Islet-Specific Tolerance Induced by T Cell Co-Receptor Therapy in Type 1 Diabetes

描述（由申请人提供）：仍然需要足够稳健的免疫疗法，以长期抑制1型糖尿病个体中正在进行的B细胞自身免疫，并逆转临床糖尿病。我们发现，短期的非消耗性（ND）抗体（Ab）的T细胞共受体CD 4和CD 8特异性逆转糖尿病在新的糖尿病NOD小鼠，并防止复发性高血糖症无限期。通过共受体治疗诱导缓解涉及两个关键事件。由于改变的运输特性，由ND aCD 4和aCD 8 Ab结合的T细胞被快速且选择性地从胰岛和引流胰腺淋巴结（PLN）清除。第二，TGF β 1的表达被胰岛常驻抗原呈递细胞上调。另一方面，缓解的维持是由PLN驻留Foxp 3 +Treg介导的，其表现出增强的抑制功能。该建议的目标是2-倍：1）确定共受体治疗在NOD小鼠中以胰岛/B细胞特异性方式诱导和维持缓解的机制，和2）将这些发现扩展到人T效应子和FOXP 3 +Treg。目的1关注共受体交联如何以组织特异性方式调节T细胞清除。将努力确定共受体交联是否类似地改变体外以及人源化小鼠体内人T细胞的运输特性。目的2研究促进胰岛特异性诱导TGF β 1的事件，以及TGF β 1在糖尿病缓解中的作用。最后，目的3将研究CD 4交联对NOD小鼠Foxp 3 +Treg的性质和功能的直接和间接影响。将在胰岛病理学的人源化小鼠模型中测试共受体疗法是否也诱导具有增强的体内功能的人FOXP 3 +Treg的不同库。总之，本研究将为调节ND aCD 4和aCD 8 Ab治疗的特异性和疗效的机制提供新的见解，此外还将更好地建立共受体治疗用于治疗人T细胞介导的病理的翻译潜力。

DESCRIPTION (provided by applicant): There continues to be a need for immunotherapies sufficiently robust to suppress ongoing B cell autoimmunity in type 1 diabetic individuals long-term, and reverse clinical diabetes. We found that a short course of nondepleting (ND) antibodies (Ab) specific for the T cell co-receptors CD4 and CD8 reverses diabetes in newly diabetic NOD mice, and prevents recurrent hyperglycemia indefinitely. Induction of remission by co-receptor therapy involves two key events. T cells bound by the ND aCD4 and aCD8 Ab are rapidly and selectively purged from the islets and draining pancreatic lymph nodes (PLN) due to altered trafficking properties. Secondly, TGFb1 expression is up-regulated by islet resident antigen presenting cells. On the other hand, maintenance of remission is mediated by PLN-resident Foxp3+Treg, which exhibit enhanced suppressor function. The goal of this proposal is 2-fold: 1) define the mechanisms by which co-receptor therapy induces and maintains remission in an islet/b cell-specific manner in NOD mice, and 2) extend these findings to human T effectors and FOXP3+Treg. Aim 1 focuses on how co-receptor crosslinking regulates T cell purging in a tissue-specific manner. Efforts will determine if co-receptor crosslinking similarly alters the trafficking properties of human T cells in vitro, as well as in vivo in humanized mice. Aim 2 investigates the events that promote islet- specific induction of TGFb1, and the role TGFb1 plays in diabetes remission. Finally, Aim 3 will study the direct and indirect effects of CD4 crosslinking on the properties and function of Foxp3+Treg in NOD mice. Whether co-receptor therapy also induces a distinct pool of human FOXP3+Treg with enhanced function in vivo will be tested in a humanized mouse model of islet pathology. Together this study will provide novel insight into mechanisms regulating the specificity and efficacy of ND aCD4 and aCD8 Ab treatment, in addition to better establishing the translational potential of co-receptor therapy for the treatment of human T cell-mediated pathologies.