Programming antigen specific dendritic cells in situ for T1DM immunotherapy

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，一年内大约有15,000名20岁以下的人将患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，但目前还没有一种治疗方案能够在不产生严重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展。树突状细胞（DC）是免疫系统中指导T细胞反应的关键角色，在自身免疫的背景下，已被证明在免疫原性和耐受性反应的发展中都很重要。我们的理论是，通过释放招募因子和局部控制DC微环境，在抗原存在的情况下靶向和编程DC，可以产生有效的耐受性反应。换句话说，在这个建议中，我们假设在1型糖尿病小鼠模型中，一个控制招募因子、编程因子和抗原时空呈现的物质系统可以引导树突状细胞产生耐受性，导致胰岛特异性耐受性，防止胰岛损失，并减弱胰岛破坏。

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.