DENDRITIC CELL MEDIATED THERAPY OF AUTOIMMUNE DIABETES

树突状细胞(DC)是最有效的抗原提呈细胞(APC)。 并已成功地用于诱导对肿瘤的免疫反应， 病毒和同种异体抗原。另一方面，DC的一些子集 来自胸腺或脾的，已被证明在 包括移植和自身免疫在内的几种模式。我们有 评价胰岛素依赖型糖尿病(IDDM)小鼠模型， 以非肥胖糖尿病(NOD)小鼠为研究手段探讨DC的作用 在自身免疫性疾病的治疗中。该模型允许评估 在胰岛炎期和移植中的DC治疗 背景是糖尿病发作后的情况。许多胰岛细胞抗原 已经确定了导致糖尿病发生的因素，并 其中一些已经被用来预防糖尿病的诱发。这个 其中一些抗原与具有耐受潜能的DC的结合 应该被证明是一种有效的方式来诱导特定的宽容，从而导致 预防糖尿病的发展。初步数据显示 我们得到了节点DC功能正常的结论，并进行了演示 我们能够同时产生刺激性和耐受性DC 这些老鼠。致耐受DC冲击对幼年NOD小鼠的体内治疗 用来自胰岛细胞抗原的多肽预防 诱发糖尿病，这表明这种疗法是有希望的。在这 我们计划测试耐受性DC可以预防的假设 和/或通过诱导NOD小鼠 免疫调节性Th2反应的发展。该计划的总体目标是 建议的工作将是检验这一假设，特别是探索 树突状细胞亚群的作用决定了 自身免疫或在体内预防自身免疫性疾病的发病。这个 这项提案的具体目的是：1)展示治疗 DC亚群预防绝缘炎和糖尿病的潜力。2)至 展示DC在疾病发展过程中的治疗潜力 糖尿病。3)证实DC诱导对胰岛耐受的能力 糖尿病NOD小鼠的同种异体移植。拟议工作的总体目标将是 以检验这一假说，并探索DC亚群在 确定自身免疫的发展或预防 体内自身免疫性疾病的发病。

Dendritic cells (DC) are the most efficient antigen presenting cells (APC) and have been successfully used to induce immune responses to tumors, viruses and alloantigens. On the other hand, some subsets of DC, either from thymus or spleen, have been shown to have tolerogenic potential in several models including transplantation as well as autoimmunity. We have evaluated the murine model of insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse, as a means to explore the role of DC in the therapy of autoimmune disease. This model allows the assessment of DC-based therapy both during the period of insulitis and in a transplant setting following the onset of diabetes. Many of the islet cell antigens that contribute to the development of diabetes have been identified and some of them have been used to prevent the induction of diabetes. The combination of some of these antigens with DC with tolerogenic potential should prove to be a powerful way to induce specific tolerance that leads to protection against the development of diabetes. Preliminary data that we have obtained suggests that NOD DC function normally, and demonstrates that we are able to generate both stimulatory and tolerogenic DC from these mice. In vivo therapy of young NOD mice with tolerogenic DC pulsed with peptides derived from islet cell antigens resulted in prevention of diabetes induction, suggesting that this therapeutic has promise. In this proposal we plan to test the hypothesis that tolerogenic DC can prevent and/or cure diabetes in the NOD mouse via their ability to induce the development of an immunoregulatory Th2 response. The overall aim of the work proposed will be to test this hypothesis and, in particular, explore the role of subsets of DC in determining either the development of autoimmunity or prevention of the onset of autoimmune disease in vivo. The specific aim of this proposal are: 1) To demonstrate the therapeutic potential of DC subsets to prevent insulitis and diabetes. 2) To demonstrate the therapeutic potential of DC during the development of diabetes. 3) To demonstrate the ability of DC to induce tolerance to islet allografts in diabetic NOD mice. The overall aim of the work proposed will be to test this hypothesis and to explore the role of subsets of DC in determining either the development of autoimmunity or prevention of the onset of autoimmune disease in vivo.