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The Antigen Repertoire of CD4 T cells from Pancreatic Islets

胰岛 CD4 T 细胞的抗原库

基本信息

批准号：
10700133
负责人：
Maki Nakayama
金额：
$ 47.24万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700133
关键词：
Affinity Alleles Amino Acid Motifs Antibodies Antigen Targeting Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Diseases Automobile Driving Bar Codes Beta Cell Biological Biological Assay Blood CD4 Positive T Lymphocytes Cell Separation Cells Clinical Trials Design Computer Analysis DNA Development Diabetes prevention Disease Disease Progression Epitopes Glutamate Decarboxylase Goals Grant HLA-DR3 Antigen HLA-DR4 Antigen Health Heterogeneity Human Hybridomas Hybrids Immune Immunotherapy Individual Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Link MHC Class II Genes Mass Spectrum Analysis Organ Donor Pancreas Pathogenesis Pathogenicity Patients Peptide Library Peptides Phenotype Positioning Attribute Process Proinsulin Protein Databases Proteins Reaction Risk Source Specificity Spleen T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Testing Tissues Virus antigen-specific T cells autoimmune pathogenesis cell motility cellular transduction combinatorial diabetes pathogenesis diabetes risk disease heterogeneity genetic association genomic locus gut microbiome improved insulin secretion islet islet autoimmunity islet cell antibody lymph nodes molecular phenotype non-diabetic preproinsulin prevent response transcriptome zinc-binding protein

项目摘要

Project Summary Type 1 diabetes (T1D) is a tissue-specific autoimmune disorder. Strong genetic association with the HLA class II gene locus suggests the importance of CD4 T cells in initiating and driving the disease process. We and others have isolated T cells from the pancreas of T1D organ donors and identified T cell epitopes specific to insulin, and its precursor preproinsulin, as well as fusion peptides. An important next step is to elucidate the phenotypes of such islet-derived T cells in health and disease. Concurrently, the previous studies uncovered the fact that antigens for the majority of T cells in the islets are still unknown, and we do not even know whether those T cells are islet antigen-specific. Identifying antigen specificity of islet-CD4 T cells is critical to dissect disease pathogenicity and heterogeneity to develop antigen-specific immunotherapy to halt disease progression using appropriate antigens in a given individual. Therefore, the goal of this grant is to identify antigen specificity of CD4 T cells in the islets and link antigen-specific responses to T cell phenotypes. Multiple lines of evidence suggest that there may be `common' or preferred CD4 T cell epitopes within subsets of T1D patients. First, the vast majority of T1D patients have risk HLA class II alleles, and specific class II alleles are associated with development of an initial islet autoantibody (e.g. insulin autoantibodies develop in those with HLA-DR4, and glutamic acid decarboxylase-65 antibodies with HLA-DR3). Second, CD4 T cells having the same antigen specificity (e.g. proinsulin peptides and hybrid insulin peptides) are detected in the pancreata from multiple T1D organ donors, and the same reactivity is found in the blood of those with early stages of T1D. Finally, CD4 T cells specific to these epitopes have an inflammatory phenotype in the blood of T1D patients compared to non-diabetic controls. This leads us to hypothesize that islet autoimmunity is promoted and regulated by CD4 T cells reacting to `common' antigens that are shared by T1D patients having specific HLA class II molecules. We will determine the proportion of tissue-specific CD4 T cells in the islets (Aim 1) and seek to identify epitopes targeted by CD4 T cells in the islets of T1D organ donors (Aim 2). Furthermore, we will determine the molecular phenotype of islet antigen-specific T cells in the pancreatic lymph nodes and spleen of organ donors with and without T1D (Aim 3). The successful completion of this proposal will: (1) identify antigens and epitopes targeted by CD4 T cells from pancreatic islets across the stages of T1D development and (2) elucidate the molecular phenotype and features that render these T cells pathogenic. Thus, these studies will enhance our understanding of human T1D pathogenesis, dissect disease heterogeneity, and aid in improving the design of clinical trials evaluating antigen-specific immunotherapy for diabetes prevention.

项目总结