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Identifying and preventing antigen specific T cells in diabetes

识别和预防糖尿病中的抗原特异性 T 细胞

基本信息

批准号：
10634700
负责人：
Brian T Fife
金额：
$ 59.03万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-22 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634700
关键词：
Antibodies Antigens Autoantibodies Autoimmune Autoimmune Diabetes Autoimmune Diseases B-Lymphocytes Beta Cell Biological Markers Blocking Antibodies CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Death Cell Separation Cells Coupled Development Diabetes Mellitus Diabetes prevention Diabetic mouse Disease Progression Early Diagnosis Fingerprint Frequencies Functional disorder Gene Expression Profile Genetic Transcription Goals Grant Human Hybrids Immune Tolerance In Vitro Inbred NOD Mice Individual Insulin Insulin-Dependent Diabetes Mellitus Knowledge Mediating Modeling Mouse Strains Mus Non obese Onset of illness Pancreas Pathogenesis Pathogenicity Pathway Analysis Patients Peptides Peripheral Population Predisposition Prevention Preventive therapy Production Property Proteins Protocols documentation Reagent Regulatory T-Lymphocyte Research Risk Role T cell differentiation T cell regulation T-Cell Receptor T-Lymphocyte Testing anergy antigen test antigen-specific T cells autoreactivity central tolerance chimeric antigen receptor diabetes risk diabetic effective therapy genetic signature insulin dependent diabetes mellitus onset islet islet cell antibody memory CD4 T lymphocyte mouse model neoantigens novel therapeutic intervention prevent programs screening single-cell RNA sequencing targeted treatment trafficking transcriptome type I diabetic

项目摘要

SUMMARY Type 1 diabetes (T1D) is an autoimmune disease resulting from a breakdown in immunological tolerance caused by T cell-mediated destruction of islet beta cells. Diabetes is orchestrated by HLAII- restricted CD4+ T cells, through cellular interactions with both B cells and CD8+ T cells, resulting in autoantibody production and beta cell death, respectively. While anti-islet autoantibodies are currently the best predictors of T1D development, screening is limited to four islet antigens and no T cell biomarkers exist. Despite years of research, it is still unclear which antigen-specific CD4+ T cells initiate T1D. New evidence suggests that hybrid peptides (HP) formed from the fusion of islet β cell proteins may be critical antigens in T1D as recent studies identified HP-reactive CD4+ T cells from T1D patients and diabetic mice in vitro. These neo-antigens escape central tolerance and must be controlled by peripheral mechanisms including anergy or regulatory T cell control. In preliminary studies, we identified HP-specific CD4+ T cells in diabetic mouse models using tetramer reagents, and showed they are pathogenic and cause T1D in mouse transfer models. More importantly, we can block spontaneous T1D in the NOD mouse model targeting one hybrid peptide when presented in mouse MHCII using peptide-specific:MHCII blocking antibodies. Thus, we hypothesize that HPs are critical antigens and that autoreactivity to HPs initiates T1D. The goals of this proposal are to determine if HP-specific CD4+ T cells initiate T1D and if targeting them can lead to tolerance as a prevention or cure for T1D. The second goal of the grant is to determine if HP specific cells are relevant for human T1D and use of scRNA-seq analysis to uncover critical clues about shared transcriptional programs related to the pathogenic potential between human and mouse HP reactive T cells. Completion of this project could lead to better biomarkers to predict T1D risk and disease progression.

总结