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The JAK3 inhibitor CP‐690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing
Author(s) -
Conklyn Maryrose,
Andresen Catharine,
Changelian Paul,
Kudlacz Elizabeth
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0504282
Subject(s) - cd8 , biology , janus kinase 3 , cytotoxic t cell , cytokine , immunology , pharmacology , t cell , receptor , interleukin 21 , natural killer cell , endocrinology , medicine , immune system , in vitro , biochemistry
Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common γ chain, an integral component of cytokine receptors of the interleukin (IL)‐2 family, including IL‐4, ‐7, ‐9, ‐15, and ‐21. CP‐690550 is a JAK3 inhibitor with immunosuppressive properties under development for transplantation. We evaluated alterations in circulating lymphocyte subsets in cynomolgus monkey blood following chronic (3‐week), oral CP‐690550 administration. Natural killer (NK) and CD8+ T cell numbers were reduced in a dose‐ and time‐dependent manner; the latter was a primary effect on memory subsets. CD4+ T and B cell numbers were unaffected or slightly increased, respectively. NK cell numbers were reduced ∼80% (vs. 35% in vehicle‐treated animals) and returned to baseline levels within 3 weeks following treatment cessation. CD8+ T cells declined by a maximum 43% (vs. 25% for vehicle‐treated animals) but rebounded significantly (300%) within 2 weeks after the last dose. Although CP‐690550 did not result in reduction of CD4+ T cell number, these cells also increased (225%) within 2 weeks of treatment cessation. IL‐15 is important for maintaining homeostasis of these cell types, and CP‐690550 inhibited IL‐15‐induced CD69 expression in NK cells [inhibitory concentration 50% (IC 50 )=48.0±8.4 nM] and CD8+ T cells (IC 50 =16.2±1.5 nM).