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: 7036311
• 负责人: MICHELE M KOSIEWICZ
• 金额: $ 36.75万
• 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/7036311
• 关键词: CD28 molecule; CD40 molecule; MHC class II antigen; NOD mouse; antigen presenting cell; developmental immunology; disease /disorder prevention /control; flow cytometry; genetically modified animals; helper T lymphocyte; immunologic memory; immunoregulation; insulin dependent diabetes mellitus; interferon gamma; phenotype; selectins; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimmunity. 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, determine whether 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.

描述（由申请人提供）：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，但尚不清楚是否也有外周发育部位。我们最近发现CD4+CD25~T细胞在体内外周可转化为CD4+CD25+调节性T细胞。 CD4+CD25-T细胞转化为CD4+CD25+调节性T细胞可能是外周CD4+CD25+调节性T细胞稳态和维持的一个非常重要的机制，该过程的缺陷可能导致自身免疫性疾病的发展。我们发现糖尿病前期NOD小鼠胸腺中CD4+CD25+T细胞的百分比正常，但外周细胞的百分比明显较低。此外，NOD CD4+CD25-T细胞无法在体内转化为具有调节功能的CD4+CD25+细胞，强烈表明NOD小鼠在这种转化过程中可能存在缺陷，因此可能无法维持这种调节群体。该提议的中心假设是，在 NOD 小鼠中增强 CD4+CD25-T 细胞向 CD4+CD25+ 调节性 T 细胞的转化可以预防糖尿病。我们将通过研究NOD小鼠转化的机制和缺陷来检验这一假设，确定这一过程是否可以恢复以及恢复是否与疾病的改善相关。通过了解NOD小鼠中CD4+CD25-T细胞转化为CD4+CD25+调节性T细胞的缺陷，有可能设计出克服这些缺陷的策略，从而开发预防或治疗自身免疫性疾病的疗法。