New approach for immune modulation against T1D

项目摘要/摘要 1型糖尿病(T1D)是一种自身免疫性疾病，在美国18岁前每300人中就有1人受到影响。T1D是 以免疫介导的胰岛素破坏引起的急性高血糖为特征- 在胰腺中产生β细胞。目前还没有治愈T1D的方法，这种疾病需要不断地 目前的护理/管理标准是注射或泵送胰岛素的管理。因此，有一个 迫切需要为T1D患者提供新的有效治疗方案。而自身反应性的CD4和CD8 T细胞 调节性T细胞(Treg)是中枢致病的驱动力，已被证明可以抑制自身免疫并维持 通过多种机制产生免疫耐受。在T1D患者中，Treg功能受损已被证明是 对疾病易感性的影响。因此，Tregs的诱导在纠正这种异常方面有很大的希望。 自身反应性T细胞活性与预防T1D的进展然而，目前尚不清楚如何诱导 Tregs是一种安全有效的潜在治疗T1D的方法。在这里，我们建议开发一部小说 针对T1D的免疫治疗策略。为了实现这一目标，我们开发了合成高密度脂蛋白 特别适合于淋巴结靶向的纳米盘。我们的初步数据产生于一只小鼠 T1D模型和实验性自身免疫性脑脊髓炎的研究表明，携带抗原的纳米盘 只能诱导强大的Treg反应并实现免疫耐受。基于我们令人信服的概念验证 数据，我们建议开发携带抗原的纳米盘来促进抗原特异性免疫耐受 T1D。本研究将为胰腺免疫微环境的调控提供新的策略。 以及对T1D免疫耐受的途径。

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease that affects 1 in 300 people by the age of 18 in the US. T1D is characterized by acute onset of hyperglycemia resulting from immune-mediated destruction of the insulin- producing β-cells in the pancreas. There is currently no cure for T1D and the disease requires constant management where the current standard of care/management is injected or pumped insulin. Thus, there is an urgent need for new and effective treatment options for T1D patients. While self-reactive CD4 and CD8 T cells are central pathogenic drivers, regulatory T cells (Tregs) have been shown to restrain autoimmunity and maintain immune tolerance through multiple mechanisms. In T1D patients, impaired Treg function have been shown to contribute to disease susceptibility. Thus, induction of Tregs holds great promise in correcting the aberrant autoreactive T cell activities and preventing the progression of T1D. However, it remains unknown how to induce Tregs in a safe and effective manner for the potential treatment of T1D. Here, we propose to develop a novel strategy for immunotherapy against T1D. Toward this goal, we have developed synthetic high-density lipoprotein NanoDiscs that are particularly well suited for lymph node targeting. Our preliminary data generated in a murine model of T1D and experimental autoimmune encephalomyelitis have shown that NanoDiscs carrying antigens only induce robust Treg response and achieve immune tolerance. Based on our compelling proof-of-concept data, we propose to develop NanoDiscs carrying antigens to promote antigen-specific immune tolerance against T1D. The proposed research will provide a new strategy for modulating immune microenvironment of pancreas and an avenue for immune tolerance against T1D.