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

摘要 抗原提呈细胞(APC)功能和免疫调节缺陷是导致 NOD小鼠和人类I型糖尿病的发展。研究表明， NOD小鼠和糖尿病患者的CD4+CD25+调节性T细胞功能降低。我们的 初步研究表明，缺陷存在于nod APC激活的能力中。 而不是在CD4+CD25+调节性T细胞中 他们自己。我们假设NOD小鼠APC隔室的缺陷可能 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， 包括乳酸菌和结核分枝杆菌，预防或延缓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反应。 通过靶向Toll样受体(TLR)和/或C型凝集素受体(CLR) 用APC表示。出于这个原因，我们提出了防止微生物 糖尿病通过TLR和/或CLR作用于NOD APC，使APC能够激活/诱导 调节性T细胞。本提案的目标是确定是否 TLR/CLR配体可增强NOD APC激活调节细胞的能力，并阻止 或者治疗糖尿病。在目标1中，我们将分析Nod APC中的缺陷。在目标2中，我们将 评估乳杆菌预防NOD小鼠疾病的机制。在《目标3》中， 我们将检查TLR2和/或CLR配体是否已与 耐受诱导可增强CD4+CD25+调节性T细胞的NOD APC活性 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.