Immune tolerance and gene therapy in transplantation (original) (raw)
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The Journal of Immunology, 2006
Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection.
European Journal of Immunology, 1994
CBA/Ca mice may be made tolerant to minor histoincompatible B1O.BR skin grafts by treatment with a short course of non-depleting anti-mouse CD4 and CD8 monoclonal antibodies (mAb), during the transplantation period. We wished to determine when, in relation to antibody therapy, the Tcells became tolerant. This was investigated by a series of adoptive transfer experiments in which mAb-treated cells were removed from therapeutic antibody at defined times after skin grafting, and exposed to fresh antigen in the absence of further mAb treatment. We show here that Tcells do not become fully tolerant until 5 weeks after skin grafting. If antibody therapy is continued for the full 5 weeks, T cell tolerance can still be established, suggesting that antibody therapy does not prevent lymphocytes from registering the presence of antigen. Once the tolerant state is established, it is difficult to break that tolerance by lymphocyte infusions from normal donors. This "resistance" is mediated by T cells of the tolerant host. We show that the maintenance of both tolerance and "resistance" requires a continuous supply of antigen. When tolerant cells were "parked" in T celldepleted mice, tolerance and "resistance" were eventually lost by 6 months. In contrast, "parked" cells exposed to fresh antigen at any time up to 4 months remained tolerant and "resistant" indefinitely. Finally, we wished to establish whether "resistance" was peculiar to this form ofperipheral tolerance, or whether it might also be present in tolerance considered to be classically central. We observed resistance to be greater in the mAb-treated peripherally tolerant group, but noted that some of the centrally tolerant animals also exhibited a level of resistance above that of T cell-ablated controls. This suggests that a tolerance mechanism whose role is only minor in central tolerance may have a major role in antibody-mediated peripheral tolerance.
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.
Antibody-induced transplantation tolerance
2003
A short-treatment with nondepleting antibodies, such as those targeting CD4 or CD154 (CD40 ligand), allows long-term graft survival without the need for continuous immunosuppression. This state of immune tolerance is maintained by regulatory CD4+ T cells present within both the lymphoid tissue and the tolerated graft. The nature of such regulatory T cells, their relationship to CD4+CD25+ T cells, and their mode of action have all been the subjects of much attention recently. Here, we review recent progress on understanding the nature, specificity, and mechanisms of action of T cells mediating dominant tolerance brought about by antibody therapy.
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,
International Immunology, 2009
Donor-specific graft tolerance can be established by a combination of allo-antigen exposure and manipulation of T cell function, for example by donor-specific transfusion (DST) under the cover of a non-depleting anti-CD4 mAb. Yet, the cellular basis of this graft tolerance is still obscure. This report shows that T cell-deficient BALB/c nude mice reconstituted with naive unfractionated T cells are specifically tolerized to DBA/2 skin grafts by DST and anti-CD4 mAb treatment, whereas those transferred with T cell suspensions depleted of all Foxp3 1 CD25 1 CD4 1 natural regulatory T cells (Tregs) are not. The treatment inhibits Mls-1 a allo-antigen-specific expansion of CD4 1 non-Tregs expressing Vb6 TCR subfamily but leaves the expansion of Vb6-expressing Tregs unaffected, allowing the latter to selectively expand and establish donor-specific tolerance. Furthermore, anti-CD4 mAb inhibits in vitro the selective expansion of allo-antigen-specific CD4 1 non-Tregs but not natural Tregs, as observed with in vitro anti-CD154 [CD40 ligand (CD40L)] mAb or rapamycin treatment. The results collectively indicate that the differential effect of biologicals and pharmacological substances on the expansion of allo-antigen-specific Tregs and effector T cells and resulting dominance of the former can be a key general mechanism underlying dominant transplantation tolerance.
Antibody-Induced Transplantation Tolerance: The Role of Dominant Regulation
Immunologic Research, 2003
A short-treatment with nondepleting antibodies, such as those targeting CD4 or CD154 (CD40 ligand), allows long-term graft survival without the need for continuous immunosuppression. This state of immune tolerance is maintained by regulatory CD4+ T cells present within both the lymphoid tissue and the tolerated graft. The nature of such regulatory T cells, their relationship to CD4+CD25+ T cells, and their mode of action have all been the subjects of much attention recently. Here, we review recent progress on understanding the nature, specificity, and mechanisms of action of T cells mediating dominant tolerance brought about by antibody therapy.
Immunomodulation for transplantation tolerance
Eye, 1995
Here I will discuss some new immunosuppressive reagents in the context of inducing tolerance to grafts, with particular attention to T cells which mediate cellular attack on foreign cells. THE IDEAL For the transplant recipient, the ideal would be to induce specific tolerance to a graft, akin to creating a 'hole' in the immune repertoire to accommodate the graft antigens. This allows the recipient to retain full immune competence-with the exception of the 'hole'. Since no immunosuppressive therapy is required the risk of adverse side-effects (ranging from nephrotoxicity to neoplasia) is avoided. If the immune repertoire is portrayed as a library, with each book being reactive against a single type of antigen, then removal of graft-specific 'books' would create the desired hole in the library (Fig. 1). In practice physical removal of graft-reactive T cells is difficult because in vivo these are scattered through out the body. However, it has been shown that cannulation of the draining lymph nodes to capture cells as they leave an antigenic site can achieve deletion of a specific population of antigen-reactive cells. The method critically depends on total capture of antigen-reactive cells, and is not practical for clinical application. Other general approaches to creating a hole in the immune repertoire include (1) central deletion of antigen-reactive cells in the thymus, and (2) turning off the aggressive response to the graft in the peripheral circulation.• CENTRAL TOLERANCE APPROACH A central approach to tolerance induction capitalises on one of several of the intrinsic self-control systems