Genetically Engineered Antigen Specific Treg to Treat Autoimmunity

基因工程抗原特异性 Treg 治疗自身免疫性疾病

• 批准号: 7688822
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 19.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688822
• 关键词: Address; Affect; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Biology; Cell Therapy; Cell physiology; Cells; Chronic; Development; Disease; Engineering; Epidemic; Financial cost; Frequencies; Future; Generations; Genes; Genetic Engineering; Goals; Human; Human Engineering; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; Longevity; Measures; Mind; Multiple Sclerosis; Mus; Pancreas; Patients; Population; Prevention; Proinsulin; Protocols documentation; Publishing; Reporting; Rheumatoid Arthritis; Safety; Specificity; Suicide; Systemic Lupus Erythematosus; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Viral; Work; autoreactive T cell; base; clinical application; design; effective therapy; in vivo; in vivo Model; islet; migration; mouse model; novel; novel strategies; prevent; research study; response; restoration; success; therapeutic gene

Autoimmunity is reaching epidemic proportions with tens of millions of people suffering from diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes (T1D), systemic lupus erythematosus and others. In addition to its financial costs, the long term complications of these diseases can be devastating. A curative therapy is desperately needed. At present, efforts to prevent or reverse autoimmune diseases have been limited by the lack of safe and effective immunotherapies. With this challenge in mind, we believe the induction of immunological tolerance is a fundamental requirement for any effective therapy. Previous studies, including numerous published reports from our ACEs group and others, have focused on the use of regulatory T cells (Tregs) as one means of restoring tolerance in autoimmunity. This notion is based on the core "principle that treatment with Tregs will lead to the induction of long-term tolerance. Most significantly, there is strong evidence that self-antigen-specific Tregs are most effective to treat a variety of autoimmune diseases. However, the identification and application of these cells have been compromised by the lack of effective solation and expansion protocols for these low frequency cells. Thus, novel approaches are necessary to address this need. Specifically, this application proposes to develop novel approaches to generate a sufficient quantity of antigenspecific Tregs capable of restoring tolerance and averting autoimmunity. These studies will be performed as a collaborative effort between the Abbas and Bluestone labs where multiple mouse models have been established and be used to rapidly test theoretical cell manipulations. These efforts will inform and enhance the bulk researzahc efforts in his proposal develoted to human Treg studies and the development of engenerred Tregs that can be used both to study lie biology of Tregs and potentially be developed for clinical application. To address these key issues, the following pecific aims are proposed. Aim 1.Develop engineered antigen-specific Tregs by introducing autoreactive T cell eceptors (TCRs) and other therapeutic genes. Aim 2. Assess the mechanisms and safety of cellular therapy with ngineered Tregs. Aim 3. To generate high numbers of autoreactive engineered Tregs capable of suppressing 'athogenic autoreactive T cell responses.

自身免疫正在达到流行病的比例，数千万人患有多种疾病， 硬化症、类风湿性关节炎、1型糖尿病（T1D）、系统性红斑狼疮等。除了其 这些疾病的长期并发症可能是毁灭性的。一种治疗方法 needed.目前，预防或逆转自身免疫性疾病的努力因缺乏安全有效的 免疫疗法考虑到这一挑战，我们认为诱导免疫耐受是一个基本的 任何有效治疗的要求。以前的研究，包括我们的ACE小组发表的许多报告， 其他人集中于使用调节性T细胞（Tcells）作为恢复自身免疫耐受性的一种手段。这 这一概念是基于“核心“原则，即用TdR治疗将导致诱导长期耐受性。最 值得注意是，有强有力的证据表明，自身抗原特异性THBE对治疗各种自身免疫性疾病是最有效的 疾病然而，这些细胞的鉴定和应用由于缺乏有效的细胞学方法而受到损害。 这些低频电池的隔离和扩展协议。因此，需要新的方法来解决这个问题 需要的具体地，本申请提出开发新的方法来产生足够量的抗原特异性抗体。 能够恢复耐受性和避免自身免疫的抗体。这些研究将作为 Abbas和Bluestone实验室之间的合作努力，已经建立了多种小鼠模型， 用于快速测试理论细胞操作。这些努力将为以下方面的大量研究工作提供信息并加强这些工作： 他的建议发展到人类Treg研究和开发既可用于研究 因此，我们有可能开发出一种新的生物学特性用于临床应用。为了解决这些关键问题， 提出了具体目标。目的1.通过引入自身反应性T细胞开发工程化抗原特异性调节性T细胞 受体（TCR）和其他治疗基因。目标二。评估细胞疗法的机制和安全性， 设计师Tegel。目标3.为了产生大量的自身反应性的工程化的T细胞， 致病性自身反应性T细胞反应。