抗白细胞介素-7 受体-α通过调节效应 T 细胞功能逆转非肥胖型糖尿病小鼠的 1 型糖尿病。
Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.
机构信息
Rinat, Pfizer Inc, South San Francisco, CA 94080, USA.
出版信息
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12674-9. doi: 10.1073/pnas.1203795109. Epub 2012 Jun 25.
Abstract
Genetic variation in the IL-7 receptor-α (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ-producing CD4(+) (T(H)1) and IFN-γ-producing CD8(+) T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.
摘要
白细胞介素 7 受体-α（IL-7R）基因的遗传变异与人类 1 型糖尿病（T1D）的易感性相关。在这里，我们研究了 IL-7Rα 抗体在 T1D 小鼠模型中的治疗效果和机制。IL-7Rα 抗体在仅注射两到三次后，可诱导新发病的糖尿病小鼠产生持久、完全缓解。IL-7 增加，而 IL-7Rα 抗体治疗减少 IFN-γ 产生的 CD4+（T(H)1）和 IFN-γ 产生的 CD8+T 细胞。相反，IL-7 减少，而 IL-7Rα 抗体增强效应 T 细胞中程序性死亡受体 1（PD-1）的抑制性受体表达。程序性死亡受体 1 阻断逆转了 IL-7Rα 抗体治疗介导的免疫耐受。此外，IL-7Rα 抗体治疗增加了调节性 T 细胞的频率，而不影响其抑制活性。IL-7Rα 抗体治疗的持久疗效和多效性耐受机制提示了一种独特的 T1D 疾病修饰方法。
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