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 anti gens, 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 al pha (IFN-alpha) receptor (IFN-alpha R), which inhibits both the bindin g and biological activity of all the type I IFNs tested, exerted a dos e-dependent inhibition of the mixed lymphocyte reaction and induced pe rmanent survival of skin allografts in MHC-divergent Cynomologus monke ys treated with a subeffective dose of cyclosporin A. Marked differenc es were observed in the composition of T lymphocyte subpopulations in anti-IFN-alpha R mAb-treated animals relative to the various control g roups. Skin biopsies from animals treated with anti-IFN-R Mab + cyclos porin A revealed very low levels of MHC class I and class II antigen e xpression and the absence of histological signs of rejection, whereas skin biopsies from control animals exhibited high levels of MHC antige n expression and the histological signs of acute rejection, including a pronounced lymphocytic infiltrate, edema, and necrosis. No monkey an tibodies (IgG) to the mouse anti-human IFN-alpha R mAb were detected i n the serum of any of the animals treated with the anti-IFN-alpha R mA b either alone or together with cyclosporin A. Treatment of lethally i rradiated Cynomologus monkeys with the anti-IFN-alpha R mAb together w ith a subeffective dose of cyclosporin A was also found to markedly en hance the survival of animals grafted with allogeneic bone marrow cell s from donors differing in both MHC class I and class II antigens. The se results show that selective and lasting immunosuppression can be ob tained by the short-term administration of an IFN-alpha antagonist tog ether with a subeffective dose of cyclosporin A, and may have importan t implications for the therapy of human allograft rejection.