Mechanisms maintaining enhancement of allografts. I. Demonstration of a specific suppressor cell.

Hall, Bruce M.

doi:10.1084/jem.161.1.123

Cited by 57 publications

(56 citation statements)

References 25 publications

(43 reference statements)

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“…Many laboratories have shown that peripheral allograft tolerance is associated with the appearance of helper phenotype or CD4 ϩ T cell-dependent immunoregulatory mechanisms (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). A detailed characterization of these immunoregulatory T cells has been hampered, however, by the absence of a simple means to track and study these cells both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance

Sánchez‐Fueyo

Weber

Domenig

et al. 2002

The Journal of Immunology

160

109

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Immunoregulatory mechanisms dependent on regulatory CD4+ T cells are believed to be critical in the maintenance of peripheral tolerance to allografts. However, a detailed characterization of the effects of these regulatory T cells has been hampered by the absence of a simple means to track and study them. In this work we provide evidence that in a murine model of islet transplantation the interactions between alloaggressive and regulatory T cells can be studied in vitro and in vivo at the single-cell level. The observations made in both an in vitro coculture system and an in vivo CFSE-based adoptive transfer model indicate that lymphocytes from tolerant allograft recipients 1) proliferate weakly to donor strain allogeneic cells but vigorously to third-party strain cells; and 2) suppress the proliferation of naive syngeneic CD4+ and CD8+ T cells to donor tissue in a cell dose- and Ag-specific manner. These effects depend on the presence of CD4+CD25+ T cells and are neutralized by anti-CTLA4 mAb or rIL-2. The principal effect of anti-CTLA4 is directed against the naive, not regulatory, T cell population. These results can be replicated in vivo by transferring lymphocyte populations into transplant recipients, proving that the graft-protecting actions of regulatory T cells are blunted by a rise in the number of allodestructive T cells (pool size model) and depend on the presence of CD4+CD25+ T cells and the integrity of the CTLA4/B7 pathway.

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Section: Discussionmentioning

confidence: 99%

“…The presence of suppressor or regulatory CD4 ϩ T cells (T reg) 4 in tolerant hosts has been described by several laboratories, including our own (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Regulatory…”

mentioning

confidence: 99%

Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance

Sánchez‐Fueyo

Weber

Domenig

et al. 2002

The Journal of Immunology

160

109

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“…Suppressor effects have been documented in hosts immunologically enhanced (25), treated with cyclosporine (26), and undergoing total lymphoid irradiation (27) or blood transfusion (28).…”

Section: Discussionmentioning

confidence: 99%

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

Kupiec‐Weglinski¹,

Diamantstein²,

Tilney³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

107

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The mouse hybridoma ART 18 monoclonal antibody (mAb), which binds to the rat interleukin 2 (IL-2)receptor, was studied for its effect on heterotopic cardiac allograft survival m Two 'histoincompatible inbred rat strain combinations. Treatment with ART 18 mAb for 10 days after transplantation proloagediallograft survival in a dose-dependent fashion up to about 3 weeks (acute rejection normally occurs within 8 days). ART 18 mAb therapy started at 5 days after transplantation (the--time of major rejection activity) abrogated acute rejection dnd extended the survival to about 18 days. The dense cellular infiltrate noted histologically in acute rejection had virtually disappeared after ART 18 mAb treatment. Thus, IL-2 receptortargeted therapy can be successfully used to prevent and/or treat acute rejection. When spleen cells from antibody-treated recipients bearing well-functioning allografts were adoptively transferred to normal untreated rats that received cardiac; allografts 24 hr later, the survival of donor-specific, but not third-party, test cardiac allografts was prolonged significantly; this supports the idea that ART 18 mAb induced "sparing" of suppressor T lymphocytes. Combining infusion of ART 18 mAb with exogenous IL-2-rich conditioned medium produced the same effect as if the mAb alone had been administered, suggesting that an excess of IL-2 does not prevent binding of ART 18 mAb to IL-2 receptorbearing cells in vivo. These results support the important role of the IL-2 receptor,-bearing cells in the mechanism of allograft rejection; they may represent an important target for immunosuppression in clinical organ transplantation.Treatment of allograft rejection remains the major problem in clinical organ transplantation (1,2). Antirejection therapy has included high doses of steroids and polyclonal anti-lymphocyte globulins; more recently, cyclosporine and monoclonal anti-T-cell antibodies have been used. Unfortunately, these powerful immunosuppressive modalities have been only relatively successful and may produce serious complications, particularly life-threatening infections. Thus, although results of clinical transplantation have improved progressively, new strategies are still needed to obtain the elusive goal of donor-specific immunosuppression and "tolerance" by the host toward a foreign graft.Although the pivotal role of sensitized T lymphocytes in graft rejection has been long appreciated, the complex interplay among functionally defined cell phenotypes, distinctive surface protein markers expressed by these cells, and cytokines elaborated by them are not fully defined (3, 4).Helper-T-cell (Th)-derived interleukin 2 (IL-2) is the main cytotrophic factor for immunocompetent T lymphocytes (5). (9). The mouse ART 18 monoclonal antibody (ART 18 mAb), which reacts primarily with rat lymphoblasts, defines the rat IL-2 receptor (10-12). This antibody inhibits adsorption of IL-2 by IL-2 receptor-positive cells, thereby blocking IL-2-dependent T-lymphocyte proliferation. We have utilized ART 18 mA...

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“…Enhancement induced by liver graft serum leads to a typical maintenance phase of systemic unresponsiveness against donor (DA) antigens ), which we have recently shown is partly mediated by suppressor T cells; thus thoracic duct lymphocytes from such enhanced rats inhibited the graft rejection ability of normal TDL in an adoptive transfer system (unpublished observation). T cell-mediated suppression is a common feature of the maintenance phase of enhancement (Batchelor, Phillips & Grennan, 1984;Barber, Hutchinson & Morris, 1984;Hall, 1985;Hutchinson, 1986;Padberg et al, 1987). Thus, it is possible that long-term survival of DA liver grafts in PVG rats involves an enhancement-type mechanism in which the presence of anti-class II antibodies encourages, by speculative means, suppressor T cell induction.…”

Section: Discussionmentioning

confidence: 99%

Immunological tolerance induced by liver grafting in the rat: splenic macrophages and T cells mediate distinct phases of immunosuppressive activity

Yoshimura¹,

Gotoh²,

Kamada³

1991

Clinical and Experimental Immunology

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SUMMARYIn the rat combination DA into PVG, liver grafts are not rejected but induce donor-specific transplantation tolerance. We have examined the immunosuppressive properties of spleen cells from PVG recipients of DA liver grafts at various times post-grafting. The results indicate the development of two phases of cell-mediated suppressor activity, which appear to be mediated by separate spleen cell populations. Mitomycin-C-treated spleen cells taken from animals between 5 and 28 days postgrafting were able to suppress rat mixed lymphocyte reactions (MLRs). These 'early' suppressor cells were glass adherent and absent from populations purified by passage through nylon wool or GIO Sephadex columns. Suppression of MLR by purified glass adherent cells was not specific for either stimulator or responder haplotypes and was blocked by indomethacin. Nylon wool purified T cells were not suppressive at this time. Spleen cell suppressor activity declined to background levels after 35 days post-grafting. However, spleen cells from long-term surviving liver graft recipients (20 weeks or more) were again able to suppress MLR; the 'late' suppressor cells were nylon wool non-adherent and suppression was specific for the donor (DA) MHC type. We conclude that liver grafting in this combination generates early and late phases of suppression among spleen cells, that the early phase is produced by macrophages and mediated by prostaglandins and that the late phase is dependent on allospecific suppressor T cells.

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Mechanisms maintaining enhancement of allografts. I. Demonstration of a specific suppressor cell.

Cited by 57 publications

References 25 publications

Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance

Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance

Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats.

Immunological tolerance induced by liver grafting in the rat: splenic macrophages and T cells mediate distinct phases of immunosuppressive activity

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