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

T 细胞辅助受体治疗在 1 型糖尿病中诱导的胰岛特异性耐受

基本信息

批准号：
8725412
负责人：
Roland M Tisch
金额：
$ 33.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725412
关键词：
Antibodies Antigen-Presenting Cells Apoptosis Apoptotic Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Beta Cell Binding CD3 Antigens CD4 Antigens CD8B1 gene Cell physiology Cells Child Clinic Clinical Clinical Research Cues Cyclosporins Diabetes Mellitus Disease remission Dose-Limiting Drug toxicity Event Exhibits Fc Receptor Goals Human Hyperglycemia Immunotherapy In Vitro Inbred NOD Mice Individual Inflammation Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Maintenance Mediating Modeling Mus Nature Pancreas Pathology Play Property Recurrence Regulatory T-Lymphocyte Remission Induction Role Specificity T-Cell Depletion T-Lymphocyte Testing Therapeutic Time Tissues Work YARS gene crosslink diabetic diabetic patient in vivo insight insulin dependent diabetes mellitus onset islet lymph nodes mouse model novel prevent public health relevance purge receptor receptor binding response trafficking type I diabetic

项目摘要

DESCRIPTION (provided by applicant): There continues to be a need for immunotherapies sufficiently robust to suppress ongoing β 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 αCD4 and αCD8 Ab are rapidly and selectively purged from the islets and draining pancreatic lymph nodes (PLN) due to altered trafficking properties. Secondly, TGFβ1 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/β 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 TGFβ1, and the role TGFβ1 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 αCD4 and αCD8 Ab treatment, in addition to better establishing the translational potential of co-receptor therapy for the treatment of human T cell-mediated pathologies.

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 型糖尿病个体中持续的 β 细胞自身免疫，并逆转临床糖尿病。 Ab) 对 T 细胞辅助受体 CD4 和 CD8 具有特异性，可以逆转新患糖尿病的 NOD 小鼠的糖尿病，并无限期地防止高血糖复发，从而诱导缓解。共受体治疗涉及两个关键事件：由于运输特性的改变，ND αCD4 和 αCD8 Ab 结合的 T 细胞被快速、选择性地从胰岛和引流胰腺淋巴结 (PLN) 中清除。另一方面，缓解的维持是由 PLN 驻留的 Foxp3+Treg 介导的，该细胞表现出增强的抑制功能。 1) 定义了 NOD 小鼠中协同受体疗法以胰岛/β 细胞特异性方式诱导和维持缓解的机制，以及 2) 将这些发现扩展到人类 T 效应器和 FOXP3+Treg 的重点是如何协同受体治疗。受体交联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类似地改变体外和体内人类 T 细胞的运输特性。目标 2 研究促进胰岛特异性诱导 TGFβ1 的事件，以及 TGFβ1 在糖尿病缓解中的作用。最后，目标 3 将研究 CD4 交联对 Foxp3+Treg 特性和功能的直接和间接影响。在 NOD 小鼠中，共受体疗法是否也能诱导体内功能增强的独特人类 FOXP3+Treg 库，将在人源化小鼠胰岛病理模型中进行测试。该研究将为调节 ND αCD4 和 αCD8 Ab 治疗的特异性和功效的机制提供新的见解，此外还可以更好地确定共受体疗法在治疗人类 T 细胞介导的病理学方面的转化潜力。