IL2-based Immunotherapy for Type 2 Diabetes

 描述（由申请人提供）：主要研究者/项目负责人（最后，第一，中间：陈日东摘要2型糖尿病（T2 D）是心血管疾病、肾衰竭、失明、截肢和住院的主要原因。高达80%的T2 D患者超重或肥胖，这会诱导脂肪组织的慢性低度炎症，并促进胰岛素抵抗和T2 D。此外，体重增加是较老的抗糖尿病药物的常见副作用。目前的疗法不能治愈，需要每天给药。因此，迫切需要改善葡萄糖控制同时减轻体重的新疗法。CD 4 + CD 25 + Foxp 3+调节性T细胞（Treg）调节炎症和胰岛素抵抗。非常有趣的是，具有独特表型的Treg细胞在正常动物的内脏脂肪组织（VAT）中高度富集，但它们的数量在肥胖动物的胰岛素抵抗模型中显著且特异性地减少。重要的是，在肥胖的人网膜中也发现Treg数量减少。白细胞介素-2（IL-2）是通过与其高亲和力受体直接结合而使Treg产生、存活和发挥功能的关键细胞因子。 因此，用低剂量IL 2恢复VAT Treg细胞可以提供用于减轻肥胖相关的低度炎症和逆转胰岛素抵抗和T2 D的新策略。我们已经设计了一种基于IL 2的疗法，该疗法将能够选择性刺激TGFAP。在拟定的I期SBIR研究中，我们将确定每周一次治疗4周是否会改善肥胖db/db小鼠和饮食诱导肥胖小鼠的T2 D模型中的胰岛素敏感性和血糖控制，同时减少体重过度增加。该项目的长期目标是开发一种新的T2 D治疗（每周或每两周一次），单独或与当前治疗联合使用，以改善葡萄糖稳态并减轻糖尿病相关并发症，同时减少体重过度增加。

 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.