Analyzing and modulating immunoregulatory defects in autoimmune disease.

分析和调节自身免疫性疾病的免疫调节缺陷。

• 批准号: 7559008
• 负责人: MICHELE M KOSIEWICZ
• 金额: $ 35.24万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559008
• 关键词: Address; Antigens; Autoimmune Diseases; Autoimmunity; Cells; Defect; Development; Diabetes Mellitus; Disease; Exposure to; Goals; Homeostasis; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Maintenance; Mouse Strains; Mus; Organ; Peripheral; Phenotype; Population; Process; Site; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; in vivo; prevent; reconstitution; response; restoration; therapy development

Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimrnunity. Although the thymus appears to be a major site of CD4+CD25+ T cell development, it is still unclear whether there are also peripheral sites of development. We have found recently that CD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in the periphery. Conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells may be a very important mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenance, and a defect in this process could contribute to autoimmune disease development. We have found that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in the thymus, but a significantly lower percentage in the periphery. Furthermore, NOD CD4+CD25"T cells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function, strongly suggesting that NOD mice may have a defect in this conversion process and may, therefore, be unable to maintain this regulatory population. The central hypothesis of this proposal is that enhanced conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice can prevent diabetes. We will test this hypothesis by studying the mechanisms and defects in conversion in NOD mice, determinewhether this process can be restored and whether restoration is associated with amelioration of disease. By understanding the defects in conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice, it may be possible to devise strategies to overcome these defects and,thereby, develop therapies to prevent or treat autoimmune disease.

天然存在的 CD4+CD25+ 调节性 T 细胞对于控制自身免疫非常重要。 尽管胸腺似乎是 CD4+CD25+ T 细胞发育的主要部位，但它仍然是 尚不清楚是否还有外围发育部位。我们最近发现 CD4+CD25~T细胞在体内可转化为CD4+CD25+调节性T细胞 周边。 CD4+CD25” T 细胞转化为 CD4+CD25+ 调节性 T 细胞可能是一个非常重要的过程。 外周CD4+CD25+调节性T细胞稳态和维持的重要机制， 这个过程中的缺陷可能会导致自身免疫性疾病的发展。我们有 发现糖尿病前期 NOD 小鼠的 CD4+CD25+ T 细胞比例正常 胸腺，但外周的比例明显较低。此外，NOD CD4+CD25"T 细胞在体内无法转化为具有调节功能的CD4+CD25+细胞，强烈 表明 NOD 小鼠在这一转化过程中可能存在缺陷，因此可能 无法维持这个监管人口。该提案的中心假设是 NOD 小鼠中 CD4+CD25" T 细胞向 CD4+CD25+ 调节性 T 细胞的转化增强 可以预防糖尿病。我们将通过研究其机制和缺陷来检验这一假设。 在NOD小鼠中进行转化，确定该过程是否可以恢复以及是否恢复 与疾病的改善有关。通过了解转换中的缺陷 NOD 小鼠中 CD4+CD25" T 细胞转化为 CD4+CD25+ 调节性 T 细胞，这可能是 制定策略来克服这些缺陷，从而开发预防或治疗的疗法 自身免疫性疾病。