In vivo immunosuppression by targeting a novel protease receptor.

MEMBRANE receptors for blood proteases govern the clotting 1 and fibrinolytic 2 cascades, regulate signal transduction 3,4 , and control the growth of mesenchymal cells 5,6 . Despite their importance in the development of vascular injury 7 , it is unclear whether these mechanisms participate in the generation of an immune response. Here we report that targeting a factor Xa receptor, designated effector cell protease receptor-1 (EPR-1), with antisense oligonucleotide or with a monoclonal antibody (mAb 2E1) 8 inhibited CD3/T-cell receptor-dependent lymphocyte proliferation. Immunosuppression was mediated by abolishing cytokine production and down-modulating membrane expression of the interleukin (IL)-2 receptor. In vivo administration of mAb 2E1 to severe-combined-immunodeficient mice injected with human peripheral blood leukocytes suppressed production of human immunoglobulin, abolished graft-versus-host disease, and protected these xenochimaeric mice from Epstein-Barr-virus-induced human lymphoproliferative disease. These observations indicate a new role for protease receptors in the regulation of the immune response, and identify a potential target for therapeutic immunosuppression in humans.