IN-VIVO IMMUNOSUPPRESSION BY TARGETING A NOVEL PROTEASE RECEPTOR

MEMBRANE receptors for blood proteases govern the clotting(1) and fibr inolytic(2) cascades, regulate signal transduction(3,4), and control t he growth of mesenchymal cells(5,6). Despite their importance in the d evelopment of vascular injury(7), it is unclear whether these mechanis ms participate in the generation of an immune response. Here we report that targeting a factor Xa receptor, designated effector cell proteas e receptor-1 (EPR-1), with antisense oligonucleotide or with a monoclo nal antibody (mAb 2E1)(8) inhibited CD3/T-cell receptor-dependent lymp hocyte proliferation. Immunosuppression was mediated by abolishing cyt okine production and down-modulating membrane expression of the interl eukin (IL)-2 receptor. In vivo administration of mAb 2E1 to severe-com bined-immunodeficient mice injected with human peripheral blood leukoc ytes suppressed production of human immunoglobulin, abolished graft-ve rsus-host disease, and protected these xenochimaeric mice from Epstein -Barr-virus-induced human lymphoproliferative disease. These observati ons indicate a new role for protease receptors in the regulation of th e immune response, and identify a potential target for therapeutic imm unosuppression in humans.