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

描述(申请人提供)：仍然需要足够强大的免疫疗法来长期抑制1型糖尿病患者正在进行的B细胞自身免疫，并逆转临床糖尿病。我们发现，针对T细胞辅助受体CD4和CD8的短程非耗竭(ND)抗体(Ab)可以逆转新发糖尿病NOD小鼠的糖尿病，并无限期防止反复发生的高血糖。通过联合受体治疗诱导缓解涉及两个关键事件。由于运输特性的改变，与ND、aCD4和aCD8Ab结合的T细胞可以迅速和选择性地从胰岛和引流的胰腺淋巴结(PLN)中清除。其次，TGFb1的表达受胰岛常驻抗原提呈细胞的上调。另一方面，缓解的维持是由PLN驻留的Foxp3 Treg介导的，它显示出增强的抑制功能。这项建议的目标有两个：1)确定共受体治疗以胰岛/b细胞特异性方式诱导和维持NOD小鼠缓解的机制，2)将这些发现扩展到人类T效应器和FOXP3 Treg。目的1重点研究共受体交联物如何以组织特异性的方式调节T细胞的清除。将努力确定共受体交联物是否在体外以及在人源化小鼠体内类似地改变人类T细胞的运输特性。目的2研究促进胰岛特异性诱导转化生长因子b1的事件，以及转化生长因子b1在糖尿病缓解中的作用。最后，目标3将研究在NOD小鼠中，CD4交联物对Foxp3 Treg特性和功能的直接和间接影响。联合受体治疗是否也能在体内诱导具有增强功能的独特的人FOXP3 Treg池，将在人源化的胰岛病理小鼠模型中进行测试。总之，这项研究将为调节ND aCD4和aCD8Ab治疗的特异性和有效性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类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.