

    Ichim Thomas E

    2010-11-01

    Full Text Available Abstract Cellular therapy for spinal cord injury (SCI is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI.

  13. Allogeneic radiation chimeras respond to TNP-modified donor and host targets

    International Nuclear Information System (INIS)

    Lattime, E.C.; Gershon, H.E.; Stutman, O.

    1980-01-01

    Tolerance to major histocompatibility antigens as well as the ability to mount a cytotoxic response to hapten-modified cells of bone marrow donor and host origin was studied in allogeneic radiation chimeras. Lethally irradiated (C57BL/6 x DBA/2)F1 hosts reconstituted with anti-Thy 1.2 + C-treated bone marrow from (C57BL/6 x CBA)F1 mice showed tolerance to the MHC antigens of the three parental strains as measured by MLC and CML assay. The chimeras responded normally to unrelated allogeneic cells. Chimeric animals generated a cytotoxic response to hapten-modified cells of both donor (CBA) and host (DBA/2) haplotypes, as well as to C57BL/6, demonstrating that tolerance to the hapten-presenting host haplotype is sufficient to allow a cytotoxic antihapten response, and that processing through a semiallogeneic host environment does not affect the ability to generate a response to hapten in conjunction with self-determinants. Chimeras failed to mount a cytotoxic response to hapten presented on nontolerated allogeneic spleen cells

  14. Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

    International Nuclear Information System (INIS)

    McGlave, P.B.; Miller, W.J.; Hurd, D.D.; Arthur, D.C.; Kim, T.

    1981-01-01

    We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern or demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease

  15. Minocycline promotes the generation of dendritic cells with regulatory properties.

    Science.gov (United States)

    Kim, Narae; Park, Chan-Su; Im, Sun-A; Kim, Ji-Wan; Lee, Jae-Hee; Park, Young-Jun; Song, Sukgil; Lee, Chong-Kil

    2016-08-16

    Minocycline, which has long been used as a broad-spectrum antibiotic, also exhibits non-antibiotic properties such as inhibition of inflammation and angiogenesis. In this study, we show that minocycline significantly enhances the generation of dendritic cells (DCs) from mouse bone marrow (BM) cells when used together with GM-CSF and IL-4. DCs generated from BM cells in the presence of minocycline (Mino-DCs) demonstrate the characteristics of regulatory DCs. Compared with control DCs, Mino-DCs are resistant to subsequent maturation stimuli, impaired in MHC class II-restricted exogenous Ag presentation, and show decreased cytokine secretion. Mino-DCs also show decreased ability to prime allogeneic-specific T cells, while increasing the expansion of CD4+CD25+Foxp3+ T regulatory cells both in vitro and in vivo. In addition, pretreatment with MOG35-55 peptide-pulsed Mino-DCs ameliorates clinical signs of experimental autoimmune encephalitis induced by MOG peptide injection. Our study identifies minocycline as a new pharmacological agent that could be potentially used to increase the production of regulatory DCs for cell therapy to treat autoimmune disorders, allergy, and transplant rejection.

  16. Nutrition, immune function and health of dairy cattle

    DEFF Research Database (Denmark)

    Ingvartsen, Klaus Lønne; Moyes, Kasey

    2013-01-01

    not seem to be improved. Earlier reviews have covered critical periods such as the transition period in the cow and its influence on health and immune function, the interplay between the endocrine system and the immune system and nutrition and immune function. Knowledge on these topics is crucial for our......) on immune function, and to give perspectives for prevention of diseases in the dairy cow through nutrition. To a large extent, the health problems during the periparturient period relate to cows having difficulty in adapting to the nutrient needs for lactation. This may result in PI, a situation where...... the regulatory mechanisms are insufficient for the animals to function optimally leading to a high risk of a complex of digestive, metabolic and infectious problems. The risk of infectious diseases will be increased if the immune competence is reduced. Nutrition plays a pivotal role in the immune response...

  17. Are innate immune signaling pathways in plants and animals conserved?

    Science.gov (United States)

    Ausubel, Frederick M

    2005-10-01

    Although adaptive immunity is unique to vertebrates, the innate immune response seems to have ancient origins. Common features of innate immunity in vertebrates, invertebrate animals and plants include defined receptors for microbe-associated molecules, conserved mitogen-associated protein kinase signaling cascades and the production of antimicrobial peptides. It is commonly reported that these similarities in innate immunity represent a process of divergent evolution from an ancient unicellular eukaryote that pre-dated the divergence of the plant and animal kingdoms. However, at present, data suggest that the seemingly analogous regulatory modules used in plant and animal innate immunity are a consequence of convergent evolution and reflect inherent constraints on how an innate immune system can be constructed.

  18. Elsevier Trophoblast Research Award Lecture: Unique properties of decidual T cells and their role in immune regulation during human pregnancy.

    Science.gov (United States)

    Tilburgs, T; Claas, F H J; Scherjon, S A

    2010-03-01

    Maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Most studies focus on decidual NK cells and their interaction with fetal trophoblasts, whereas limited data are available on the mechanisms of fetus specific immune recognition and immune regulation by decidual T cells at the fetal-maternal interface. The aim of this review is to describe the phenotypic characteristics of decidual T cell subsets present at the fetal-maternal interface, their interaction with HLA-C expressed by fetal trophoblasts and their role in immune recognition and regulation at the fetal-maternal interface during human pregnancy. Copyright 2010 Elsevier Ltd. All rights reserved.

  19. Regulatory T cell frequencies and phenotypes following anti-viral vaccination

    NARCIS (Netherlands)

    de Wolf, A Charlotte M T; van Aalst, Susan; Ludwig, Irene S; Bodinham, Caroline L; Lewis, David J; van der Zee, Ruurd; van Eden, Willem; Broere, Femke

    2017-01-01

    Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays

  20. Cancer as an immune-mediated disease

    Directory of Open Access Journals (Sweden)

    Shurin MR

    2012-06-01

    , regulatory immune cells

  1. T-regulatory cells in chronic rejection versus stable grafts.

    Science.gov (United States)

    Al-Wedaie, Fatima; Farid, Eman; Tabbara, Khaled; El-Agroudy, Amgad E; Al-Ghareeb, Sumaya M

    2015-04-01

    Studying regulatory T cells in kidney allograft acceptance versus chronic rejection may help in the understanding of more mechanisms of immune tolerance and, in the future, may enable clinicians to induce immune tolerance and decrease the use of immunosuppressive drugs. The aim of the current study was to evaluate regulatory T cells in kidney transplant patients with stable graft versus transplant with biopsy-proven chronic rejection. The 3 groups that were studied included: kidney transplanted patients with no rejection episodes (n = 43); transplanted patients with biopsy-proven renal rejection (n = 27); and healthy age-matched nontransplanted individuals as controls (n = 42).The percentage of regulatory T cells (CD4+CD25+Foxp3+) in blood was determined by flow cytometry. The regulatory T cell percentage was significantly lower in chronic rejection patients than control or stable graft groups. No significant difference was observed in regulatory T cell percentage between the stable graft and control groups. In the stable graft group, patients on rapamycin had a significantly higher regulatory T cell percentage than patients on cyclosporine. No effect of donor type, infection, or duration after transplant was observed on regulatory T cell percentage. The results of the current study are consistent with previous studies addressing the function of regulatory T cells in inducing immunotolerance after kidney transplant. Considering the established role of regulatory T cells in graft maintenance and our observation of high regulatory T cell percentage in patients receiving rapamycin than cyclosporine, we recommend including rapamycin when possible in immunosuppressive protocols. The findings from the current study on the chronic rejection group support ongoing research of having treatment with regulatory T cells, which may constitute a novel, efficient antirejection therapy in the future.

  2. Phenotype, Immunological Reactivity and Cytokine Production Profile of Peyer`s Patch Cells from Mice Immunized Orally with Allogeneic Cells

    Czech Academy of Sciences Publication Activity Database

    Frič, Jan; Krulová, Magdalena; Zajícová, Alena; Holáň, Vladimír

    2000-01-01

    Roč. 46, č. 3 (2000), s. 119-125 ISSN 0015-5500 R&D Projects: GA ČR GA310/99/0360; GA ČR GA310/97/1261; GA ČR GA310/99/D044; GA MZd IZ3964; GA MŠk VS97099; GA MŠk ME 300 Grant - others:NATO(BE) CRG.LG972853 Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.351, year: 2000

  3. Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response.

    Science.gov (United States)

    Hus, I; Schmitt, M; Tabarkiewicz, J; Radej, S; Wojas, K; Bojarska-Junak, A; Schmitt, A; Giannopoulos, K; Dmoszyńska, A; Roliński, J

    2008-05-01

    Recently, we described that vaccination with allogeneic dendritic cells (DCs) pulsed with tumor cell lysate generated specific CD8+ T cell response in patients with B-cell chronic lymphocytic leukemia (B-CLL). In the present study, the potential of autologous DCs pulsed ex vivo with tumor cell lysates to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Twelve patients at clinical stage 0-2 as per Rai were vaccinated intradermally up to eight times with a mean number of 7.4 x 10(6) DCs pulsed with B-CLL cell lysate. We observed a decrease of peripheral blood leukocytes and CD19+/CD5+ leukemic cells in five patients, three patients showed a stable disease and four patients progressed despite DC vaccination. A significant increase of specific cytotoxic CD8+ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination. In patients with a clinical response, an increase of interleukin 12 (IL-12) serum levels and a decrease of the frequency of CD4+CD25(+)FOXP3+ T regulatory cells were observed. Taken together, the study demonstrated that vaccination with autologous DC in CLL patients is feasible and safe. Immunological and to some extend hematological responses could be noted, justifying further investigation on this immunotherapeutical approach.

  4. Treatment with mPEG-SPA improves the survival of corneal grafts in rats by immune camouflage.

    Science.gov (United States)

    Wang, Shuangyong; Li, Liangliang; Liu, Ying; Li, Chaoyang; Zhang, Min; Wang, Bowen; Huang, Zheqian; Gao, Xinbo; Wang, Zhichong

    2015-03-01

    We investigated the immune camouflage effects of methoxy polyethylene glycol succinimidyl propionate (mPEG-SPA) on corneal antigens and explored a novel approach for reducing corneal antigenicity, thereby decreasing corneal graft rejection. Importantly, this approach did not alter normal local immunity. Corneal grafts were treated with mPEG-SPA 5KD or 20KD (3% W/V), which could shield major histocompatibility antigen class I molecules (RT1-A) of corneal grafts. Skin grafts of Wistar rats were transplanted to SD rats. Then the splenic lymphocytes were isolated from SD rats. Subsequently, the lymphocytes were co-cultured with autologous corneal grafts or untreated corneal grafts and PEGylated grafts treated with mPEG-SPA 5KD or 20KD obtained from the counterpart skin donors, which were used as autologous control, allogeneic control, mPEG-SPA 5KD group and mPEG-SPA 20KD group, respectively. Lymphocyte proliferation was lower in mPEG-SPA 5KD group and mPEG-SPA 20KD group than in the allogeneic control. SD rats with corneal neovascularisation were used as recipients for high-risk corneal transplantation and were randomly divided into four groups: autologous control, allogeneic control, mPEG-SPA 5KD group and mPEG-SPA 20KD group. The recipients received corneal grafts from Wistar rats. Corneal graft survival was prolonged and graft rejection was reduced in the mPEG-SPA 5KD group and the mPEG-SPA 20KD group compared to the allogeneic control. Thus, we think that mPEG-SPA could immunologically camouflage corneal antigens to prolong corneal grafts survival in high-risk transplantation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats.

    Directory of Open Access Journals (Sweden)

    Shuo Huang

    Full Text Available Mesenchymal stem cells (MSCs have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1 Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2 Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91. Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn't show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study

  6. Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery.

    Science.gov (United States)

    Warner, Matthew A; Welsby, Ian J; Norris, Phillip J; Silliman, Christopher C; Armour, Sarah; Wittwer, Erica D; Santrach, Paula J; Meade, Laurie A; Liedl, Lavonne M; Nieuwenkamp, Chelsea M; Douthit, Brian; van Buskirk, Camille M; Schulte, Phillip J; Carter, Rickey E; Kor, Daryl J

    2017-08-18

    The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications. This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon's two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures. Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC washing of allogeneic RBCs and its potential impact on ameliorating

  7. Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery

    Science.gov (United States)

    Warner, Matthew A; Welsby, Ian J; Norris, Phillip J; Silliman, Christopher C; Armour, Sarah; Wittwer, Erica D; Santrach, Paula J; Meade, Laurie A; Liedl, Lavonne M; Nieuwenkamp, Chelsea M; Douthit, Brian; van Buskirk, Camille M; Schulte, Phillip J; Kor, Daryl J

    2017-01-01

    Introduction The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications. Methods and analysis This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon’s two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures. Ethics and dissemination Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC

  8. Skin innate immune system

    Directory of Open Access Journals (Sweden)

    Berna Aksoy

    2013-06-01

    Full Text Available All multicellular organisms protect themselves from external universe and microorganisms by innate immune sytem that is constitutively present. Skin innate immune system has several different components composed of epithelial barriers, humoral factors and cellular part. In this review information about skin innate immune system and its components are presented to the reader. Innate immunity, which wasn’t adequately interested in previously, is proven to provide a powerfull early protection system, control many infections before the acquired immunity starts and directs acquired immunity to develop optimally

  9. Oral candidosis in relation to oral immunity.

    Science.gov (United States)

    Feller, L; Khammissa, R A G; Chandran, R; Altini, M; Lemmer, J

    2014-09-01

    Symptomatic oral infection with Candida albicans is characterized by invasion of the oral epithelium by virulent hyphae that cause tissue damage releasing the inflammatory mediators that initiate and sustain local inflammation. Candida albicans triggers pattern-recognition receptors of keratinocytes, macrophages, monocytes and dendritic cells, stimulating the production of IL-1β, IL-6 and IL-23. These cytokines induce the differentiation of Th17 cells and the generation of IL-17- and/or IL-22-mediated antifungal protective immuno-inflammatory responses in infected mucosa. Some immune cells including NKT cells, γδ T cells and lymphoid cells that are innate to the oral mucosa have the capacity to produce large quantities of IL-17 in response to C. albicans, sufficient to mediate effective protective immunity against C. albicans. On the other hand, molecular structures of commensal C. albicans blastoconidia, although detected by pattern-recognition receptors, are avirulent, do not invade the oral epithelium, do not elicit inflammatory responses in a healthy host, but induce regulatory immune responses that maintain tissue tolerance to the commensal fungi. The type, specificity and sensitivity of the protective immune response towards C. albicans is determined by the outcome of the integrated interactions between the intracellular signalling pathways of specific combinations of activated pattern-recognition receptors (TLR2, TLR4, Dectin-1 and Dectin-2). IL-17-mediated protective immune response is essential for oral mucosal immunity to C. albicans infection. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Approaches Mediating Oxytocin Regulation of the Immune System.

    Science.gov (United States)

    Li, Tong; Wang, Ping; Wang, Stephani C; Wang, Yu-Feng

    2016-01-01

    The hypothalamic neuroendocrine system is mainly composed of the neural structures regulating hormone secretion from the pituitary gland and has been considered as the higher regulatory center of the immune system. Recently, the hypothalamo-neurohypophysial system (HNS) emerged as an important component of neuroendocrine-immune network, wherein the oxytocin (OT)-secreting system (OSS) plays an essential role. The OSS, consisting of OT neurons in the supraoptic nucleus, paraventricular nucleus, their several accessory nuclei and associated structures, can integrate neural, endocrine, metabolic, and immune information and plays a pivotal role in the development and functions of the immune system. The OSS can promote the development of thymus and bone marrow, perform immune surveillance, strengthen immune defense, and maintain immune homeostasis. Correspondingly, OT can inhibit inflammation, exert antibiotic-like effect, promote wound healing and regeneration, and suppress stress-associated immune disorders. In this process, the OSS can release OT to act on immune system directly by activating OT receptors or through modulating activities of other hypothalamic-pituitary-immune axes and autonomic nervous system indirectly. However, our understandings of the role of the OSS in neuroendocrine regulation of immune system are largely incomplete, particularly its relationship with other hypothalamic-pituitary-immune axes and the vasopressin-secreting system that coexists with the OSS in the HNS. In addition, it remains unclear about the relationship between the OSS and peripherally produced OT in immune regulation, particularly intrathymic OT that is known to elicit central immunological self-tolerance of T-cells to hypophysial hormones. In this work, we provide a brief review of current knowledge of the features of OSS regulation of the immune system and of potential approaches that mediate OSS coordination of the activities of entire neuroendocrine-immune network.

  11. Herpesvirus microRNAs for use in gene therapy immune-evasion strategies.

    Science.gov (United States)

    Bots, S T F; Hoeben, R C

    2017-07-01

    Transplantation of allogeneic cells as well as of genetically corrected autologous cells are potent approaches to restore cellular functions in patients suffering from genetic diseases. The recipient's immune responses against non-self-antigens may compromise the survival of the grafted cells. Recipients of the graft may therefore require lifelong treatment with immunosuppressive drugs. An alternative approach to reduce graft rejection could involve the use of immune-evasion molecules. Expression of such molecules in cells of the graft may subvert recognition by the host's immune system. Viruses in particular are masters of exploitation and modulation of their hosts immune response. The Herpesviridae family provides a proof of concept for this as these viruses are capable to establish latency and a lifelong persistence in the infected hosts. While several viral proteins involved in immune evasion have been characterized, the Herpesviridae also encode a multitude of viral microRNA (miRNAs). Several of these miRNAs have been demonstrated to reduce the sensitivity of the infected cells to the destructive action of the host's immune cells. In this review, the miRNAs of some common herpesviruses that are associated with immune modulation will be discussed with a focus on their potential use in strategies aiming at generating non-immunogenic cells for transplantation.

  12. Regulation of intestinal homeostasis by innate and adaptive immunity.

    Science.gov (United States)

    Kayama, Hisako; Takeda, Kiyoshi

    2012-11-01

    The intestine is a unique tissue where an elaborate balance is maintained between tolerance and immune responses against a variety of environmental factors such as food and the microflora. In a healthy individual, the microflora stimulates innate and adaptive immune systems to maintain gut homeostasis. However, the interaction of environmental factors with particular genetic backgrounds can lead to dramatic changes in the composition of the microflora (i.e. dysbiosis). Many of the specific commensal-bacterial products and the signaling pathways they trigger have been characterized. The role of T(h)1, T(h)2 and T(h)17 cells in inflammatory bowel disease has been widely investigated, as has the contribution of epithelial cells and subsets of dendritic cells and macrophages. To date, multiple regulatory cells in adaptive immunity, such as regulatory T cells and regulatory B cells, have been shown to maintain gut homeostasis by preventing inappropriate innate and adaptive immune responses to commensal bacteria. Additionally, regulatory myeloid cells have recently been identified that prevent intestinal inflammation by inhibiting T-cell proliferation. An increasing body of evidence has shown that multiple regulatory mechanisms contribute to the maintenance of gut homeostasis.

  13. Functional comparison of innate immune signaling pathways in primates.

    Directory of Open Access Journals (Sweden)

    Luis B Barreiro

    2010-12-01

    Full Text Available Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection. Consistent with that notion, genes involved in immunity-related processes are strongly enriched among recent targets of positive selection in primates, suggesting that immune responses evolve rapidly, yet providing only indirect evidence for possible inter-species functional differences. To directly compare immune responses among primates, we stimulated primary monocytes from humans, chimpanzees, and rhesus macaques with lipopolysaccharide (LPS and studied the ensuing time-course regulatory responses. We find that, while the universal Toll-like receptor response is mostly conserved across primates, the regulatory response associated with viral infections is often lineage-specific, probably reflecting rapid host-virus mutual adaptation cycles. Additionally, human-specific immune responses are enriched for genes involved in apoptosis, as well as for genes associated with cancer and with susceptibility to infectious diseases or immune-related disorders. Finally, we find that chimpanzee-specific immune signaling pathways are enriched for HIV-interacting genes. Put together, our observations lend strong support to the notion that lineage-specific immune responses may help explain known inter-species differences in susceptibility to infectious diseases.

  14. Immune selection of tumor cells in TCR β-chain transgenic mice.

    Science.gov (United States)

    Silaeva, Yulia Yu; Grinenko, Tatyana S; Vagida, Murad S; Kalinina, Anastasia A; Khromykh, Ludmila M; Kazansky, Dmitry B

    2014-10-01

    The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (K(d)I(d)D(b)) mice to allogeneic EL4 (H-2(b)) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2K(b) molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a