PREVENTION OF DIABETES IN NOD MICE

非肥胖糖尿病（NOD）小鼠自发地产生胰岛素- 依赖性糖尿病是一种由自身免疫性疾病引起的多基因疾病 破坏产生胰岛素的β细胞。糖尿病发展 在NOD小鼠中，免疫抑制明显依赖于T细胞功能; 抑制T细胞功能的药物（环孢菌素、抗胸腺细胞 球蛋白、硫唑嘌呤和泼尼松）或耗尽成熟T细胞 （抗CD 3、抗CD 4和抗CD 8单克隆抗体）可预防 发展自身免疫性糖尿病时，他们给予在早期的年龄。 抗淋巴细胞血清（ALS），另一种有效的T细胞免疫抑制剂 试剂，也诱导长期废除自身免疫时， 在糖尿病发作后早期服用。 我们最近发现，白细胞介素-3（IL-3） 从15-40天开始预防或延迟糖尿病的发病， NOD小鼠。此外，IL-3处理的小鼠的骨髓细胞似乎延迟了 糖尿病的发病，当他们被收养转移， 糖尿病NOD小鼠脾细胞。因为缺乏（或缺乏）免疫力 调节细胞被假定为潜在的机制， 自身免疫性糖尿病的发展，我们假设， 在NOD小鼠中早期给予IL-3可预防糖尿病的发展 通过刺激骨髓中的自身免疫调节细胞 干扰自身免疫反应拟议的研究 将检验这个假设。四个具体目标是：1）确定一个 IL-3给药的最佳方案，2）确定 从IL-3获得骨髓细胞的免疫调节活性 给予NOD小鼠，3）表征诱导的免疫调节细胞， 通过IL-3给药，和4）确定IL-3的免疫调节活性， 用IL-3体外刺激骨髓细胞。我们相信这些 研究将提供有关机制的重要信息 NOD小鼠糖尿病发展的基础，并深入了解 可能的新的治疗方式，将防止自身免疫性糖尿病 无全身免疫抑制或相关副作用 与目前大多数免疫疗法相结合。

The non-obese diabetic (NOD) mouse spontaneously develops insulin- dependent diabetes mellitus, a polygenic disease caused by autoimmune destruction of the insulin-producing beta-cells. Development of diabetes in the NOD mouse clearly depends on T-cell function; immunosuppressive agents which suppress T-cell function (cyclosporin, antithymocyte globulin, azathioprine and prednisone) or which deplete mature T cells (anti-CD3, anti-CD4 and anti-CD8 monoclonal antibodies) prevent the development of autoimmune diabetes when they are given at an early age. Anti-lymphocyte serum (ALS), another potent T cell immunosuppressive agent, also induces a long-term abrogation of autoimmunity when administered early after the onset of diabetes. We have recently found that the administration of interleukin-3 (lL-3) starting at 15-40 days of age prevents or delays the onset of diabetes in NOD mice. Moreover, bone marrow cells of lL-3 treated mice appear to delay the onset of diabetes when they are adoptively transferred together with diabetic NOD mouse splenocytes. Because the lack (or deficiency) of immune regulatory cells has been postulated as a possible mechanism underlying the development of autoimmune diabetes, we hypothesize that administration of lL-3 at an early age in NOD mice prevents development of diabetes through stimulation of autoimmune regulatory cells in the bone marrow which interfere with auto reactive immune responses. The proposed studies will test this hypothesis. Four specific aims are: 1) to determine an optimal protocol for lL-3 administration, 2) to determine the immunoregulatory activity of bone marrow cells obtained from lL-3 administered NOD mice, 3) to characterize immunoregulatory cells induced by lL-3 administration, and 4) to determine immunoregulatory activity of bone marrow cells stimulated in vitro by lL-3. We believe that these studies will provide important information concerning the mechanism(s) underlying the development of diabetes in NOD mice and insight into a possible new therapeutic modality which would prevent autoimmune diabetes without generalized immunosuppression or the adverse effects associated with most of the current immunotherapeutic regimens.