Página 1 dos resultados de 1193 itens digitais encontrados em 0.007 segundos

‣ Peptídeos urinários no transplante renal humano: busca de um perfil diferencial na tolerância operacional; Urine peptides in human kidney transplantation: research for a differential profile on operational tolerance

Takenaka, Maisa Carla Silveira
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 16/07/2010 Português
Relevância na Pesquisa
47.831885%
Um grupo especial de indivíduos transplantados renais mantém a função do enxerto estável após a total retirada da terapia imunossupressora, alcançando um estado imunológico chamado de Tolerância operacional. Ainda não há marcadores moleculares e celulares que discriminem a tolerância no transplante humano, e os seus mecanismos estão sendo investigados. O perfil de peptídeos presentes na urina pode trazer informações importantes sobre o estado fisiopatológico renal. Nós investigamos se a tolerância operacional apresenta um perfil diferencial de peptídeos urinários, potencialmente, relevante para diagnóstico deste estado imunológico, assim como para a compreensão de seus mecanismos. Realizamos análises qualitativas do extrato de peptídeos da urina de indivíduos dos diferentes grupos do estudo: saudáveis (SA, n=6), tolerantes operacionais (TO, n=5), rejeição crônica (RC, n=8) e estável sob terapia imunossupressora convencional (EST, n=5), utilizando a abordagem proteômica de Shotgun. Identificamos um total de 15283 diferentes peptídeos em todos os grupos, correspondentes a 646 proteínas distintas, distribuídas nos diferentes grupos: TO = 189, RC = 296, EST = 205 e no grupo SA 219 proteínas. Observamos proteínas exclusivas dos diferentes grupos: TO teve 87 proteínas exclusivas...

‣ In vivo induction of antigen-specific transplantation tolerance to Qa1a by exposure to alloantigen in the absence of T-cell help.

Rees, M A; Rosenberg, A S; Munitz, T I; Singer, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1990 Português
Relevância na Pesquisa
47.81501%
A goal of transplantation immunology is to be able to induce antigen-specific tolerance in transplant recipients. In the present study we describe an in vivo model of antigen-specific transplantation tolerance to skin allografts using mice congenic at Qa1, a ubiquitously expressed class I-like molecule encoded to the right of H-2D. B6 mice are deficient in Qa1a-specific T-helper cells and only reject Qa1a disparate tail skin grafts when a second graft expressing additional helper determinants is also present. We report that animals initially engrafted with Qa1a disparate skin, in the absence of any source of additional help, are rendered tolerant to Qa1a disparate skin allografts despite the subsequent presence of inducer skin grafts expressing additional helper allodeterminants. The nonresponsive state is Qa1a-specific, because HY-bearing inducer grafts are rejected normally. In vitro, Qa1a-tolerant animals are specifically unable to generate anti-Qa1a T-killer cells, which provides the cellular basis for their failure in vivo to reject Qa1a skin allografts. Thus, initial exposure to Qa1a allodeterminants, in the absence of T-cell help, leads to a state of Qa1a-specific transplantation tolerance. This study suggests that antigen-specific transplantation tolerance may be induced by exposing naive T-killer cells to tissue alloantigens under conditions in which T-cell help is not generated.

‣ Virus-Induced Abrogation of Transplantation Tolerance Induced by Donor-Specific Transfusion and Anti-CD154 Antibody

Welsh, Raymond M.; Markees, Thomas G.; Woda, Bruce A.; Daniels, Keith A.; Brehm, Michael A.; Mordes, John P.; Greiner, Dale L.; Rossini, Aldo A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2000 Português
Relevância na Pesquisa
47.8621%
Treatment with a 2-week course of anti-CD154 antibody and a single transfusion of donor leukocytes (a donor-specific transfusion or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials of this methodology in humans are contemplated, concern has been expressed that viral infection of graft recipients may disrupt tolerance to the allograft. We report that acute infection with lymphocytic choriomeningitis virus (LCMV) induced allograft rejection in mice treated with DST and anti-CD154 antibody if inoculated shortly after transplantation. Isografts resisted LCMV-induced rejection, and the interferon-inducing agent polyinosinic:polycytidylic acid did not induce allograft rejection, suggesting that the effect of LCMV is not simply a consequence of nonspecific inflammation. Administration of anti-CD8 antibody to engrafted mice delayed LCMV-induced allograft rejection. Pichinde virus also induced acute allograft rejection, but murine cytomegalovirus and vaccinia virus (VV) did not. Injection of LCMV ∼50 days after tolerance induction and transplantation had minimal effect on subsequent allograft survival. Treatment with DST and anti-CD154 antibody did not interfere with clearance of LCMV, but a normally nonlethal high dose of VV during tolerance induction and transplantation killed graft recipients. We conclude that DST and anti-CD154 antibody induce a tolerant state that can be broken shortly after transplantation by certain viral infections. Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients.

‣ Axotrophin and leukaemia inhibitory factor (LIF) in transplantation tolerance

Metcalfe, Su M
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.965244%
Immune self-tolerance is controlled by a subset of T lymphocytes that are regulatory (Treg) and epigenetically programmed to suppress auto-reactive immune effector cells in vivo. By extrapolation, donor-specific transplantation tolerance might be controlled by donor-specific Treg that have acquired the appropriate epigenetic program for tolerance. Although such tolerance has yet to be achieved in man, proof of concept comes from mouse models where regulatory transplantation tolerance can be induced within the complex micro-environment of the spleen or draining lymph node. By studying whole spleen cell populations in a murine model of transplantation tolerance we have incorporated a complexity of environmental factors when looking for specific features that characterize tolerance versus aggression. This approach has revealed unexpected patterns of gene activity in tolerance and most notably that a novel stem cell gene, axotrophin, regulates T lymphocyte responsiveness both in terms of proliferation and in release of leukaemia inhibitory factor (LIF). Since LIF is a regulator of stem cells in addition to being a key neuropoietic cytokine, these preliminary results linking both axotrophin and LIF to transplantation tolerance lead us to propose that regulatory pathways encoded during the epigenetic development of Treg cells are related to pathways that regulate fate determination of stem cells.

‣ PDL1 Is Required for Peripheral Transplantation Tolerance and Protection from Chronic Allograft Rejection1

Tanaka, Katsunori; Albin, Monica J.; Yuan, Xueli; Yamaura, Kazuhiro; Habicht, Antje; Murayama, Takaya; Grimm, Martin; Waaga, Ana Maria; Ueno, Takuya; Padera, Robert F.; Yagita, Hideo; Azuma, Miyuki; Shin, Tahiro; Blazar, Bruce R.; Rothstein, David M.; Say
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/10/2007 Português
Relevância na Pesquisa
47.796543%
The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-γ-producing alloreactive T cells and expansion of effector CD8+ T cells in the periphery, and a decline in the percentage of Foxp3+ graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.

‣ Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells

Tian, Chaorui; Yuan, Xueli; Bagley, Jessamyn; Blazar, Bruce R.; Sayegh, Mohamed H.; Iacomini, John
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.796543%
The observation that bone marrow derived hematopoietic cells are potent inducers of tolerance has generated interest in trying to establish transplantation tolerance by inducing a state of hematopoietic chimerism through allogeneic bone marrow transplantation. However, this approach is associated with serious complications that limit its utility for tolerance induction. Here we describe the development of a novel approach that allows for tolerance induction without the need for an allogeneic bone marrow transplant by combining non-myeloablative host conditioning with delivery of donor alloantigen by adoptively transferred T cells. CBA/Ca mice were administered 2.5Gy whole body irradiation (WBI). The following day the mice received Kb disparate T cells from MHC class I transgenic CBK donor mice, as well as rapamycin on days 0–13 and anti-CD40L monoclonal antibody on days 0–5, 8,11 and 14 relative to T cell transfer. Mice treated using this approach were rendered specifically tolerant to CBK skin allografts through a mechanism involving central and peripheral deletion of alloreactive T cells. These data suggest robust tolerance can be established without the need for bone marrow transplantation using clinically relevant non-myeloablative conditioning combined with antigen delivery by T cells.

‣ Viral Infection: A Potent Barrier to Transplantation Tolerance

Miller, David M.; Thornley, Thomas B.; Greiner, Dale L.; Rossini, Aldo A.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.86175%
Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

‣ Antagonistic effect of toll-like receptor signaling and bacterial infections on transplantation tolerance*

Alegre, Maria-Luisa; Chen, Luqiu; Wang, Tongmin; Ahmed, Emily; Wang, Chyung-Ru; Chong, Anita
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/05/2009 Português
Relevância na Pesquisa
47.897705%
The induction of donor-specific tolerance remains a major goal in the field of transplantation immunology. Therapies that target costimulatory molecules can induce tolerance to heart and pancreatic islet allografts in mouse models, but fail to do so following transplantation of skin or intestinal allografts. We have proposed that organs colonized by commensal bacteria such as skin, lung and intestine may be resistant to such therapies as a result of bacterial translocation at the time of transplantation, which may promote antigen-presenting cell (APC) maturation and the production of pro-inflammatory cytokines, consequently enhancing responses of alloreactive T cells. Our results indicate that the inability to sense signaling by most toll-like receptors (TLRs), as well as by interleukin (IL)-1R and IL-18R, as a result of genetic ablation of myeloid differentiation factor 88 (MyD88) promotes the acceptance of skin allografts. Conversely, TLR signals and infections by a model bacterium, Listeria monocytogenes (LM), at the time of transplantation can prevent the induction of transplantation tolerance. The effects of the TLR9 agonist CpG are MyD88-dependent, while the pro-rejection capacity of LM depends on the intracellular sensing of LM and the production of type I interferon (IFN). Therefore...

‣ A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo

Fehr, Thomas; Lucas, Carrie L.; Kurtz, Josef; Onoe, Takashi; Zhao, Guiling; Hogan, Timothy; Vallot, Casey; Rao, Anjana; Sykes, Megan
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 11/02/2010 Português
Relevância na Pesquisa
47.881777%
Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1−/− mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus...

‣ Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

Pilat, N; Baranyi, U; Klaus, C; Jaeckel, E; Mpofu, N; Wrba, F; Golshayan, D; Muehlbacher, F; Wekerle, T
Fonte: Blackwell Publishing Inc Publicador: Blackwell Publishing Inc
Tipo: Artigo de Revista Científica
Publicado em /04/2010 Português
Relevância na Pesquisa
47.85954%
Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-β induced Tregs) were effective in this setting. Thus...

‣ An Unexpected Counter-Regulatory Role of IL-10 in B-Lymphocyte-Mediated Transplantation Tolerance

Zhao, G.; Moore, D. J.; Lee, K. M.; Kim, J. I.; Duff, P. E.; O’Connor, M. R.; Hirohashi, T.; Lei, J.; Yang, M.; Markmann, J. F.; Deng, S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.924746%
Monoclonal antibody against the CD45RB protein induces stable transplantation tolerance to multiple types of allograft. We have previously established that this tolerance protocol relies on the regulatory function of B lymphocytes for its effect. B lymphocytes have also been reported to participate in immune regulation in several other settings. In most of these systems, the regulatory function of B lymphocytes depends on the production of IL-10. Therefore, we investigated the role of IL-10 in the anti-CD45RB model of B-cell-mediated transplantation tolerance. Surprisingly, using antibody-mediated neutralization of IL-10, IL-10-deficient recipients and adoptive transfer of IL-10-deficient B lymphocytes, we found that IL-10 actually counter-regulates tolerance induced by anti-CD45RB. Furthermore, neutralization of IL-10 reduced the development of chronic allograft vasculopathy compared to anti-CD45RB alone and reduced the production of graft reactive alloantibodies. These data suggest that the participation of regulatory B lymphocytes in transplantation tolerance may be distinct from how they operate in other systems. Identifying the specific B lymphocytes that mediate transplantation tolerance and defining their mechanism of action may yield new insights into the complex cellular network through which antigen-specific tolerance is established and maintained.

‣ Bacterial Infections, Alloimmunity, and Transplantation Tolerance

Ahmed, Emily B.; Daniels, Melvin; Alegre, Maria-Luisa; Chong, Anita S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/01/2011 Português
Relevância na Pesquisa
47.97184%
Transplantation of solid organs across histocompatibility barriers in the absence of immunosuppression is invariably followed by acute allograft rejection. Although several immunosuppressive regimens have been developed to prevent allograft rejection, these global immunosuppressive agents effectively inhibit all T cells leaving the host vulnerable to infections. Thus a major goal in transplantation immunology is to induce donor-specific tolerance that results in the extended suppression of allograft-specific immune responses, while leaving the remainder of the immune system competent to fight infections and malignancies. Initial successes in identifying approaches that successfully induce transplantation tolerance in experimental models have led to a newer research focus of identifying potential barriers to the induction of such tolerance as well as events that may reverse established allograft tolerance. Both clinical and experimental studies have identified bacterial infections as a possible trigger of allograft rejection. Recently, experimental models of transplantation tolerance have identified that bacterial signals can promote acute allograft rejection either by preventing the induction of transplantation tolerance or by reversing tolerance after it has been stably established. This review summarizes experimental and clinical literature supporting the hypothesis that bacterial infections and innate immunity can qualitatively and quantitatively alter adaptive alloreactivity through effects on innate immune responses.

‣ Transplantation Tolerance and its Outcome during Infections and Inflammation

Chong, Anita S.; Alegre, Maria-Luisa
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2014 Português
Relevância na Pesquisa
47.91531%
Much progress has been made towards understanding the mechanistic basis of transplantation tolerance in experimental models, which includes clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells that mediate infectious tolerance and linked-suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, but the basis for these challenges are beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long-periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable lifelong tolerance in transplant recipients.

‣ Transplantation tolerance: from theory to clinic

Fuchs, Ephraim J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2014 Português
Relevância na Pesquisa
47.860854%
Tolerance induction and alloreactivity can be applied to the clinic for the transplantation of solid organs and in the treatment of human cancers respectively. Hematopoietic chimerism, the stable coexistence of host and donor blood cells, guarantees that a solid organ from the same donor will be tolerated without a requirement for maintenance immunosuppression, and it also serves as a platform for the adoptive immunotherapy of hematologic malignancies using donor lymphocyte infusions. This review focuses on clinically relevant methods for inducing hematopoietic chimerism and transplantation tolerance, with a special emphasis on reduced intensity transplantation conditioning and high dose, post-transplantation cyclophosphamide to prevent graft rejection and graft-versus-host disease (GVHD). Reduced intensity transplantation regimens permit a transient cooperation between donor and host immune systems to eradicate malignancy without producing GVHD. Their favorable toxicity profile also enables the application of allogeneic stem cell transplantation to treat non-malignant disorders of hematopoiesis and to induce tolerance for solid organ transplantation.

‣ Transplantation tolerance

Salisbury, Emma M.; Game, David S.; Lechler, Robert I.
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.908843%
Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of “transplant tolerance” in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance.

‣ T Helper Cells Fate Mapping by Co-stimulatory Molecules and its Functions in Allograft Rejection and Tolerance

Abdoli, R.; Najafian, N.
Fonte: Avicenna Organ Transplantation Institute Publicador: Avicenna Organ Transplantation Institute
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.654756%
T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development. In the field of transplantation, directing the T cell differentiation process can lead to therapeutic possibilities that promote allograft tolerance, and hinder unfavorable alloimmune responses. Therefore, understanding the details of T cell differentiation process, including the influence of co-stimulatory signals, is of paramount importance. It is important to note there is functional overlap between co-stimulatory molecules. It has been observed that some co-stimulatory signals have different effects on different T cell subsets. Hence, blockade of a co-stimulatory signal pathway, as part of a therapeutic regimen in transplantation, may have far reaching effects beyond the initial therapeutic intent and inhibit co-stimulatory signals necessary for desirable regulatory responses. In this review, co-stimulatory molecules involved in the differentiation of naïve T cells into T helper 1 (Th1)...

‣ Differential signaling through the T cell receptor: from biochemistry to transplantation tolerance

Madrenas, J.; Lazarovits, A.I.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
Português
Relevância na Pesquisa
57.49329%
Recent advances in our understanding of the structural nature of T cell activation and signal transduction from the T cell receptor for antigen make possible the development of new tolerogenic strategies. Here. we summarize the evidence supporting a critical role for the CO-receptor molecule (CD4 or CD8) and CD45 in determining the pattern of T cell receptormediated signaling. The consequences of this differential signaling can range from T cell proliferation and cytokine production to the establishment of a state of proliferative unresponsiveness known as T cell anergy. Inducing T cell anergy can be an alternative approach for the establishment of transplantation tolerance.

‣ Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Yuan, Xueli; Ansari, M. Javeed; D'Addio, Francesca; Paez-Cortez, Jesus; Schmitt, Isabella; Donnarumma, Michela; Boenisch, Olaf; Zhao, Xiaozhi; Popoola, Joyce; Clarkson, Michael R.; Yagita, Hideo; Akiba, Hisaya; Freeman, Gordon J.; Iacomini, John; Turka, L
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
47.89709%
The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-co-stimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.

‣ The role of peripheral T-cell deletion in transplantation tolerance.

Wells, A D; Li, X C; Strom, T B; Turka, L A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 29/05/2001 Português
Relevância na Pesquisa
47.89709%
The apoptotic deletion of thymocytes that express self-reactive antigen receptors is the basis of central (thymic) self-tolerance. However, it is clear that some autoreactive T cells escape deletion in the thymus and exist as mature lymphocytes in the periphery. Therefore, peripheral mechanisms of tolerance are also crucial, and failure of these peripheral mechanisms leads to autoimmunity. Clonal deletion, clonal anergy and immunoregulation and/or suppression have been suggested as mechanisms by which 'inappropriate' T-lymphocyte responses may be controlled in the periphery. Peripheral clonal deletion, which involves the apoptotic elimination of lymphocytes, is critical for T-cell homeostasis during normal immune responses, and is recognized as an important process by which self-tolerance is maintained. Transplantation of foreign tissue into an adult host represents a special case of 'inappropriate' T-cell reactivity that is subject to the same central and peripheral tolerance mechanisms that control reactivity against self. In this case, the unusually high frequency of naive T cells able to recognize and respond against non-self-allogeneic major histocompatibility complex (MHC) antigens leads to an exceptionally large pool of pathogenic effector lymphocytes that must be controlled if graft rejection is to be avoided. A great deal of effort has been directed toward understanding the role of clonal anergy and/or active immunoregulation in the induction of peripheral transplantation tolerance but...

‣ Spontaneous restoration of transplantation tolerance after acute rejection

Miller, Michelle L.; Daniels, Melvin D.; Wang, Tongmin; Chen, Jianjun; Young, James; Xu, Jing; Wang, Ying; Yin, Dengping; Vu, Vinh; Husain, Aliya N.; Alegre, Maria-Luisa; Chong, Anita S.
Fonte: Nature Pub. Group Publicador: Nature Pub. Group
Tipo: Artigo de Revista Científica
Publicado em 07/07/2015 Português
Relevância na Pesquisa
47.908843%
Transplantation is a cure for end-stage organ failure but, in the absence of pharmacological immunosuppression, allogeneic organs are acutely rejected. Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts. Transplantation tolerance can be induced in animals and a subset of humans, and enables long-term acceptance of allografts without maintenance immunosuppression. However, graft rejection can occur long after a state of transplantation tolerance has been acquired. When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost. Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant. These data demonstrate a setting in which the memory of allograft tolerance dominates over the memory of transplant rejection.