Role of the type I interferons in allograft rejection

Type I interferons are potent immuno-modulatory cytokines that enhance expression of the major histocompatibility complex (MHC) class I antigens, T-cell cytotoxicity, and natural killer (NK) cell activity, all of which are implicated in graft rejection. A monoclonal antibody (mAb) directed against the extracellular domain of the human interferon gamma (IFN-gamma) receptor (IFN-alpha R), which inhibits both the binding and biological activity of all the type I IFNs tested, exerted a dose-dependent inhibition of the mixed lymphocyte reaction and induced permanent survival of skin allografts in MHC-divergent Cynomologus monkeys treated with a subeffective dose of cyclosporin A. Marked differences were observed in the composition of T lymphocyte subpopulations in anti-IFN-alpha R mAb-treated animals relative to the various control groups. Skin biopsies from animals treated with anti-IFN-R Mab + cyclosporin A revealed very low levels of MHC class I and class II antigen expression and the absence of histological signs of rejection, whereas skin biopsies from control animals exhibited high levels of MHC antigen expression and the histological signs of acute rejection, including a pronounced lymphocytic infiltrate, edema, and necrosis. No monkey antibodies (IgG) to the mouse anti-human IFN-alpha R mAb were detected in the serum of any of the animals treated with the anti-IFN-alpha R mAb either alone or together with cyclosporin A. Treatment of lethally irradiated Cynomologus monkeys with the anti-IFN-alpha R mAb together with a subeffective dose of cyclosporin A was also found to markedly enhance the survival of animals grafted with allogeneic bone marrow cells from donors differing in both MHC class I and class II antigens. These results show that selective and lasting immunosuppression can be obtained by the short-term administration of an IFN-alpha antagonist together with a subeffective dose of cyclosporin A, and may have important implications for the therapy of human allograft rejection.