IL2-based Immunotherapy for Type 2 Diabetes

 描述(由申请人提供)：首席研究员/项目主任(最后、第一、中间：陈日东)摘要2型糖尿病(T2D)是心血管疾病、肾功能衰竭、失明、截肢和住院的主要原因。高达80%的T2D患者超重或肥胖，这会导致脂肪组织的慢性低度炎症，并促进胰岛素抵抗和T2D。此外，体重增加是老式抗糖尿病药物常见的副作用。目前的治疗方法不是治愈的，需要每天服用。因此，迫切需要新的治疗方法来改善血糖控制，同时减轻体重。CD4+CD25+Foxp3+调节性T细胞(Treg)调节炎症和胰岛素抵抗。有趣的是，具有独特表型的Treg细胞在正常动物的内脏脂肪组织(VAT)中高度丰富，但在肥胖动物的胰岛素抵抗模型中，它们的数量显著减少。重要的是，在肥胖的人的大网膜中也发现了Treg数量的减少。白介素2(IL-2)通过与其高亲和力受体直接结合，是Treg产生、存活和功能的关键细胞因子。 因此，用小剂量IL2修复VAT Treg细胞可能为减轻肥胖相关的低度炎症、逆转胰岛素抵抗和T2D提供一种新的策略。我们已经设计了一种基于IL2的疗法，可以选择性刺激Tregs。在拟议的第一阶段SBIR研究中，我们将确定每周治疗4周是否能改善肥胖db/db小鼠和饮食诱导肥胖小鼠的T2D模型的胰岛素敏感性和血糖控制，同时减少过度的体重增加。该项目的长期目标是开发一种新的治疗T2D的方法(每周或每两周)，单独或与现有疗法结合使用，以改善葡萄糖稳态，减少糖尿病相关并发症，同时减少过度的体重增加。

 DESCRIPTION (provided by applicant): Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Type-2 diabetes (T2D) is a leading cause of cardiovascular disease, renal failure, blindness, amputations and hospitalization. Up to 80% of T2D patients are overweight or obese, which induces chronic, low-grade inflammation of adipose tissue and promotes insulin resistance and T2D. Moreover, weight gain is the common side-effect of older anti-diabetic drugs. Current therapies are not a cure and require daily administration. Hence, novel therapy that improves glucose control while simultaneously reducing body weight is urgently needed. CD4+CD25+Foxp3+ regulatory T cells (Treg) modulate inflammation and insulin resistance. Very interestingly, Treg cells with a unique phenotype are highly enriched in the visceral adipose tissue (VAT) of normal animals, but their numbers are strikingly and specifically reduced in insulin-resistant models of obese animals. Importantly, decreased numbers of Treg are also found in obese human omental. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor. Hence, restoration of VAT Treg cells with low-dose IL2 may offer a novel strategy for mitigating obesity related low-grade inflammation and reversing insulin resistance and T2D. We have designed an IL2-based therapy that will enable selective stimulation of Tregs. In the proposed Phase I SBIR study, we will determine whether weekly treatment for 4 weeks leads to improvement of insulin sensitivity and glucose control, while reducing excessive body weight gain in the T2D models of obese db/db mice and diet-induced obese mice. The long-term goal of this project is to develop a novel treatment (weekly or bi-weekly) for T2D, alone or in combination with current therapies, to improve glucose homeostasis and attenuate diabetes-associated complications while simultaneously reducing excessive body weight gain.