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 JAK-3, 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.
Kudlacz
Elizabeth
E
Department of Immunology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. elizabeth_m_kudlacz@groton.pfizer.com
Perry
Bret
B
Sawyer
Perry
P
Conklyn
Maryrose
M
McCurdy
Sandra
S
Brissette
William
W
Flanagan And
Mark
M
Changelian
Paul
P
D000818:Animals; D002469:Cell Separation; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D053616:Janus Kinase 3; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D013997:Time Factors; D014180:Transplantation
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3