Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy

摘要/摘要 仍然需要足够强大的免疫疗法来抑制β细胞自身免疫并安全地预防和 临床治疗1型糖尿病(T1D)。这一需求在日益增长的 T1D在美国和世界范围内的发病率。我们之前曾报道过，一个短期的 T细胞辅受体CD_4和CD_8α特异性非耗竭(ND)抗体逆转糖尿病 大多数新发病的NOD小鼠，而且这种缓解是无限期的。自我耐受性在组织中重新建立- 具体方式和获得性免疫力不受影响。值得注意的是，最近的发现表明，新城疫抗体特异性 对于人类CD_4和CD_8，本课题组设计的α在人源化小鼠中表现出类似的耐受特性 模特们。正在进行的工作已经做出了令人兴奋的观察，即辅助受体治疗对中枢和 外周耐受性，涉及许多新的机制。因此，这项提案的目标是 明确胸腺和外周的辅受体治疗调节的分子和细胞事件 长期的组织特异性耐受。在目标1中，我们将研究辅受体治疗的机制 调节胸腺选择的效率。在AIM 2中，工作重点将是确定辅受体如何治疗 影响T细胞介导的外周免疫调节，以及抗自身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_8α抗体来测试辅受体治疗的体内效应 人源化小鼠胸腺细胞发育和外周免疫耐受的研究。通过推荐的 研究将为该方法的成功和安全的临床应用建立治疗参数。 重要的是，辅受体疗法不仅适用于T1D的预防和治疗，而且还适用于： 一)其他T细胞介导的自身免疫性疾病和病理，以及二)诱导移植 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.