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） 并且已经成功地用于诱导针对肿瘤的免疫应答， 病毒和同种异体抗原。另一方面，DC的一些子集， 来自胸腺或脾脏，已被证明具有致耐受性潜力， 包括移植和自身免疫在内的几种模型。我们有 评价了胰岛素依赖型糖尿病（IDDM）的小鼠模型， 以非肥胖糖尿病（NOD）小鼠为研究对象，探讨DC的作用 自身免疫性疾病的治疗。该模型允许评估 在胰岛炎期间和移植期间的DC为基础的治疗 在糖尿病发病后。许多胰岛细胞抗原 导致糖尿病发展的因素已经被确定， 其中一些已被用于预防糖尿病的诱发。的 这些抗原中的一些与具有致耐受性潜力的DC的组合 应该被证明是一种诱导特异性耐受的有效方法， 预防糖尿病的发展。初步数据显示， 我们已经获得的结果表明，NOD DC功能正常，并证明 我们能够产生刺激性和致耐受性DC， 这些老鼠。用致耐受性DC脉冲的年轻NOD小鼠的体内治疗 与来自胰岛细胞抗原的肽， 糖尿病诱导，这表明这种治疗有希望。在这 我们计划测试耐受性DC可以预防 和/或通过它们诱导糖尿病的能力治愈NOD小鼠的糖尿病。 免疫调节性Th 2应答的发展。的总体目标 建议的工作将是测试这一假设，特别是，探索 DC亚群在决定 自身免疫性或预防体内自身免疫性疾病的发作。的 该建议的具体目的是：1）证明治疗 DC亚群预防胰岛炎和糖尿病的潜力。2)到 证明DC在发展过程中的治疗潜力 糖尿病3)为了证明DC诱导对胰岛的耐受的能力， 糖尿病NOD小鼠的同种异体移植物。拟议工作的总体目标将 为了验证这一假设，并探讨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作。

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.