An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus
An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus
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DOI：
10.1002/art.23428
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发表时间：
2008-05-01
影响因子：
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通讯作者：
Daikh, David I.
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文献类型：
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作者：
Bahjat, Frances Rena;Pine, Polly R.;Daikh, David I.
Objective.为了评估R788（一种口服生物可利用的脾酪氨酸激酶（Syk）依赖性信号传导的小分子抑制剂）是否可以通过抑制Fc受体（FcR）和B细胞受体信号传导来调节狼疮倾向（NZ B x NZW）F-1（NZ B/NZW）小鼠中的疾病。在疾病发作之前和之后向NZB/NZW小鼠施用R788。定期检查蛋白尿、血尿素氮水平和自身抗体滴度，并在长期治疗（24-34周）后评估总生存率和肾脏病理特征。在研究终止时评价各种脾T细胞和B细胞亚群的分布和免疫表型。用R788或Fc阻断抗体（抗CD 16/32）预处理的NZB/NZW小鼠的Arthus反应也被检查。当R788在疾病发作之前或之后给药时，它延迟了蛋白尿和氮质血症的发作，减少了肾脏病理和肾脏浸润，并显着延长了狼疮易感NZB/NZW小鼠的生存期;在整个研究中，自身抗体滴度受到的影响最小。在R788处理小鼠的脾脏中，表达高水平CD 44或CD 69的CD 4+活化T细胞数量的剂量依赖性减少是明显的。长期药物治疗后，观察到对每个脾脏表达CD 62配体的初始T细胞数量和总CD 8 + T细胞数量的影响极小。R788预处理导致NZB/NZW小鼠的Arthus反应降低，与FcR阻断抗体预处理小鼠的结果相似。我们证明了一种新的Syk选择性抑制剂可以预防肾脏疾病的发展，并治疗已建立的小鼠狼疮肾炎。这些数据表明，Syk抑制剂可能对人类狼疮和相关疾病具有治疗益处。
Objective. To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk)-dependent signaling, could modulate disease in lupus-prone (NZB x NZW)F-1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling.Methods. R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24-34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined.Results. When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody.Conclusion. We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders.