Programming antigen specific dendritic cells in situ for type 1 diabetes immunoth

描述（由申请人提供）：在美国，估计有2360万人患有糖尿病，其中5-10%患有1型糖尿病，并且在一年内约有15，000名20岁以下的个体将发展为1型糖尿病。尽管最近在药物开发和器官移植方面取得了进展，但没有治疗选择可以产生持久的1型糖尿病治愈而不引起显著的副作用。自身免疫仍然是开发1型糖尿病治愈方法的重大挑战。1型糖尿病的免疫是胰岛特异性T细胞慢性激活的结果，导致胰岛的最终破坏和糖尿病的发展。树突状细胞（DC）是免疫系统中的关键参与者，其指导T细胞应答，并且在自身免疫的情况下，已经显示对于产生免疫原性和致耐受性应答两者都是重要的。我们的理论是，通过在抗原存在下通过释放募集因子靶向和编程DC以及通过局部控制DC微环境，可以产生有效的致耐受性应答。换句话说，在这个提议中，我们假设一个控制招募因子、编程因子和抗原的时空呈递的材料系统可以将树突状细胞导向致耐受性命运，并导致胰岛特异性耐受，预防胰岛损失，并在1型糖尿病小鼠模型中减弱胰岛破坏。 公共卫生相关性：1型糖尿病在美国影响1至2百万人，并且患有该疾病的人数正在以越来越快的速度增长。不幸的是，随着时间的推移，这种疾病会损害血管，导致严重的发病率，并且不存在没有实质性副作用的治疗方法。这项研究的目的是重新编程免疫系统，以预防或治愈1型糖尿病。

DESCRIPTION (provided by applicant): In the United States an estimated 23.6 million people have diabetes, of those 5-10% have type 1 diabetes and within a year approximately 15,000 individuals under the age of 20 will develop type 1 diabetes. Despite recent advances in pharmaceutical development and in organ transplantation, no treatment options exist to generate a durable cure for type 1 diabetes without causing substantial side effects. Autoimmunity remains a significant challenge in developing a cure for type 1 diabetes. The immunity in type 1 diabetes is the result of chronic activation of islet-specific T cells, leading to the eventual destruction of the islets and the development of diabetes. Dendritic cells (DC) are key players in the immune system that direct T cell responses and, in the setting of autoimmunity, have been shown to be important for developing both immunogenic and tolerogenic responses. We theorize that by both targeting and programming DC in the presence of antigen through the release of recruitment factors and by locally controlling the DCs microenvironment, potent tolerogenic responses can be developed. In other words, in this proposal we hypothesize that a material system that controls the spatiotemporal presentation of a recruiting factor, programming factor, and antigen can direct dendritic cells to a tolerogenic fate and lead to islet specific tolerance, the prevention of islet loss, and the attenuation of islet destruction in a murine model of type 1 diabetes. PUBLIC HEALTH RELEVANCE: Type 1 diabetes affects 1 to 2 million people in the United States and the number of people with the disease is growing at an increasing rate. Unfortunately, over time the disease damages the blood vessels leading to significant morbidity and a cure without substantial side effects does not exist. The goal of this research is to reprogram the immune system to prevent the onset or to cure type 1 diabetes.