Prolonged Allograft Survival in Cynomolgus Monkeys Treated with a Monoclonal Antibody to the Human Type I Interferon Receptor and Low Doses of Cyclosporine

Abstract

A monoclonal antibody (mAb) directed against the extracellular domain of the IFNAR1 chain of the human interferon-α (IFN-α) receptor (IFN-αR), which inhibits activation of the Jak-Stat signal transduction pathway, administered together with a subeffective dose of cyclosporine induced prolonged survival of skin allografts in major histocompatibility complex (MHC) divergent cynomolgus monkeys. Skin biopsies from animals treated with anti-IFN-αR mAb and cyclosporine revealed very low levels of MHC class I and class II antigen expression and the absence of histologic signs of rejection. Monkey antibodies (IgG) to the mouse antihuman IFN-αR mAb were not detected in the serum of any of the animals treated with the anti-IFN-αR mAb either alone or together with cyclosporine. The anti-IFN-αR mAb abrogated activation of the Jak-Stat signal transduction pathway in IFN-treated cells. These results, which show that selective and long-lasting immunosuppression can be obtained by short-term administration of an IFN-α antagonist together with a subeffective dose of cyclosporine, may have important implications for the therapy of human allograft rejection.