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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/文摘