The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models

JAK- 3 has been shown to play a key role in cytokine signaling via gammac, e. g. IL- 2, 4, 7, 9, 15, 21. The current study describes the immunosuppressive effects of CP- 690550, a novel, small molecule inhibitor of JAK3, in various murine models. In vitro, CP- 690550 effectively inhibited a murine mixed lymphocyte reaction (MLR) (IC50 = 91 nM). Mice chronically dosed with CP- 690550 (1.5- 15 mg/ kg/ day) demonstrated dose- and time- dependent alterations in lymphocyte subsets when examined by flow cytometry. The most dramatic change observed was a 96% reduction in splenic NK1.1 + TCRbeta - cell numbers following 21 days of treatment. Delayed- type hypersensitivity (DTH) responses in sensitized mice were reduced in a dose- dependent manner following treatment with the JAK- 3 inhibitor (1.87- 30 mg/ kg, s. c.). Extended survival of neonatal Balb/ c hearts implanted into the ear pinna of MHC mismatched C3H/ HEN mice was observed with CP- 690550 monotherapy (10- 30 mg/ kg/ day), but improved upon combination with cyclosporin (10 mg/ kg/ day). These data support the participation of JAK- 3 in various lymphocyte homeostatic functions in mature mice. Furthermore, the ability of CP- 690550 to extend cardiac allograft survival in murine models suggests it may afford a new treatment for prevention of transplant rejection.