Treatment of overtly diabetic NOD mice

描述（由申请人提供）：1型糖尿病是由不充分的 由T细胞介导的自身免疫性疾病引起的功能性β细胞群的数量 杀伤性在1型糖尿病的NOD小鼠模型中， 可以通过抗T细胞免疫治疗来预防， 出现胰岛炎。然而，治疗糖尿病倾向，但非糖尿病 个体，特别是青少年，免疫抑制药物不是一个 由于与以下疾病相关的潜在并发症， 长期使用药物。与此相反， 如果治疗具有以下特点，那么完全的自身免疫性糖尿病可能是合理的： 达到临床疾病缓解的潜力。我们已经证明， 公开糖尿病NOD小鼠与抗淋巴细胞血清（ALS），一个多克隆 抗T细胞抗体，在大约50例患者中诱导长期临床缓解 %（如果在发病后2周内开始治疗，则为75%） 并诱导无自身免疫的条件。我们的结果 随后由Chatenoud等人证实，他们使用单克隆抗CD 3 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， 完全型糖尿病患者的疾病缓解。我们将调查两个 使用1型糖尿病的NOD小鼠模型的治疗方法。一是 将研究ALS和exendin-4结合的有效性， 它已被证明可以促进胰岛素分泌，β细胞复制， 辨证分型，在增加发病率的同时，疾病缓解期缩短 恢复时间第二，我们将调查是否应用 ALS/雷帕霉素/供体BMC输注方案，一种有效的非放射性治疗 同种异体移植耐受诱导方案，可用于恢复持久 在明显糖尿病NOD小鼠中胰岛同种异体移植后的正常血糖。 我们认为，拟议研究的结果将有助于 建立一种临床上适用的治疗方案， 患有严重糖尿病的患者。

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.