Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy

共受体治疗对胸腺和外周自身反应性 T 细胞的调节

基本信息

批准号：
10623181
负责人：
Roland M Tisch
金额：
$ 38.88万
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：
2019
资助国家：
美国
起止时间：
2019-05-25 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623181
关键词：
Affect Affinity Antibodies Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmunity Automobile Driving Avidity Beta Cell Binding CD4 Antigens CD8B1 gene Clinic Defect Development Diabetes Mellitus Disease remission Emigrant Engineering Event Exhibits FOXO1A gene FOXP3 gene Genetic Transcription Goals Human IgG4 Immunotherapy Impairment Inbred NOD Mice Incidence Infiltration Insulin-Dependent Diabetes Mellitus Mediating Modeling Molecular Mus Pancreas Pathogenicity Pathology Pathway interactions Peripheral Phenotype Prevention Property Regulation Regulatory T-Lymphocyte Reporting Residual state Self Tolerance Signal Transduction T cell regulation T-Lymphocyte Testing Therapeutic Thymocyte Development Thymus Gland Tissues Transplantation Tolerance Treatment Efficacy Tumor Debulking United States Work acquired immunity autoreactive T cell autoreactivity cell type central tolerance clinical application experimental study humanized mouse immunoregulation in vivo in vivo evaluation insight islet lymph nodes mouse model novel peripheral tolerance preservation prevent receptor thymocyte trafficking translational potential

项目摘要

SUMMARY/ABSTRACT Still needed are immunotherapies sufficiently robust to suppress β cell autoimmunity and safely prevent and treat type 1 diabetes (T1D) in the clinic. This need is becoming more urgent in the face of an increasing incidence of T1D in the United States and world-wide. We previously reported that a short-course of nondepleting (ND) antibodies (Ab) specific for the T cell coreceptors CD4 and CD8α reverses diabetes in the majority of new onset NOD mice, and that remission is indefinite. Self-tolerance is reestablished in a tissue- specific manner and acquired immunity is unaffected. Notably, recent findings demonstrate that ND Ab specific for human CD4 and CD8α engineered by our group exhibit similar tolerogenic properties in humanized mouse models. Ongoing work has made the exciting observation that coreceptor therapy impacts both central and peripheral tolerance, involving a number of novel mechanisms. Accordingly, the goal of this proposal is to define the molecular and cellular events regulated by coreceptor therapy in the thymus and periphery that drive long-term tissue-specific tolerance. In AIM 1, we will investigate the mechanisms by which coreceptor therapy regulates the efficiency of thymic selection. In AIM 2, work will focus on determining how coreceptor therapy influences T cell-mediated peripheral immunoregulation, and the pathogenicity of anti-self T cells. In both Aims, experiments will exploit our ND anti-human CD4 and CD8α Ab to test the in vivo effects of coreceptor therapy on thymocyte development and peripheral tolerance in humanized mice. Insight gained via the proposed studies will establish treatment parameters for successful and safe clinical application of the approach. Importantly, coreceptor therapy will be applicable not only for the prevention and treatment of T1D, but also for: i) other T cell-mediated autoimmune diseases and pathologies, as well as ii) induction of transplantation tolerance.

摘要/摘要仍然需要足够强大的免疫疗法来抑制 β 细胞自身免疫并安全地预防和治疗随着临床治疗 1 型糖尿病 (T1D) 的增加，这一需求变得更加迫切。我们之前报道过，T1D 在美国和世界范围内的发病率是短期的。 T 细胞辅助受体 CD4 和 CD8α 特异性的非消耗 (ND) 抗体 (Ab) 可逆转糖尿病大多数新发病的 NOD 小鼠的自我耐受性是无限期地在组织中重新建立的。值得注意的是，最近的研究结果表明 ND Ab 具有特异性。我们团队设计的人类 CD4 和 CD8α 在人源化小鼠中表现出相似的耐受性正在进行的工作已经令人兴奋地观察到，辅助受体疗法对中枢和中枢神经系统都有影响。外周耐受性，涉及许多新颖的机制。因此，该提案的目标是定义由胸腺和外周共受体治疗调节的分子和细胞事件，这些事件驱动在 AIM 1 中，我们将研究辅助受体治疗的机制。在 AIM 2 中，工作重点是确定辅助受体治疗的方式。影响 T 细胞介导的外周免疫调节以及抗自身 T 细胞的致病性。实验将利用我们的 ND 抗人 CD4 和 CD8α 抗体来测试辅助受体疗法的体内效果通过提议获得的关于人源化小鼠胸腺细胞发育和外周耐受性的见解。研究将为该方法的成功和安全临床应用建立治疗参数。重要的是，辅助受体疗法不仅适用于预防和治疗 T1D，还适用于： i) 其他 T 细胞介导的自身免疫性疾病和病理，以及 ii) 移植诱导宽容。