Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates
Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates
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DOI：
10.1097/01.tp.0000157117.30290.6f
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发表时间：
2005-04-15
期刊：
影响因子：
6.2
通讯作者：
Morris, RE
中科院分区：
文献类型：
--
作者：
Borie, DC;Changelian, PS;Morris, RE
背景Janus激酶3（JAK 3）使用共同链（γ c）介导来自细胞因子受体的信号转导。由于编码γ c或JAK 3的基因突变导致免疫缺陷，我们研究了合理设计的JAK 3抑制剂CP-690，550预防非人灵长类动物肾移植排斥反应的潜力。在混合白细胞反应不匹配、ABO血型匹配的食蟹猴之间进行维持生命的肾移植。用CP-690，550（n = 18）或其载体（对照，n = 3）处理动物，并在第90天或更早的时间（如果存在同种异体移植物排斥）实施安乐死。用CP-690，550处理的动物的平均存活时间（平均值的+/-标准误差）（53 +/- 7天）显著长于对照动物（7 +/- 1天，P = 0.0003），并且与药物暴露呈正相关（r = 0.79，P < 0.01）。在90天时对4只给药动物处以安乐死，最终病理学检查时肾功能正常，排斥反应程度较低。在治疗动物中，排斥反应的发生显著延迟（移植后46 +/-7天vs.对照组7 +/-1天，P = 0.0003）。在高暴露动物中观察到持续性贫血、多瘤病毒样肾炎（n = 2）和尿碳酸钙沉积（n = 3）。在给药动物中，自然杀伤细胞和CD 4（+）和CD 8（+）T细胞数量显著减少。血糖、血脂水平和动脉血压在治疗动物的正常范围内，并且没有显示出癌症。CP-690，550是第一个报道的JAK 3抑制剂，在非人灵长类动物同种异体移植的临床前模型中结合了疗效和良好的耐受性，因此在人类中具有有趣的免疫抑制潜力。
Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gamma c). Because mutations in genes encoding gamma c or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates.Methods. Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection.Results. Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P = 0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4(+) and CD8(+) T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated.Conclusions. CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.