Targeting TLR/CLR to enhance immunoregulation and prevent or treat diabetes.

摘要 抗原呈递细胞（APC）功能和免疫调节的缺陷是免疫缺陷的基础。 NOD小鼠和人类中I型糖尿病的发展。研究表明 NOD小鼠和糖尿病患者中CD 4 + CD 25+调节性T细胞功能降低。我们 初步研究表明，这种缺陷存在于NOD APC激活 CD 4 + CD 25+调节性T细胞，而不是CD 4 + CD 25+调节性T细胞 自己我们假设NOD小鼠APC区室的缺陷可能 导致调节性T细胞活化不足，并可能导致糖尿病 发展感染或治疗多种不同类型的微生物， 包括M.结核病，预防或延迟NOD小鼠的糖尿病。 有趣的是，微生物可以通过诱导耐受性来逃避免疫应答 通过靶向Toll样受体（TLR）和/或C型凝集素受体（TLR）， APC表示。因此，我们建议， 糖尿病通过TLR和/或TLR作用于NOD APC，使APC能够激活/诱导 调节性T细胞本提案的目的是确定 TLR/TLR配体可以增强NOD APC激活调节细胞的能力，并防止NOD APC的表达。 或治疗糖尿病。在目标1中，我们将分析NOD APC中的缺陷。在目标2中，我们 评估乳酸杆菌预防NOD小鼠疾病的机制。在目标3中， 我们将检查TLR 2和/或CLR配体是否与 耐受诱导可增强NOD APC对CD 4 + CD 25+调节性T细胞的活化 并预防老鼠的疾病。这些实验的结果应该提供一个基础 用于开发治疗糖尿病的新策略。

Abstract Defects in antigen presenting cell (APC) function and immunoregulation underlie the development of type I diabetes in NOD mice and humans. Studies have shown that CD4+CD25+ regulatory T cell function is reduced in NOD mice and diabetic patients. Our preliminary studies suggest the defect resides in the ability of NOD APC to activate CD4+CD25+ regulatory T cells rather than in the CD4+CD25+ regulatory T cells themselves. We hypothesize that a defect in the APC compartment in NOD mice may result in deficient regulatory T cell activation and may contribute to diabetes development. Infection or treatment with a number of different types of microorganisms, including lactobacillus and M. tuberculosis, prevent or delay diabetes in NOD mice. Interestingly, microorganisms can evade the immune response by inducing tolerance through the targeting of Toll-like receptors (TLR) and/or C-type lectin receptors (CLR) expressed by APC. For this reason, we propose that the microorganisms that prevent diabetes act on NOD APC via TLR and/or CLR, enabling the APC to activate/induce regulatory T cells. The objective of the present proposal is to determine whether TLR/CLR ligands can enhance NOD APC ability to activate regulatory cells, and prevent or treat diabetes. In Aim 1, we will analyze the defect in NOD APC. In Aim 2, we will evaluate the mechanisms by which Lactobacilli prevent disease in NOD mice. In Aim 3, we will examine whether TLR2 and/or CLR ligands that have been associated with tolerance induction can enhance NOD APC activation of CD4+CD25+ regulatory T cells and prevent disease in mice. The results of these experiments should provide a basis for the development of novel strategies for the treatment of diabetes.