The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+cell numbers in cynomolgus monkey blood following chronic oral dosing
The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+cell numbers in cynomolgus monkey blood following chronic oral dosing
复制标题
DOI：
10.1189/jlb.0504282
复制
发表时间：
2004-12-01
影响因子：
5.5
通讯作者：
Kudlacz, E
中科院分区：
文献类型：
--
作者：
Conklyn, M;Andresen, C;Kudlacz, E
Janus激酶3（JAK 3）是一种与常见γ链相关的细胞质酪氨酸激酶，是白细胞介素（IL）-2家族细胞因子受体（包括IL-4、-7、-9、-15和-21）的组成部分。CP-690550是一种JAK 3抑制剂，具有免疫抑制特性，正在开发用于移植。我们评价了CP-690550长期（3周）经口给药后食蟹猴血液中循环淋巴细胞亚群的变化。自然杀伤细胞（NK）和CD 8 + T细胞数量以剂量和时间依赖性方式减少;后者是对记忆亚群的主要影响。CD 4 + T和B细胞数量分别未受影响或略有增加。NK细胞数量减少了约80%（相比之下，溶剂处理动物为35%），并在停止处理后3周内恢复至基线水平。CD 8 + T细胞最多下降43%（与溶剂处理动物的25%相比），但在末次给药后2周内显著反弹（300%）。尽管CP-690550未导致CD 4 + T细胞数量减少，但这些细胞在治疗停止后2周内也增加（225%）。IL-15对维持这些细胞类型的稳态很重要，CP-690550抑制NK细胞[抑制浓度50%（IC 50）=48.0+/-8.4 nM]和CD 8 + T细胞（IC 50 =16.2+/-1.5 nM）中IL-15诱导的CD 69表达。
Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common gamma 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 similar to80% (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% (IC50)=48.0+/-8.4 nM] and CD8+ T cells (IC50 =16.2+/-1.5 nM).