Analyzing and modulating immunoregulatory defects in autoimmune disease

描述(由申请人提供)：自然产生的CD4+CD25+调节性T细胞在控制自身免疫方面很重要。虽然胸腺似乎是CD4+CD25+T细胞发育的主要部位，但目前仍不清楚是否也有外围发育部位。我们最近发现，在体内，外周血中的CD4+CD25~+T细胞可以转化为CD4+CD25+调节性T细胞。CD4+CD25-T细胞向CD4+CD25+调节性T细胞的转化可能是外周血中CD4+CD25+调节性T细胞动态平衡和维持的重要机制，这一过程中的缺陷可能导致自身免疫性疾病的发生。我们发现糖尿病前期NOD小鼠胸腺中的CD4+CD25+T细胞比例正常，但外周的比例明显降低。此外，NOD小鼠体内的CD4+CD25-T细胞不能转化为具有调节功能的CD4+CD25+细胞，这强烈提示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。这一建议的中心假设是，在NOD小鼠中，促进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小鼠转换过程中的机制和缺陷来验证这一假说，确定这一过程是否可以恢复，以及恢复是否与疾病的改善有关。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，从而开发出预防或治疗自身免疫性疾病的治疗方法。

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.