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The Novel JAK‐3 Inhibitor CP‐690550 Is a Potent Immunosuppressive Agent in Various Murine Models
Author(s) -
Kudlacz Elizabeth,
Perry Bret,
Sawyer Perry,
Conklyn Maryrose,
McCurdy Sandra,
Brissette William,
Flanagan and Mark,
Changelian Paul
Publication year - 2004
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1046/j.1600-6143.2003.00281.x
Subject(s) - medicine , pharmacology , cancer research
JAK‐3 has been shown to play a key role in cytokine signaling via γc, 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) (IC 50 = 91 n m ). 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 + TCRβ– 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.