Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy

总结/摘要 仍然需要足够稳健的免疫疗法来抑制β细胞自身免疫并安全地预防和治疗β细胞自身免疫。 1型糖尿病（T1 D）的治疗面对日益增长的 美国和世界范围内的T1 D发病率。我们之前报道过， T细胞辅助受体CD 4和CD 8 α特异性非消耗性（ND）抗体（Ab）逆转糖尿病， 大多数新发NOD小鼠，并且缓解是无限期的。在组织中重新建立自我耐受性- 特异性方式和获得性免疫不受影响。值得注意的是，最近的研究结果表明， 本研究组设计的人CD 4和CD 8 α在人源化小鼠中表现出相似的致耐受性 模型正在进行的工作已经取得了令人兴奋的观察结果，即辅助受体治疗既影响中枢神经系统， 外周耐受，涉及一些新的机制。因此，本提案的目标是 定义胸腺和外周中由辅助受体治疗调节的分子和细胞事件， 长期组织特异性耐受性。在AIM 1中，我们将研究辅助受体治疗 调节胸腺选择的效率。在AIM 2中，工作将集中在确定辅助受体治疗如何 影响T细胞介导的外周免疫调节和抗自身T细胞的致病性。在这两个目标中， 实验将利用我们的ND抗人CD 4和CD 8 α Ab来测试辅助受体治疗的体内效应 对人源化小鼠胸腺细胞发育和外周耐受性的影响。通过拟议的 研究将确定该方法成功和安全临床应用的治疗参数。 重要的是，辅助受体疗法不仅适用于预防和治疗T1 D，还适用于： i）其他T细胞介导的自身免疫疾病和病理，以及ii）移植的诱导 宽容

SUMMARY/ABSTRACT Still needed are immunotherapies sufficiently robust to suppress β cell autoimmunity and safely prevent and treat type 1 diabetes (T1D) in the clinic. This need is becoming more urgent in the face of an increasing incidence of T1D in the United States and world-wide. We previously reported that a short-course of nondepleting (ND) antibodies (Ab) specific for the T cell coreceptors CD4 and CD8α reverses diabetes in the majority of new onset NOD mice, and that remission is indefinite. Self-tolerance is reestablished in a tissue- specific manner and acquired immunity is unaffected. Notably, recent findings demonstrate that ND Ab specific for human CD4 and CD8α engineered by our group exhibit similar tolerogenic properties in humanized mouse models. Ongoing work has made the exciting observation that coreceptor therapy impacts both central and peripheral tolerance, involving a number of novel mechanisms. Accordingly, the goal of this proposal is to define the molecular and cellular events regulated by coreceptor therapy in the thymus and periphery that drive long-term tissue-specific tolerance. In AIM 1, we will investigate the mechanisms by which coreceptor therapy regulates the efficiency of thymic selection. In AIM 2, work will focus on determining how coreceptor therapy influences T cell-mediated peripheral immunoregulation, and the pathogenicity of anti-self T cells. In both Aims, experiments will exploit our ND anti-human CD4 and CD8α Ab to test the in vivo effects of coreceptor therapy on thymocyte development and peripheral tolerance in humanized mice. Insight gained via the proposed studies will establish treatment parameters for successful and safe clinical application of the approach. Importantly, coreceptor therapy will be applicable not only for the prevention and treatment of T1D, but also for: i) other T cell-mediated autoimmune diseases and pathologies, as well as ii) induction of transplantation tolerance.