Prolonged allograft survival in cynomolgus monkeys treated with a monoclonal antibody to the human type I interferon receptor and low doses of cyclosporine

A monoclonal antibody (mAb) directed against the extracellular domain of the IFNAR1 chain of the human interferon-alpha (IFN-alpha) receptor (IFN-alpha R), 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-alpha R 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-alpha R mAb were not detected in the serum of any of the animals treated with the anti-IFN-alpha R mAb either alone or together with cyclosporine, The anti-IFN-alpha R 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-alpha antagonist together with a subeffective dose of cyclosporine, may have important implications for the therapy of human allograft rejection.