Programming antigen specific dendritic cells in situ for T1DM immunotherapy

描述(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，一年内约有15000名20岁以下的人将发展为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，但没有治疗方案可以在不引起实质性副作用的情况下持久治愈1型糖尿病。自身免疫仍然是开发1型糖尿病治疗方法的一个重大挑战。1型糖尿病的免疫是胰岛特异性T细胞慢性激活的结果，最终导致胰岛的破坏和糖尿病的发生。树突状细胞(DC)是免疫系统中引导T细胞反应的关键分子，在自身免疫的背景下，已被证明对发展免疫原性和耐受性反应都很重要。我们的理论是，在抗原存在的情况下，通过释放募集因子来靶向和编程DC，以及通过局部控制DC的微环境，可以发展出强大的耐受反应。换句话说，在这项建议中，我们假设，在1型糖尿病小鼠模型中，控制招募因子、编程因子和抗原的时空呈现的物质系统可以引导树突状细胞走向耐受性命运，并导致胰岛特异性耐受，防止胰岛丢失，并减轻胰岛破坏。 与公共卫生相关：在美国，1型糖尿病影响着100万至200万人，而且该疾病的患病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，导致显著的发病率，而没有实质性副作用的治疗方法并不存在。这项研究的目标是对免疫系统进行重新编程，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.