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A Study of the Selection and Peripheral Function of Human Insulin-Reactive T-cells in a Type 1 Diabetic Immune System

1 型糖尿病免疫系统中人胰岛素反应性 T 细胞的选择和外周功能研究

基本信息

批准号：
10066743
负责人：
Rachel Caroline Madley
金额：
$ 3.42万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-01-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066743
关键词：
Adult Affect Antigen Presentation Antigens Apoptosis Apoptotic Aspirate substance Autoantigens Autoimmune Diseases Autoimmune Process Beta Cell Biological Assay Biological Models Blood Bone Marrow Cell physiology Cells Cessation of life Characteristics Defect Development Diabetes Mellitus Disease Exhibits Failure Generations Genes Genetic Genetic study HLA-DQ8 antigen Hematopoietic stem cells Homeostasis Human IL2RA gene Immune Immune System Diseases Immune Tolerance Immune system Immunological Models Impairment Inbred BALB C Mice Inbred NOD Mice Individual Injections Insulin Insulin deficiency Insulin-Dependent Diabetes Mellitus Investigation Knockout Mice Lead Lymphocyte Modeling Mus Mutate Non obese Organ Culture Techniques Pathogenesis Pathogenicity Patients Peripheral Phenotype Prevention strategy Proteins Regulation Regulatory T-Lymphocyte Research Resistance Signaling Molecule Single Nucleotide Polymorphism Structure of beta Cell of islet Study models T memory cell T-Cell Development T-Cell Receptor T-Lymphocyte Techniques Testing Thymic Tissue Thymus Gland Transgenic Organisms Transplantation Travel Variant autoreactive T cell biobank central tolerance diabetes mellitus genetics diabetic diabetogenic fetal genetic variant genomic locus human fetal thymus human tissue humanized mouse immune system function insulitis lentivirally transduced mouse genetics mouse model peripheral tolerance prevent reconstitution risk variant stem cells therapeutic development therapy development treatment strategy type I diabetic

项目摘要

Project Summary In Type 1 diabetes (T1D), beta cell antigen-reactive T-cells escape negative selection in the thymus, travel to the periphery, and kill insulin-producing pancreatic beta cells. In healthy individuals, central and peripheral immune tolerance mechanisms prevent this type of autoimmune attack. It is not known which level of tolerance fails in cases of T1D. Introduction of an insulin-reactive T-cell receptor (TCR) derived from a T1D patient to the periphery of humanized mice can initiate diabetes, consistent with the notion that escape of autoreactive T-cells from negative selection promotes disease. On the other hand, beta cell antigen-reactive T-cells have also been isolated from the blood of healthy control (HC) individuals, raising the possibility that defective peripheral tolerance mechanisms may promote T1D. Genetic studies have identified over 40 risk variants for T1D, including genes implicated in both central and peripheral tolerance mechanisms. We hypothesize that there are both hematopoietic stem cell (HSC)-intrinsic and thymus-intrinsic genetic variants in T1D individuals that a) lead to the failure of negative selection of diabetogenic T-cell receptors during T-cell development in the thymus and, additionally or alternatively; b) alter the characteristics of autoreactive T-cells to increase their diabetogenicity. We have established a Personalized Immune (PI) mouse model that allows us to generate an adult human's immune system de novo in immunodeficient NOD/LtSz-scid IL2R gamma null mice (NSG) mice receiving patient HSCs and a partially HLA-matched fetal thymus graft. We have also demonstrated that the patient HSCs can be lentivirally transduced to express a specific TCR and subsequently used to reconstitute NSG mice or human thymus tissue in thymic organ culture assays. With these techniques and with access to HSC and thymus tissue from T1D and HC donors, we will study the thymic selection and subsequent peripheral function of insulin-reactive TCRs expressed on T-cells derived from T1D HSCs and selected in a T1D thymus. In these studies, we aim to determine if there is a genetically-predetermined defect in the central tolerance mechanism of negative selection and/or peripheral immune tolerance mechanisms in T1D.

项目总结