Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models
Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models
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DOI：
10.4049/jimmunol.1700192
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发表时间：
2017-09-01
影响因子：
4.4
通讯作者：
Maeyama, Kazutaka
中科院分区：
文献类型：
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作者：
Liu, Shuang;Hasegawa, Hitoshi;Maeyama, Kazutaka
钙库操纵的钙释放激活的钙通道（CRAC）参与类风湿性关节炎（RA）的发病机制，并已被研究为RA管理的治疗靶点。我们研究了CRAC抑制剂，包括中和抗体（hCRACM 1-IgG）和YM-58483在治疗RA中的疗效和安全性。患者来源的T细胞和B细胞活性被hCRACM 1-IgG以及YM-58483抑制。系统常数，s.c.输注的CRAC抑制剂在人-NOD/SCID异种移植RA模型中显示出抗炎活性以及对软骨和骨破坏的保护作用。hCRACM 1-IgG似乎对于全身应用是安全的，而YM-58483在异种移植小鼠中显示肝和肾毒性。用两种CRAC抑制剂治疗也引起异种移植小鼠的高血糖症。这些结果表明hCRACM 1-IgG和YM-58483作为抗免疫剂用于治疗RA的潜力。然而，在临床使用之前，应解决一些安全性问题并优化应用方法。
Store-operated Ca2+ release-activated Ca2+ (CRAC) channels are involved in the pathogenesis of rheumatoid arthritis (RA) and have been studied as therapeutic targets in the management of RA. We investigated the efficacy and safety of CRAC inhibitors, including a neutralizing Ab (hCRACM1-IgG) and YM-58483, in the treatment of RA. Patient-derived T cell and B cell activity was suppressed by hCRACM1-IgG as well as YM-58483. Systemically constant, s.c. infused CRAC inhibitors showed anti-inflammatory activity in a human-NOD/SCID xenograft RA model as well as protective effects against the destruction of cartilage and bone. hCRACM1-IgG appeared to be safe for systemic application, whereas YM-58483 showed hepatic and renal toxicity in xenograft mice. Treatment with both CRAC inhibitors also caused hyperglycemia in xenograft mice. These results indicate the potential of hCRACM1-IgG and YM-58483 as anti-immunological agents for the treatment of RA. However, some safety issues should be addressed and application methods should be optimized prior to their clinical use.