Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice

NOD 小鼠年龄依赖性胸腺事件和自身免疫 T 细胞的发育

• 批准号: 7984541
• 负责人: Roland M Tisch
• 金额: $ 36.72万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984541
• 关键词: Affect; Age; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Models; CD8B1 gene; Cells; Colitis; Development; Diabetes Mellitus; Event; Female; Genes; Genetic; Goals; Implant; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Kidney; Mediating; Modeling; Molecular; Mus; Newborn Infant; Non obese; Pathogenicity; Pathology; Phenotype; Production; Regulation; Regulatory T-Lymphocyte; Role; Salivary Gland Tissue; Shapes; Sialadenitis; Specificity; T-Cell Development; T-Lymphocyte; Thymus Gland; Thyroid Gland; Thyroiditis; Tissues; Transplantation; age related; autoreactive T cell; capsule; diabetic; fetal; insight; novel; public health relevance; reconstitution; thymocyte

DESCRIPTION (provided by applicant): The goal of this proposal is to define the key events ongoing in the thymus that shape the repertoire of autoreactive T cells. For this purpose, we will exploit a novel model system in which thymi from NOD female mice of varying ages are transplanted under the kidney capsule of NOD.scid recipients resulting in T cell reconstitution of the periphery. Thymi prepared from fetal and newborn NOD donors produce CD4+ and CD8+ T cells characterized by a type 1 phenotype. Importantly, the NOD.scid recipients develop overt diabetes, in addition to thyroiditis. In marked contrast, NOD.scid mice transplanted with thymi from 4 week-old or older NOD donors develop severe colitis but remain free of diabetes and thyroiditis. We hypothesize that age- dependent events regulate the efficacy of thymic positive and negative selection that in turn promote the temporal development of pathogenic T precursors. Three Specific Aims have been established to determine the mechanisms regulating the temporal development of T cell tissue-specificity. The first will determine how age-dependent thymic events shape the repertoire of autoreactive T precursors. The second Specific Aim will determine the cellular events ongoing in the thymus that mediate the temporal development of T precursors mediating autoimmunity and colitis. The final Specific Aim will ascertain the contribution of genetic background and thymic expressed tissue antigens in the temporal development of tissue-specific T cells. In this way, novel insight will be gained into the critical events that shape the repertoire of autoreactive thymocytes. PUBLIC HEALTH RELEVANCE: Type 1 diabetes and other tissue-specific autoimmune diseases are mediated by T cells. The critical events that promote development of autoreactive T cells, however, remain poorly understood. This proposal employs a novel model system to define the cellular and molecular events that regulate the development of autoreactive T precursors in the thymus.

描述（由申请人提供）：该提案的目的是定义胸腺中正在进行的关键事件，以塑造自动反应性T细胞的曲目。为此，我们将利用一种新型的模型系统，在该模型系统中，来自不同年龄段的NOD雌性小鼠的百里香在点头的肾脏胶囊下移植。SCID受体，导致外围T细胞重建。由胎儿和新生儿点头供体制备的百里香产生以1型表型为特征的CD4+和CD8+ T细胞。重要的是，除了甲状腺炎外，点头的接受者患有明显的糖尿病。在明显的对比中，从4周大或以上的点头供体移植的胸腺的点头小鼠会出现严重的结肠炎，但仍然没有糖尿病和甲状腺炎。我们假设年龄依赖的事件调节胸腺正和阴性选择的功效，从而促进了致病性T前体的时间发展。已经建立了三个具体目标，以确定调节T细胞组织特异性时间发育的机制。第一个将决定年龄依赖性的胸腺事件如何塑造自动反应性t前体的曲目。第二个特定目的将确定胸腺中持续的细胞事件，介导介导自身免疫性和结肠炎的T前体的时间发育。最终的具体目的将确定遗传背景和胸腺表达的组织抗原在组织特异性T细胞的时间发育中的贡献。这样，新颖的见解将获得塑造自动反应性胸腺细胞曲目的关键事件。 公共卫生相关性：1型糖尿病和其他组织特异性自身免疫性疾病是由T细胞介导的。然而，促进自动反应性T细胞发展的关键事件仍然知之甚少。该建议采用一种新型的模型系统来定义调节胸腺自动反应性t前体发展的细胞和分子事件。