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

• 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
• 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

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型糖尿病个体中正在进行的β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 的非消耗性 (ND) 抗体 (Ab) 的短期疗程可逆转新患糖尿病的 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。由于运输特性的改变，ND αCD4 和 αCD8 Ab 结合的 T 细胞会被快速、选择性地从胰岛和引流胰腺淋巴结 (PLN) 中清除。其次，胰岛驻留抗原呈递细胞上调 TGFβ1 表达。另一方面，缓解的维持是由 PLN 驻留的 Foxp3+Treg 介导的，其表现出增强的抑制功能。该提案的目标有两个：1) 明确 NOD 小鼠中共受体疗法以胰岛/β细胞特异性方式诱导和维持缓解的机制，2) 将这些发现扩展到人类 T 效应器和 FOXP3+Treg。目标 1 重点关注共受体交联​​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​​是否会类似地改变人类 T 细胞在体外以及人源化小鼠体内的运输特性。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，Aim 3将研究CD4交联对NOD小鼠中Foxp3+Treg的性质和功能的直接和间接影响。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，将在胰岛病理学人源化小鼠模型中进行测试。这项研究将为调节 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。