Treatment of overtly diabetic NOD mice

描述(由申请人提供)：1型糖尿病是由营养不良引起的 T细胞介导的自身免疫引起的功能性β细胞团的数量 毁灭。在NOD小鼠1型糖尿病模型中，糖尿病的发生 可以通过在早期开始抗T细胞免疫治疗来预防 有胰岛素炎的征象。然而，治疗易患糖尿病但非糖尿病的 个人，特别是青少年，服用免疫抑制药物并不是 理想的治疗形式，因为潜在的并发症与 长期使用药物。相比之下，慢性阻塞性肺疾病患者的免疫治疗 如果治疗方法有效，完全的自身免疫性糖尿病可能是合理的 实现临床疾病缓解的潜力。我们已经证明了这种治疗 多克隆抗淋巴细胞血清(ALS)对糖尿病NOD小鼠的影响 抗T细胞抗体，在大约50人中诱导长期临床缓解 百分比(如果在发病后两周内开始治疗，则为75%) 并诱导无自身免疫状态的小鼠。我们的结果是 随后得到了Chatenoud等人的证实。世卫组织使用了抗CD3的单抗 抗体作为抗T细胞试剂。拟议研究的总体目标 是设计一种有效的治疗方案，它将有效地诱导 全面糖尿病患者的疾病缓解。我们将调查两个 使用NOD小鼠1型糖尿病模型的治疗方法。首先，我们 将调查联合应用肌萎缩侧索硬化症和exendin-4的有效性 它已被证明可以促进胰岛素分泌，β细胞复制和 辨证分型，在增加疾病缓解率方面具有较短的 恢复时间到了。第二，我们将调查是否应用了 ALS/雷帕霉素/供体BMC输注方案--一种有效的非放射治疗方案 同种异体移植耐受诱导方案，可用于恢复长效 糖尿病NOD小鼠同种异体胰岛移植后血糖正常。 我们相信，拟议研究取得的结果将有助于 一种临床适用的治疗方案的建立 患有全面糖尿病的患者。

DESCRIPTION (provided by applicant): Type 1 diabetes results from an inadequate amount of functioning beta cell mass caused by T cell-mediated autoimmune destruction. In an NOD mouse model of type 1 diabetes, development of diabetes can be prevented by anti-T cell immunotherapy started early before the appearance of insulitis. However, treatment of diabetes-prone, yet non-diabetic individuals, particularly juveniles, with immunosuppressive drugs is not a desirable form of therapy because of potential complications associated with chronic use of the drugs. In contrast, immunotherapy of patients with full-blown autoimmune diabetes may be well justified if the therapy has the potential to achieve clinical disease remission. We have shown that treatment of overtly diabetic NOD mice with antilymphocyte serum (ALS), a polyclonal anti-T cell antibody, induces long-term clinical remission in approximately 50 percent (or 75 percent if treatment starts within 2 weeks after disease onset) of treated mice and induces autoimmune-free conditions. Our results were subsequently confirmed by Chatenoud et al. who used monoclonal anti-CD3 antibody as an anti-T cell reagent. The overall objective of the proposed study is to design an effective treatment regimen which will effectively induce disease remission in patients with full-blown diabetes. We will investigate two therapeutic approaches using an NOD mouse model of type 1 diabetes. First, we will investigate the effectiveness of combining ALS and exendin-4, an agent which has been shown to promote insulin secretion, beta cell replication and differentiation, in increasing the incidence of disease remission with shorter recovery time. Second, we will investigate whether application of an ALS/rapamycin/donor BMC-infusion protocol, an effective non-radiation-based allograft tolerance induction protocol, can be used to restore long-lasting normoglycemia following islet allotransplantation in overtly diabetic NOD mice. We believe that the results obtained from the proposed study will contribute to the establishment of a clinically applicable therapeutic regimen to treat patients with full-blown diabetes.