The 2004 FASEB Summer Research Conference on Transplant Immunology: Closer to the Goal of Transplant-Specific Tolerance (original) (raw)
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Stem cell–mediated tolerance inducing strategies in organ transplantation
Kidney International, 2004
Stem cell-mediated tolerance inducing strategies in organ transplantation. The scope of possible tools to modulate the recipients immune response towards tolerance induction basically includes deletional and non deletional mechanisms, which are currently targeted by various strategies including monoclonal antibodies, cytokine deviation, chimerism induction and the support of regulating T-cells. Here we summarize the main findings in the field derived from experimental animal studies and currently performed clinical studies. This review focuses to give a clinically relevant overview over relevant tolerance inducing concepts, taking into consideration risk profiles and clinical efficacy associated with specific immunosuppressive regiments currently applied in the clinical setting of transplantation.
Regulating the Immune Response to Transplants
Immunity, 2001
ing came at a time when the notion of T cell-mediated suppression was in disrepute with claims that T suppressors were within the CD8 subset of complex regulatory circuits; a role for I-J, antigen-specific suppressor-factors; and a host of other irreconcilable claims. The existence of CD4 ϩ T cells that could suppress graft rejection in mice was shown in 1993 (Qin et al.). Transplantation tolerance induced in mice, using a short pulse of nondepleting antibody therapy with anti-mouse Introduction CD4 and CD8, was associated with CD4 ϩ T cells that Transplantation of cells and organs is now a rapidly could, on adoptive transfer, suppress graft rejection by evolving therapeutic modality for the correction of a naive T cells. Although these initial studies were conwide range of disease states. This has been made posducted with skin grafts mismatched for multiple minor sible by the development of powerful immunosupprestransplantation antigens, CD4 ϩ regulatory T cells were sant drugs that can stave off the rejection process. also found in mice tolerating heart grafts mismatched However, these drugs usually require lifelong adminisacross the whole MHC (Chen et al., 1996). Since then, tration, patient compliance, and risk a wide range of unthe demonstration of CD4 ϩ regulatory or suppressor wanted side effects, including susceptibility to infec-T cells in a wide range of models of transplantation toltions and cancer. Ideally, one would like to avoid these erance in rodents (Yin and Fathman, 1995; Davies et al., complications by induction of "operational tolerance" 1996a; Waldmann and Cobbold, 1998, 2000; Zhai and to the transplant. The term operational tolerance is care-Kupiec-Weglinski, 1999) makes their existence now fully chosen, as any such acquired tolerant state need indisputable . not reflect the same hierarchy of mechanisms that the Nevertheless, knowledge of the characteristics of these immune system normally uses to ensure self-tolerance cells is limited as compared to other types of CD4 ϩ but, rather, any among those that enable the trans-T cells. There are probably four main reasons why. First, planted organ to function without being the target of a there is the element of overactive yet unjustified destructive immunological attack. scepticism that has potentially limited the number of The pioneering experiments of Medawar and his colresearchers entering the field of suppression. Second, leagues, who injected donor marrow into newborn mice,
Immune Tolerance and Transplantation
Seminars in Oncology, 2012
Successful allogeneic hematopoietic stem cell transplantation (HSCT) and solid organ transplantation require development of a degree of immune tolerance against allogeneic antigens. T lymphocytes play a critical role in allograft rejection, graft failure, and graft versus host disease (GVHD). T cell tolerance occurs by two different mechanisms; i) depletion of self-reactive T cells during their maturation in the thymus (central tolerance) ii) suppression/elimination of selfreactive mature T cells in the periphery (peripheral tolerance). Induction of transplant tolerance improves transplantation outcomes. Adoptive immunotherapy with immune suppressor cells including regulatory T cells, NK-T cells, veto cells and facilitating cells are promising therapies for modulation of immune tolerance. Achieving mixed chimerism with the combination of thymic irradiation and T cell depleting antibodies, costimulatory molecule blockade with/without inhibitory signal activation and elimination of alloreactive T cells with varying methods including pre or post-transplant cyclophosphamide administration appear to be effective methods to induce transplant tolerance. Immune Tolerance and Transplantation Successful allogeneic hematopoietic stem cell transplantation (HSCT) and solid organ transplantation requires a certain degree of immune tolerance development against allogeneic antigens. Achievement of immune tolerance may prevent a host versus graft reaction, which leads to graft rejection and failure, as well as preventing a graft versus host reaction, which results in graft versus host disease (GVHD) in recipients of HSCT. Induction of immune tolerance decreases the risk of acute and chronic graft rejection after solid organ transplantation and can improve transplanted organ survival. Lymphocytes, specifically T lymphocytes, play a critical role in allograft rejection, graft failure, and GVHD. Therefore, in this review we will focus on T cell tolerance. T Cell Tolerance and Thymopoiesis Our immune system is very adaptive, able to mount an immune response to varying immunological targets. In some conditions the immune system becomes unresponsive to certain antigens 1. T cell tolerance occurs by two different mechanisms. The first is the depletion of self-reactive T cells during their maturation in the thymus; only 1-2 % of thymocytes are able to reach a mature T cell status before they are released from the thymus.
Concise review: immunologic lessons from solid organ transplantation for stem cell-based therapies
Stem cells translational medicine, 2013
Clinical organ transplantation became possible only after powerful immunosuppressive drugs became available to suppress the alloimmune response. After decades of solid organ transplantation, organ rejection is still a major challenge. However, significant insight into allorecognition has emerged from this vast experience and should be used to inform future stem cell-based therapies. For this reason, we review the current understanding of selected topics in transplant immunology that have not been prominent in the stem cell literature, including immune responses to ischemia/reperfusion injuries, natural killer cells, the adaptive immune response, some unresolved issues in T-cell allorecognition, costimulatory molecules, and the anticipated role of regulatory T cells in graft tolerance.
Induction of Immunologic Tolerance for Transplantation
Physiological Reviews, 1999
Rossini, Aldo A., Dale L. Greiner, and John P. Mordes. Induction of Immunologic Tolerance for Transplantation. Physiol. Rev. 79: 99–141, 1999. — In the second half of the 20th century, the transplantation of replacement organs and tissues to cure disease has become a clinical reality. Success has been achieved as a direct result of progress in understanding the cellular and molecular biology of the immune system. This understanding has led to the development of immunosuppressive pharmaceuticals that are part of nearly every transplantation procedure. All such drugs are toxic to some degree, however, and their chronic use, mandatory in transplantation, predisposes the patient to the development of infection and cancer. In addition, many of them may have deleterious long-term effects on the function of grafts. New immunosuppressive agents are constantly under development, but organ transplantation remains a therapy that requires patients to choose between the risks of their primary il...
Transplant Immunology, 2008
Several studies have shown that recipient-derived CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) are involved in transplantation tolerance. However, it is not clear whether allogeneic donor-derived Tregs are able to regulate T cell alloreactivity after solid organ allograft transplantation. Related studies in experimental bone marrow transplantation have shown that allogeneic donor-derived Tregs are capable of promoting early and long-term allogeneic hematopoietic engraftment, accompanied by tolerance to donor and recipient antigens. However, in these models, donor-derived Tregs are syngeneic with respect to the T responder cells. The role of Tregs in solid organ transplantation models where recipient-derived T responder and donor-derived Tregs are allogeneic has been scarcely studied. In order to determine whether allogeneic Tregs were able to regulate T cell alloreactivity, CD4+ CD25− and CD8+ T responder cells were cultured with stimulator dendritic cells in several responder-stimulator strain combinations (C57BL/6→BALB/c, BALB/c→C57BL/6 and C3H→BALB/c) in the presence of responder-derived, stimulator-derived or 3rd-party-derived Tregs. Then, the frequency of IFN-γ+ alloreactive T cells was determined by means of ELISPOT assay. The results of this study demonstrate that, regardless of the responder-stimulator strain combination, both responder-derived and stimulator-derived Tregs, but not 3rd-party-derived Tregs, significantly inhibited CD4+ and CD8+ T cell alloreactivity. The effect of allogeneic stimulator-derived Tregs was dependent on IL-10 and TGF-β and reversed by exogenous IL-2. In vivo experiments in nu/nu recipients reconstituted with CD4+ CD25− T responder and Tregs showed that recipient and donor-derived, but not 3rd-party-derived Tregs, significantly enhanced skin allograft survival. Importantly, T cells from both recipient-derived and donor-derived Treg-reconstituted nu/nu recipients exhibited donor-specific unresponsiveness in vitro. These results show that allogeneic donor-derived Tregs significantly inhibit T cell alloreactivity and suggest their potential use in the induction of transplantation tolerance.
International journal of organ transplantation medicine, 2010
Progress in understanding the cellular and molecular biology of the immune system, in the second half of the 20(th) century brings the transplantation of replacement organs and tissues in clinical reality to cure disease. Immunosuppressive agents that are part of nearly every transplantation procedure, are toxic to some extent and their chronic use predisposes the patient to the development of infection and cancer. Alternatives to immunosuppression include modulation of host immune system to reduce the immune response and the induction of a state of immunologic tolerance. Induction of hematopoietic mixed chimerism through donor bone marrow transplantation offers a promising approach for tolerance induction as a prelude to organ transplantation. Furthermore, mesenchymal stromal cells have important effects on the host immune system and possess immune modulation properties that make them attractive for potential use in organ transplantation as immunosuppressant. Both modalities might ...
Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation
Transplant Immunology, 2003
Infusions of donor bone marrow derived cells (DBMC) continue to be tested in clinical protocols intended to induce specific immunologic tolerance of solid organ transplants based on the observations that donor-specific tolerance is induced this way in animal models. We studied the immunological effects of human DBMC infusions in renal transplantation using modifications in lymphoproliferation (MLR) and cytotoxicity (CML) assays. The salient observations and tentative conclusions are summarized in this review. Among many types of organs transplanted using DBMC at this center, it was found that the cadaver renal recipients (CAD) had significantly decreased chronic rejection and higher graft survival when compared to equivalent non-infused controls. DBMC infusion was also associated with a marginal and non-specific immune depression. It was also observed that the number of chimeric donor cells gradually increased in the iliac crest bone marrow compartment with a concomitant decrease in the peripheral blood and that the increase was more rapid in living-related donor (LRD)-kidneyyDBMC recipients in spite of a lower number of DBMC infused (-25%) than in the CAD-kidneyyDBMC group. In the LRD recipients with residual anti-donor responses, purified chimeric cells of either donor or recipient inhibited recipient immune responses to the donor significantly more strongly than the freshly obtained bone marrow from the specific donor or volunteer suggesting an active regulatory role for chimeric cells. A number of (non-chimeric) subpopulations of bone marrow cells including CD34 stem cells and the q CD34 early progeny like CD38 , CD2 , CD5 and CD1 lymphoid cells as well as CD33 (but CD15 ) myeloid cells y q q q q q y down-regulated the MLR and CML responses of allogeneic PBMC stimulated with (autologous) donor spleen cells. These regulatory effects appeared to be refractory to the action of commonly used immunosuppressive drugs and occurred during the early phase of the immune response through cell-cell interactions. Most of these DBMC sub-populations had stimulatory capabilities, albeit markedly lower than donor spleen cells, but only through the indirect antigen presentation pathway. When cocultured with allogeneic stimulators, purified CD34 cells were found to give rise both to CD3 TCRab , as well as CD3 q y q q TCRab cells and, thereby, responded in MLR to allogeneic stimulation (but did not generate cytotoxic effector cells). Also, a q number of DBMC subpopulations inhibited the CML and to a lesser extent the MLR, of autologous post-thymic responding T cells stimulated with allogeneic irradiated cells, mediated through soluble factors. Finally, non-chimeric DBMC also inhibited the proliferative and cytotoxic responses of autologous T cells to EBV antigens, inducing T suppressor cells, which in turn could inhibit autologous anti-EBV CTL generation and B cell anti-CMV antibody production. These studies all suggested a strong inhibitory property of a number of DBMC sub-populations in vitro and in vivo with the notion that they promote unresponsiveness. ᮊ