New approach for immune modulation against T1D

项目概要/摘要 1 型糖尿病 (T1D) 是一种自身免疫性疾病，在美国，每 300 人中就有 1 人患有 18 岁糖尿病。 T1D 是 其特征是由于免疫介导的胰岛素破坏而导致急性高血糖发作。 在胰腺中产生β细胞。目前 T1D 尚无治愈方法，该疾病需要持续治疗 目前的护理/管理标准是注射或泵入胰岛素。因此，有一个 T1D 患者迫切需要新的有效治疗方案。而自身反应性 CD4 和 CD8 T 细胞 调节性 T 细胞 (Treg) 是主要的致病驱动因素，已被证明可以抑制自身免疫并维持 通过多种机制实现免疫耐受。在 T1D 患者中，Treg 功能受损已被证明 有助于疾病的易感性。因此，Tregs 的诱导在纠正异常方面具有巨大的希望。 自身反应性 T 细胞活性并预防 T1D 的进展。但目前尚不清楚如何诱导 Tregs 以安全有效的方式潜在治疗 T1D。在这里，我们建议开发一部小说 针对 T1D 的免疫治疗策略。为了这个目标，我们开发了合成高密度脂蛋白 NanoDisc 特别适合淋巴结靶向。我们在小鼠身上生成的初步数据 T1D 和实验性自身免疫性脑脊髓炎模型表明，NanoDiscs 携带抗原 只有诱导强有力的Treg反应并实现免疫耐受。基于我们令人信服的概念验证 数据显示，我们建议开发携带抗原的NanoDiscs，以促进抗原特异性免疫耐受 T1D。该研究将为调节胰腺免疫微环境提供新策略 以及针对 T1D 的免疫耐受的途径。

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.