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：
10395438
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395438
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 Eragrostis 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 base 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 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/摘要仍然需要免疫疗法足以抑制自身免疫性并安全预防和治疗诊所中的1型糖尿病（T1D）。面对越来越多的需求，这种需求变得越来越紧迫 T1D在美国和全球的发病率。我们以前报道过对T细胞共肽CD4和CD8α特异性的非非排气（ND）抗体（AB）逆转糖尿病大多数新的发病小鼠，这种缓解是无限的。在组织中重新建立自耐特定的方式和获得的免疫力不受影响。值得注意的是，最近的发现表明ND AB特异性对于由我们组设计的人CD4和CD8α，在人源性小鼠中暴露了相似的耐受性特性型号。正在进行的工作使令人兴奋的观察结果是，共素治疗会影响中心和外围耐受性，涉及多种新型机制。根据该提议的目标是定义由胸腺和外围的共感受器治疗调节的分子和细胞事件长期组织特异性耐受性。在AIM 1中，我们将调查圆锥体治疗的机制调节胸腺选择的效率。在AIM 2中，工作将集中于确定如何治疗影响T细胞介导的外周免疫调节以及抗自身T细胞的致病性。在两个目标中，实验将利用我们的ND抗人CD4和CD8αAB来测试CORECEPTOR治疗的体内效应关于人义小鼠的胸腺细胞发育和外周耐受性。通过提议获得的洞察力研究将建立治疗参数，以成功且安全的临床应用。重要的是，训练器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。