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PubMed1994

Mechanisms of transplantation tolerance.

Transplantation tolerance, the long-term acceptance of grafted tissue in the absence of continuous immunosuppression, remains an elusive goal in humans, but it has been achieved in animal models using numerous approaches. The mechanisms behind graft acceptance vary according to the means used to create the state of acceptance. Several major mechanisms can now be recognized. While thymic deletion of T cells appears to be a mainstay of self-tolerance, its role in transplantation tolerance now seems to be less significant. In contrast, extrathymic mechanisms of transplantation tolerance seem to be major factors in long-term graft acceptance. If donor antigens are presented in a nonimmunogenic manner on the graft, e.g. due to modification of graft tissue by culture, peripheral T cells of the recipient may ignore the graft. Alternatively, nonstimulatory presentation of donor antigens on graft tissue can induce a state of unresponsiveness in recipient T cells, i.e. anergy, rather than activating them to destroy the graft. Suppression mechanisms also operate to control graft rejection and may be specific or nonspecific in nature. Specific suppression mechanisms might act in an idiotype or antigen-specific fashion, and evidence is accumulating that this may be mediated through the elaboration of cytokines. Donor antigen-specific T cells may be activated to produce "protective" cytokines which then regulate the generation of destructive T cells. Future therapies will be aimed at affecting graft acceptance through these peripheral mechanisms.

Animals↗
PubMed1998

Apoptosis, graft rejection, and transplantation tolerance.

Transplantation tolerance can be achieved through several mechanisms, including the action of suppressor cells, the induction of anergy, or the deletion of graft-reactive donor T cells. In this article, the possible involvement of programmed cell death (apoptosis) in allograft rejection and transplantation tolerance is discussed. The recent characterization of members of the tumor necrosis factor-alpha gene family has identified ligands (Fas ligand and TRAIL) and corresponding death receptors (DR). In rejected organ transplants, apoptotic cells are frequently encountered. Conversely, high-level expression of Fas ligand on the allograft correlates with graft acceptance in some models of organ transplantation. Furthermore, some of the immunosuppressive drugs currently in clinical use might exert their activity at least in part through effects on apoptotic pathways. From the available data, it can be inferred that apoptosis contributes to the outcome after organ transplantation, being involved both in graft rejection and in transplantation tolerance.

Animals↗
PubMed2003

CD25+ immunoregulatory CD4 T cells mediate acquired central transplantation tolerance.

Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4+CD25+) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4+CD25- and CD4+CD25+ T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.

Adoptive Transfer↗
PubMed2001

Mechanisms of acquired thymic tolerance: induction of transplant tolerance by adoptive transfer of in vivo allomhc peptide activated syngeneic T cells.

BACKGROUND: Our most recent observation that i.v. injection of Wistar-Furth (WF) major histocompatibility complex Class I peptide 5 (P5)-pulsed self-myeloid or lymphoid dendritic cells (DC) induces transplantation tolerance suggests that adoptive transfer of in vivo allopeptide-primed host T cells might induce acquired tolerance through their interaction with thymic DC. METHODS: To examine this hypothesis, host myeloid DC cultured in rat granulocyte/macrophage colony stimulating factor and interleukin 4 were pulsed in vitro with P5 and injected intravenously into syngeneic ACI rats. The T cells primed to P5 via the indirect pathway of allorecognition were harvested 7 days later and administered by either intravenously or intrathymically into syngeneic ACI recipients of WF cardiac allografts. RESULTS: Syngeneic T cells obtained from the spleen of P5-primed rats had a high mixed lymphocyte reaction proliferative response to P5 presented by self-DC. I.v. administration of 2x107 P5-primed alloreactive purified host splenic T cells alone on day -7 significantly (P<0.001) prolonged cardiac allograft survival from 10.5+/-1.0 days to 18.6+/-1.8 days in the WF-to-ACI rat combination. I.v. injection of P5-activated host T cells combined with 0.5 ml antilymphocyte serum (ALS)-transient immunosuppression on day -7 led to 100% donor-specific permanent graft survival (>200 days). Thymectomy before i.v. injection of P5-activated syngeneic T cells led to acute graft rejection, suggesting that the homing of in vivo activated T cells to the host thymus might play a role in the induction of tolerance. To further define the role of the recipient thymus in this model, we examined the effects of intrathymic (i.t.) injection of P5-primed alloreactive T cells on graft survival and found that i.t. administration of the P5-primed T cells on day -7 alone significantly prolonged graft survival (15.0+/-0.7 days) and when combined with 0.5 ml ALS led to donor-specific permanent graft survival. The long-term unresponsive recipients permanently (>100 days) accepted second-set donor-specific cardiac allografts but not third-party (Lewis) grafts. CONCLUSIONS: These findings demonstrate that the adoptive transfer of splenic T cells primed to an indirectly presented donor peptide induces transplantation tolerance in a transiently immunosuppressed secondary syngeneic recipient. Our data suggest that the interaction of thymic DC with activated peripheral T cells induces alloantigen (Ag)-specific T-cell tolerance by either inactivation or deletion of alloreactive T cells in the thymus. This observation provides the first formal evidence that the interaction between thymic DC and activated peripheral T cells that continuously circulate through the thymus plays an important role in the induction and maintenance of Ag-specific tolerance.

Adoptive Transfer↗
PubMed1992

Transplantation tolerance in heart transplant recipients as demonstrated by unresponsiveness in cell-mediated lympholysis.

Transplantation tolerance or adaptation to an allograft is associated with unresponsiveness to donor-specific transplantation antigens measured in in vitro cell-mediated lympholysis (CML). We here demonstrate in a longitudinal follow-up that CML nonreactivity develops in seven of ten patients following heart transplantation. The first manifestation of this nonreactivity manifested between 3 and 27 months after transplantation. CML nonreactivity correlated with time after transplantation and the percentage of activated lymphocytes in peripheral blood. CML nonreactivity was also associated with good graft function, i.e., in condition of nonresponsiveness patients did not manifest acute rejection. The only exception was seen in one patient in whom the immunosuppressive therapy was strongly reduced. A more detailed evaluation of this patient indicated that the underlying mechanism for CML nonreactivity is clonal anergy or active suppression of the alloreactive cells.

Cytotoxicity, Immunologic↗
PubMed1992

Antigen recognition and IL-2 receptor gene expression as evidence against clonal deletion in mice with neonatally induced transplantation tolerance.

Neonatal transplantation tolerance was induced in B10.A mice by the injection of spleen and bone marrow cells from semiallogeneic [C57BL/10(B10) x B10.A] F1 donors. The neonatally treated mice accepted skin grafts from B10 donors. Spleen cells from tolerant animals did not respond by proliferation to tolerated B10 antigens in vitro. However, spleen cells from tolerant mice recognized specific (B10) antigens and synthesized mRNA for the inducible 55-kDa interleukin-2 receptor (IL-2R) as did cells from normal animals. Maintenance of this early phase of cell activation upon contact with tolerated antigens is direct evidence against clonal deletion as a mechanism, in this particular model of neonatally induced transplantation tolerance.

Animals↗
PubMed1996

Production of high levels of Th1 and Th2 cytokines in mice with acquired transplantation tolerance.

Specific transplantation tolerance was induced in newborn mice by the intravenous injection of hematopoietic cells from semiallogeneic donors. Success of tolerance induction was tested by skin allografts. Spleen cells from mice bearing tolerated allografts for more than 60 days after transplantation spontaneously produced high levels of various cytokines. Production of both Th1 (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines, as well as of IL-3, was significantly increased in tolerant animals. The elevated production of Th1 cytokines was associated with the high secretory activity of CD4+ cells, while the production of Th2 cytokines was high in both CD4+ and CD8+ cell populations. The hyperproduction of cytokines was an intrinsic property of the T cells from tolerant animals and was not caused by a larger size of major T-cell subsets. The production of high levels of cytokines was a consequence of neonatal induction of tolerance and persisted for a long time after skin grafting of neonatally tolerized animals. These results show that neonatal induction of transplantation tolerance results in the production of enhanced levels of Th1 and Th2 cytokines which could be involved in the establishment and maintenance of immunological tolerance.

Animals↗
PubMed2001

Mixed chimerism and transplantation tolerance.

Achieving transplantation tolerance is an important goal in the effort to reduce long-term morbidity and mortality in organ transplant recipients. Robust, lifelong, donor-specific tolerance can be reliably achieved by induction of mixed chimerism in various animal models. To date, the clinical application of these proto-cols has been impeded partly by the potential toxicity of the required host conditioning regimens and the lack of successful studies in large animals. This article reviews the progress achieved in recent years in developing considerably milder conditioning protocols in rodents, and in extending some of these models to achieve permanent mixed chimerism and tolerance in large animals. Advances in the induction of xenogeneic tolerance through mixed chimerism are also discussed.

Animals↗
PubMed1997

Mixed hematopoietic chimerism and transplantation tolerance.

Durable transplantation tolerance can be reliably achieved by inducing engraftment of hematopoietic cells in recipients initially depleted of T-lymphocytes. Engraftment of donor pluripotent hematopoietic stem cells (PPHSC) produces mixed hematopoietic chimeras in which both host and donor cells coexist and are tolerant of each other. The major mechanism of tolerance in these chimeras is central, intrathymic clonal deletion, which is induced and maintained by immigration of both host and donor marrow-derived cells to the host thymus, ensuring the ongoing central deletion of donor- and host-reactive cells. In this article, approaches developed in our laboratory to induce stable mixed hematopoietic chimerism and specific central deletional allogeneic and xenogeneic tolerance without toxic or myeloablative host conditioning are reviewed.

Animals↗
PubMed1991

Influence of I-E expression on induction of neonatal transplantation tolerance.

Neonatal transplantation tolerance was one of the first experimental systems to reveal that tolerance could be achieved to non-self antigens in living animals. Functional and direct evidence (obtained by the use of monoclonal antibodies directed at T cell receptors specifically reactive with I-E molecules) confirm that tolerance is achieved, at least in part, via clonal elimination of developing thymocytes. In this report, we show that induction of tolerance of class I alloantigens in neonatal mice is governed by expression of I-E molecules. Neonatal I-E non-expressor mice proved to be highly resistant to the acquisition of class I tolerance if the donor inoculum expressed disparate class I antigens as well as I-E molecules. The spleens of the few class I-tolerant, I-E non-expressor mice that were generated were found to be depleted of I-E-reactive (RR315+) T cells, whereas no such depletion was observed in their neonatally injected, but non-tolerant littermates. By contrast we found no resistance to tolerance of I-A alloantigens when neonatal I-E non-expressor mice received injections of I-A-disparate, I-E-bearing donor cells. In these tolerant mice, splenic I-E-reactive T cells were readily detected in apparently normal amounts. These results indicate that lack of I-E expression in newborn mice confers resistance to tolerance induction to class I alloantigens, especially when the latter are expressed on donor cells that also display I-E molecules. The possible mechanisms operating to produce resistance to tolerance induction in neonatal mice are discussed, including the possibilities that (a) I-E may act as a restricting element during tolerance induction (an ontogenic process), and (b) the expression of I-E on H-2-disparate, I-E-expressing test skin allografts may provide a source of "help" for CD8+ cytotoxic T cell precursors, leading to graft rejection.

Animals↗
PubMed1983

Adult transplantation tolerance induced by lentil lectin. III. Induction of transplantation tolerance by lentil lectin in mouse strain combinations with different H-2 disparities: tolerogenic effect of H-2D region antigens.

The survival time of skin allografts was investigated in 28 combinations of mouse strains differing at various loci, in adult recipients treated with lentil seed lectin (LCA). The recipients were given 1 mg of LCA daily (i.v. or i.p.) after transplantation of the skin graft. The immunosuppressive effect of LCA was generally inversely related to the conventional strength of the allotransplantation reaction, i.e. the rate of rejection of allografts on untreated recipients. In the case of H-2D antigenic disparities, the grafts usually survived for more than 100 days. The H-2A or H-2K disparity appeared to be relatively resistant to induction of tolerance by LCA treatment. The relative resistance of various H-2 antigens toward the induction of tolerance by LCA differs to some extent from that observed in experiments on the induction of neonatal tolerance by semiallogeneic lymphocytes as described in literature.

Animals↗
PubMed1984

[Mechanisms in the induction and maintenance of transplantation tolerance: an overview].

Transplantation tolerance is used as model for investigation of mechanisms in recognition of "self" and "non-self". The clonal deletion of specific lymphocytes as reason transplantation tolerance is called more and more in question. Active mechanims, as for instance induction and maintenance by suppressor cells are more possible. Suppressor cells may be active not only in inhibition of inductor phase but also in blocking of effector cells. A synergistic effect of blocking factors is supposed too. The thymus plays an important role in induction of transplantation tolerance. Different methods for induction of tolerance are described.

Animals↗
PubMed2002

Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance.

CD4(+)CD25(+) T cells have been proposed as the principal regulators of both self-tolerance and transplantation tolerance. Although CD4(+)CD25(+) T cells do have a suppressive role in transplantation tolerance, so do CD4(+)CD25(-) T cells, although 10-fold less potent. Abs to CTLA-4, CD25, IL-10, and IL-4 were unable to abrogate suppression mediated by tolerant spleen cells so excluding any of these molecules as critical agents of suppression. CD4(+)CD25(+) T cells from naive mice can also prevent rejection despite the lack of any previous experience of donor alloantigens. However, this requires many more naive than tolerized cells to provide the same degree of suppression. This suggests that a capacity to regulate transplant rejection pre-exists in naive mice, and may be amplified in "tolerized" mice. Serial analysis of gene expression confirmed that cells sorted into CD4(+)CD25(+) and CD4(+)CD25(-) populations were distinct in that they responded to TCR ligation with very different programs of gene expression. Further characterization of the differentially expressed genes may lead to the development of diagnostic tests to monitor the tolerant state.

Abatacept↗
PubMed1982

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

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

Animals↗
PubMed2002

Maternal-fetal relationship, natural chimerism and bilateral transplantation tolerance as the basis for non-myeloablative stem cell transplantation.

Bone marrow transplantation (BMT) which represents an important clinical tool for treatment of patients with a wide variety of malignant and non-malignant diseases, however, the procedure is associated with procedure-related toxicity and mortality as well as unavoidable late complications. Many of the undesirable consequences of BMT are caused directly or indirectly by the intensive conditioning administered during the pre-transplant period. However, if the main goal of the BMT procedure is to enable immunotherapy by alloreactive donor lymphocytes, the conditioning prior to BMT needs to be reconsidered, because transplantation tolerance across major histocompatibility complex (MHC) occurs spontaneously in nature, as evidenced by the fact that pregnant females do not reject their conceptus. In fact, as shown by Owens in the 1940s, placental parabiosis in utero leads to permanent mixed chimerism and bilateral transplantation tolerance. These observations followed by experiments carried out in the 1950s by Billingham et al. suggested that infusion of parental stem cells into neonates with no exogenous immunosuppressive treatment resulted in mixed chimerism and permanent transplantation tolerance to donor alloantigens. Thus, a window of opportunity provided shortly after delivery, was sufficient for induction of tolerance without the need for heavy conditioning. Tolerant recipients were shown to be chimeras with only a small proportion of donor cells. However, without corroborating evidence that transplantation tolerance could be intentionally induced, the approach could not be applied in clinical practice for immunocompetent recipients. Starting in 70s, we documented the feasibility of establishing bilateral transplantation tolerance by mixed chimerism following non-myeloablative conditioning in immu. nologically mature recipients across MHC in mice, rats and dogs. Several studies have shown that reduced intensity conditioning can be very useful for immunoregulation whereas more intensive the pre-grafting immunosuppression resulted in more aggressive the GVHD. These and other findings suggested that lower intensity conditioning may be sufficient for engraftment of donor stem cells, thus suggesting that immunosuppression without myeloablation may be sufficient for prevention of allograft rejection. Following engraftment of donor stem cells, donor lymphocytes infused with bone marrow or mobilized blood stem cells can eradicate residual hematopoietic cells of host origin, occasionally non-hematopoietic tumor cells of host origin as well. Whenever indicated, donor lymphocytes infusion (DLI) can be used at a later stage post BMT to eradicate residual malignant cells of host origin or for the treatment of residual or recurrent disease. Taken together, ongoing clinical studies suggest that high-dose, myeloablative chemoradiotherapy, could be safely replaced with non-myeloablative conditioning (NST).

Animals↗
PubMed2001

Islet cell transplantation tolerance.

Curative islet transplantation for type 1 diabetes currently requires lifelong systemic immunosuppression. Induction of islet transplantation tolerance would be far preferable. We have previously demonstrated that blockade of costimulation by the administration of a donor-specific transfusion in combination with anti-CD154 monoclonal antibody leads to permanent islet and prolonged skin allograft survival in mice. The protocol requires the presence of CD4+ T cells, interferon-gamma, and CTLA4, and involves the deletion of CD8+ alloreactive T cells. Translation of this strategy into clinical practice will, however, require attention to at least two issues. First, we have observed that the presence of viral infection during tolerance interferes with tolerance induction. Second, we have observed that our tolerance induction protocol is ineffective in autoimmune nonobese diabetic mice. We hypothesize that resistance to tolerance induction in nonobese diabetic mice is due to the presence of memory autoreactive cells. To overcome the deleterious effects of viral infection and of primed memory responses, it may be necessary to modify current tolerance induction strategies based on costimulatory blockade. These modifications may require patient isolation, the generation of hematopoietic chimerism, or treatments that target the specific T-cell populations, cytokines, and/or costimulatory factors responsible for resistance. Such modifications may make it possible to extend tolerance induction to the "real world" situation of individuals with type 1 diabetes who are likely to harbor both memory allo-and autoreactive immune cells.

Animals↗