Programming antigen specific dendritic cells in situ for T1DM immunotherapy

原位编程抗原特异性树突状细胞用于 T1DM 免疫治疗

• 批准号: 8144429
• 负责人: roger warren sands
• 金额: $ 4.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2013-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144429
• 关键词: Adverse effects; Affect; Age; Antigen Presentation; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Blood Vessels; CD8B1 gene; Cell Therapy; Cell Transplants; Cells; Chronic; Clinical Research; Control Animal; Dendritic Cell Therapy; Dendritic Cells; Dendritic cell activation; Development; Diabetes Mellitus; Diagnosis; Disease; Engineering; Future; Goals; Immune system; Immunity; Immunosuppressive Agents; Immunotherapy; In Situ; Individual; Insulin-Dependent Diabetes Mellitus; Lead; Modeling; Morbidity - disease rate; Multiple Sclerosis; Mus; Organ Transplantation; Pancreas; Patients; Pharmacologic Substance; Prediabetes syndrome; Prevention; Proteins; RNA Interference; Recruitment Activity; Research; Rheumatoid Arthritis; Role; Stem cells; System; T cell differentiation; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapy Clinical Trials; Time; Treatment Efficacy; United States; Vaccines; attenuation; autoreactivity; cost; endocrine pancreas development; high risk; immunogenic; islet; knowledge of results; novel; prevent; programs; prophylactic; public health relevance; response; spatiotemporal; tool; trafficking; type I diabetic

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.

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 岁以下的人将患上 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，但尚不存在能够持久治愈 1 型糖尿病而不引起严重副作用的治疗选择。自身免疫仍然是开发 1 型糖尿病治疗方法的重大挑战。 1 型糖尿病的免疫是胰岛特异性 T 细胞慢性激活的结果，导致胰岛最终遭到破坏并发展为糖尿病。树突状细胞 (DC) 是免疫系统中指导 T 细胞反应的关键参与者，并且在自身免疫的情况下，已被证明对于产生免疫原性和耐受性反应非常重要。我们推测，在抗原存在的情况下，通过释放募集因子来靶向和编程 DC，并通过局部控制 DC 微环境，可以产生有效的耐受性反应。换句话说，在这个提议中，我们假设控制募集因子、编程因子和抗原时空表达的物质系统可以引导树突状细胞产生耐受性命运，并在 1 型糖尿病小鼠模型中导致胰岛特异性耐受、预防胰岛丢失和减弱胰岛破坏。 公共卫生相关性：1 型糖尿病影响着美国 1 至 200 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，导致显着的发病率，并且不存在没有明显副作用的治疗方法。这项研究的目标是重新编程免疫系统以预防 1 型糖尿病的发作或治愈 1 型糖尿病。