Characterizing autoimmunity NOD mouse islets, PLN/spleen

表征自身免疫性 NOD 小鼠胰岛、PLN/脾

• 批准号: 7210042
• 负责人: DANIEL KAUFMAN
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210042
• 关键词: NOD mouse; T lymphocyte; antibody specificity; autoantigens; autoimmune disorder; biomarker; cytotoxic T lymphocyte; developmental immunology; enzyme linked immunosorbent assay; helper T lymphocyte; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; lymph nodes; pancreatic islets; pathologic process; phenotype; spleen

DESCRIPTION (provided by applicant): Scientific Abstract: We lack a basic understanding how spontaneous autoimmune disease arises. Studies of antigen-tolerized transgenic NOD mice have suggested the primacy of different autoantigens in initiating the autoimmunity that leads to type 1 diabetes (T1D). However, theoretical considerations based on our knowledge of T cell tolerance induction predict that beta-cell autoimmunity should be initially lost to many beta-cell antigens simultaneously but there is little experimental evidence in support of this scenario. We have developed a modified ELISPOT assay that enables the characterization of autoreactive T cells within the pancreatic lymph nodes (PLN) and islet-infiltrating T cell population. Our preliminary data indicate that antigen-specificity and phenotype of autoreactive T cells within the target tissue is quite different from the current picture that was obtained through analysis of T cell populations in the periphery of NOD mice. We expect that our further longitudinal characterization of autoreactive CD4+ and CD8+ T cell responses in the PLN, islets and spleen will lead to a new conceptualization of the autoimmune processes in NOD mice. Our analysis of the functional avidity of early T cell autoreactivity in the PLN and islets will provide an independent line of evidence to support either the "hierarchal" or the "simultaneous" model of the development of T cell autoimmunity. The lessons learned will support/refute the hypothesis that autoimmunity can be circumvented by tolerizing individuals to "initiating" target antigens. Our studies will also elucidate the relationship between peripheral T cell responses and those in the target tissue. As only PBMC are available from humans, understanding the relationship between T cell autoreactivities in the periphery and target tissue is important to assess the feasibility of using T cell-based markers to monitor disease progression, the efficacy of interventive therapies, and the status of transplanted islets. Laypersons: We lack a basic understanding how spontaneous autoimmune disease arises. We have established the ability to directly characterize autoreactive T cells within the pancreatic lymph nodes (PLN, wherein autoimmunity is thought to first arise) and the islet-infiltrating T cell population, which heretofore has not been feasible. We expect that the results of this proposal will lead to a new conceptualization of the autoimmune process in NOD mice. The same basic processes may also occur in human organ-specific autoimmune diseases. The results will help guide our thinking on potential therapeutic approaches, as well as the utility of biomarkers based on peripheral T cell responses.

描述（由申请人提供）：科学摘要：我们缺乏基本的理解自发自身免疫性疾病。对抗原耐酸的转基因NOD小鼠的研究表明，不同自身抗原在启动导致1型糖尿病（T1D）的自身免疫性方面的至高无上。但是，基于我们对T细胞耐受性诱导知识的理论考虑预测，β细胞自身免疫最初应同时丢失许多β细胞抗原，但几乎没有实验证据来支持这种情况。我们已经开发了一种改良的ELISPOT分析，该测定法可以表征胰腺淋巴结（PLN）和胰岛浸润T细胞群体内的自动反应性T细胞。我们的初步数据表明，靶组织内自动反应性T细胞的抗原特异性和表型与通过分析NOD小鼠外围的T细胞群体获得的当前图片完全不同。我们预计，我们对PLN，胰岛和脾脏中自动反应性CD4+和CD8+ T细胞反应的进一步纵向表征将导致NOD小鼠自身免疫过程的新概念化。我们对PLN和胰岛早期T细胞自动反应性的功能亲和力的分析将提供独立的证据线，以支持T细胞自身免疫性开发的“层次”或“同时”模型。所学的教训将支持/反驳以下假设：可以通过容忍个体“启动”靶抗原来规避自身免疫性。我们的研究还将阐明周围T细胞反应与目标组织中的T细胞反应之间的关系。由于只有人类才能获得PBMC，因此了解周围和靶组织中T细胞自我反应性之间的关系对于评估使用基于T细胞的标记来监测疾病进展，干预疗法的疗效以及移植胰岛的状态很重要。外行：我们缺乏基本的了解自发自身免疫性疾病。我们已经建立了直接表征胰腺淋巴结内自动反应性T细胞的能力（PLN，其中自身免疫性首先出现）和胰岛浸润的T细胞群，而迄今为止，这些T细胞群体尚不可行。我们预计该提案的结果将导致NOD小鼠自身免疫过程的新概念化。人类特异性的自身免疫性疾病也可能发生相同的基本过程。结果将有助于指导我们对潜在的治疗方法的思考，以及基于周围T细胞反应的生物标志物的实用性。