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细胞共受体CD4和CD8的非消耗（ND）抗体（Ab）的短期疗程可以逆转新糖尿病NOD小鼠的糖尿病，并无限期地防止复发性高血糖。通过共受体治疗诱导缓解涉及两个关键事件。由于转运特性的改变，与ND aCD4和aCD8 Ab结合的T细胞可以快速和选择性地从胰岛和引流胰淋巴结（PLN）中清除。其次，胰岛驻留抗原呈递细胞上调TGFb1的表达。另一方面，缓解的维持是由pln驻留的Foxp3+Treg介导的，它们表现出增强的抑制功能。本研究的目标有两个方面：1)确定NOD小鼠中共受体治疗以胰岛/b细胞特异性方式诱导和维持缓解的机制；2)将这些发现扩展到人类T效应物和FOXP3+Treg。目的1侧重于共受体交联如何以组织特异性方式调节T细胞清除。我们将努力确定共受体交联是否会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TGFb1的事件，以及TGFb1在糖尿病缓解中的作用。最后，Aim 3将研究CD4交联对NOD小鼠Foxp3+Treg特性和功能的直接和间接影响。在胰岛病理人源化小鼠模型中，共同受体治疗是否也能诱导具有增强功能的不同的人类FOXP3+Treg库。总之，本研究将为ND aCD4和aCD8 Ab治疗的特异性和疗效调节机制提供新的见解，并更好地建立共同受体治疗治疗人类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.