Immune Tolerance Against Type I Diabetes in Mice

小鼠对 I 型糖尿病的免疫耐受

• 批准号: 6929619
• 负责人: HABIB ZAGHOUANI
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929619
• 关键词: NOD mouse; T lymphocyte; antibody receptor; antigen antibody reaction; antigen presenting cell; autoantibody; autoantigens; autoimmunity; chimeric proteins; diabetes mellitus therapy; disease /disorder model; disease /disorder prevention /control; enzyme linked immunosorbent assay; flow cytometry; gene environment interaction; immune tolerance /unresponsiveness; immunoglobulin isotypes; immunosuppression; immunotherapy; insulin dependent diabetes mellitus; pancreatic islets; protein engineering; transport proteins

DESCRIPTION (provided by applicant): Type I diabetes (T1D) is a spontaneous autoimmune disease in which the insulin-producing beta cells of the islets of langerhans are destroyed as a consequence of inflammatory reactions triggered by genetic and environmental factors. Transfer of T helper type 1 (Th1) lymphocytes specific for p cell-associated antigens such as insulin beta (INSbeta) chain or glutamic acid decarboxylase (GAD) can confer disease into healthy animals suggesting that the immune system plays a primordial role in T1D. Modulation of diabetogenic Th1 cells offers a viable antigen-specific strategy against T1D. The objective in this proposal is to test a new antigen-specific approach for modulation of diabetogenic T cells in young mice prior to insulitis where The T cells remain peripheral to the islets and in older animals with ongoing insulitis where the T cells have become islet-residents. These studies should yield information useful for the development of a regimen suitable for intervention against the disease in susceptible subjects before progression to hyperglycemia. The new approach will use immunoglobulins (Igs) to vehicle diabetogenic peptides for presentation to autoreactive T cells in a tolerogenic fashion. Accordingly, select peptides will be genetically engineered into Igs and the resulting Ig peptide chimeras will be injected into animals in a soluble (sol) or aggregated (agg) form but while free of adjuvant. In vivo, the Ig-peptide chimeras will be internalized into antigen presenting cells (APCs) mainly via FcgammaR leading to endosomai processing, and access of the peptide to newly synthesized MHC molecules. Additionally agg chimeras will induce the production of IL-10 by APCs and augment the tolerogenic functions of the approach. Efficient loading of the peptide onto MHC molecules will occur, yet due to the autologous nature of Igs, peptide presentation will lack costimulation. Furthermore, the T cells will be exposed to IL-10, a cytokine defined to be suppressive for Th1 cells. Consequently, the approach should drive effective down-regulation of diabetogenic T cells and suppress diabetes. The driving hypothesis in this proposal postulates that diabetogenic T cells residing within the pancreatic islets are subject to different regulatory mechanisms from those located peripheral to the islets. In this case antigen-specific suppression of diabetes would require discrete modulatory mechanisms in young versus older insulitis-positive mice. To test this hypothesis, we propose to express INSp and GAD peptides on Igs and utilize the resulting Ig-INSp and Ig- GAD to define the requirements for restoration of T cell tolerance and suppression of diabetes. The NOD mouse, which develops spontaneous T1D, as well as mutant NOD strains, will be the animal model of choice for these investigations.

描述（由申请人提供）：I型糖尿病（T1D）是一种自发的自身免疫性疾病，其中兰格汉斯胰岛的产生胰岛素的β细胞由于遗传和环境因素引起的炎症反应而被破坏。 T辅助1型（Th1）淋巴细胞的转移对P细胞相关的抗原（例如胰岛素β（INSBETA）链）或谷氨酸脱羧酶（GAD）的转移可以将疾病传递到健康的动物中，这表明免疫系统在T1D中起着原始系统的作用。糖尿病性TH1细胞的调节提供了针对T1D的可行抗原特异性策略。 该建议的目的是测试一种新的抗原特异性方法，用于在胰岛炎之前调节年轻小鼠的糖尿病性T细胞，其中T细胞仍然是胰岛周围和持续胰岛炎的老年动物，其中T细胞已成为胰岛居民。这些研究应产生用于开发适合于易感受试者干预疾病的方案的信息，然后再促进高血糖。 这种新方法将使用免疫球蛋白（IG）对型型糖尿病肽进行耐受性T细胞以耐受性的方式呈现。因此，将精选的肽遗传化为Ig，所得的Ig肽嵌合体将以可溶性（SOL）或聚集（AGG）形式注入动物，但不含辅助剂。在体内，Ig肽嵌合体将主要通过FCGAMMAR内部化为抗原呈递细胞（APC），导致内孢子加工，并将肽访问新合成的MHC分子。另外，Agg Chimeras将通过APC诱导IL-10产生，并增强该方法的耐受性功能。将发生肽在MHC分子上的有效负载，但由于IG的自体性，肽表现将缺乏共刺激。此外，T细胞将暴露于IL-10，这是一种定义为Th1细胞抑制性的细胞因子。因此，该方法应驱动有效的糖尿病性T细胞下调并抑制糖尿病。 该提案中的驱动假设假设胰岛内的糖尿病性T细胞与位于胰岛外围的糖尿病中的糖尿病性T细胞受到不同的调节机制。在这种情况下，抗原特异性抑制糖尿病将需要年轻的胰岛炎阳性小鼠与旧胰岛炎阳性小鼠的离散调节机制。为了检验这一假设，我们建议在IG上表达INSP和GAD肽，并利用所得的Ig-INSP和Ig-GAD来定义恢复T细胞耐受性和抑制糖尿病的要求。发展自发T1D的点头小鼠以及突变的点头菌株将成为这些研究的首选动物模型。