A role for Th2 cytokines in the suppression of CD8⁺ T cell‐mediated graft rejection

Abstract

A major histocompatibility complex (MHC) class I-specific T cell receptor (TCR)-transgenic mouse was used to study classical-type transplantation tolerance in the adult. Engraftment of MHC class I-incompatible bone marrow and tolerance to donor-type skin grafts were obtained using dimethylmyeleran (DMM) as a myeloablative agent and a non-depleting anti-CD8 monoclonal antibody (mAb) as the sole immunosuppressant. Surprisingly, bone marrow engraftment was facilitated by host CD4+ T cells, a subset normally considered unable to reject class I MHC-incompatible grafts. A combination of mAb to interleukins (IL)-4 and -10 antagonized the "permissive" effects of host CD4+ T cells, indicating a possible role for Th2-type immunoregulation that can act on CD8+ T cells in this form of transplantation tolerance. The fate of graft-reactive T cells was monitored using anti-clonotypic antibodies. It was observed that bone marrow engraftment then led to peripheral deletion of mAb-blockaded, clonotype+ CD8+ T cells.

Fc-Disabled Anti-Mouse CD40L Antibodies Retain Efficacy in Promoting Transplantation Tolerance

“…The stark reality, though, was that the original anti-human CD40L antibody (hu5c8) risks thrombosis. All current alternative antibodies have their own seeming limitations such as thrombogenicity (34,35) or reduced immunosuppressive efficacy relative to hu5c8 (36)(37)(38)(39)(40)(41) (42)(43)(44) but also in the mouse (17,18,43). Given this, how can the results presented here be reconciled with data suggesting that target cell depletion underlies anti-CD40L efficacy?…”

Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease

“…Donor DC2 may induce host T cells to produce IL-4 and IL-10, which suppress Th1 and cytotoxic responses, favoring engrafment. 35,36 Thus, the manipulation of DC subsets may be useful in stem cell therapy for the induction of tolerance to hematopoietic cells or solid organ allografts. It has been reported that DC2 might capture alloantigen and undergo maturation after transfer into the host.…”

Anergic T cells act as suppressor cellsin vitro andin vivo

“…Although inhibitory cytokines appear to contribute in some experimental models, with IL-10 playing a particularly important role [13,29], there are other circumstances in which no evidence could be obtained for cytokine-mediated regulation. The concept that anergic T cells could act as suppressor cells was first proposed over a decade ago [30].…”

“…The cytokines that have been implicated under these circumstances are interleukin (IL-) -4, IL-10, and TGF-g . Support for this hypothesis has been provided in some transplant systems [8][9][10][11][12][13], and in some models of autoimmune disease [5,14]. However, there are many situations in which regulatory cytokines do not appear to provide a satisfactory explanation for the observed tolerance [15,16].…”