Sunao Imada

Effects of AS2541019, a novel selective PI3Kδ inhibitor, on antibody production and hamster to rat xenotransplantation

&NA; B cell‐mediated antibodies play a critical role in protecting the body from infections; however, excessive antibody production is involved in the pathogenesis of autoimmune diseases and transplanted organ rejection. Regulation of antibody production is therefore crucial for overcoming these complications. Phosphatidylinositol‐3‐kinase p110&dgr; (PI3K&dgr;), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation and proliferation, with a small molecule PI3K&dgr; inhibitor having been approved for the treatment of B cell lymphoma. However, the effect of PI3K&dgr; inhibitors on B cell‐mediated antibody production has not been clearly elucidated. In this study, we investigated the effect of the selective PI3K&dgr; inhibitor, AS2541019, on B cell immunity and antibody production. Our results show that AS2541019 effectively prevented B cell activation and proliferation in vitro, and that oral administration of AS2541019 resulted in significant inhibition of both T‐dependent and T‐independent de novo antibody production in peripheral blood. Further, in a hamster to rat concordant xenotransplant model, AS2541019 significantly prolonged graft survival time by inhibiting xenoreactive antibody production. Therefore, our study demonstrates that the selective PI3K&dgr; inhibitor AS2541019 inhibits antibody production through potent inhibitory effects on B cell activation, and can protect against organ dysfunction.