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：
10296946
负责人：
Brian T Fife
金额：
$ 59万
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/10296946
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 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 Interferons Knowledge Lead 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.

概括 1 型糖尿病 (T1D) 是一种因免疫系统崩溃而导致的自身免疫性疾病 T 细胞介导的胰岛 β 细胞破坏引起的耐受性是由 HLAII- 精心策划的。通过与 B 细胞和 CD8+ T 细胞的细胞相互作用，限制 CD4+ T 细胞，从而导致分别是自身抗体的产生和β细胞死亡，而抗胰岛自身抗体目前是。 T1D 发展的最佳预测因子，筛选仅限于四种胰岛抗原，不含 T 细胞尽管经过多年的研究，仍不清楚哪些抗原特异性 CD4+ T 细胞存在。新证据表明杂合肽（HP）是由胰岛β细胞融合形成的。蛋白质可能是 T1D 的关键抗原，因为最近的研究发现，HP 反应性 CD4+ T 细胞来自 T1D 患者和糖尿病小鼠在体外这些新抗原逃脱了中枢耐受性，必须进行处理。受外周机制控制，包括无反应性或调节性 T 细胞控制。研究中，我们使用四聚体试剂在糖尿病小鼠模型中鉴定了 HP 特异性 CD4+ T 细胞，并表明它们是致病性的，并在小鼠转移模型中导致 T1D。更重要的是，我们可以。阻断 NOD 小鼠模型中的自发性 T1D，靶向一种混合肽（当存在于使用肽特异性：MHCII 阻断抗体的小鼠 MHCII 因此，我们追求 HP 是关键抗原以及对 HP 的自身反应引发 T1D。该提案的目标是确定 HP 特异性 CD4+ T 细胞是否引发 T1D，以及靶向它们是否可以导致耐受性预防或治疗 T1D 的第二个目标是确定 HP 特定细胞是否有效。与人类 T1D 相关，并使用 scRNA-seq 分析来揭示有关共享的关键线索与人类和小鼠 HP 反应性致病潜力相关的转录程序 T 细胞的完成可以产生更好的生物标志物来预测 T1D 风险和疾病。进展。