Genetically Engineered Antigen Specific Treg to Treat Autoimmunity

自身免疫正在达到流行的程度，数千万人患有多发性硬化症等疾病 硬化症、类风湿性关节炎、1型糖尿病(T1D)、系统性红斑狼疮等。除了它的 除了经济成本，这些疾病的长期并发症可能是毁灭性的。一种根治疗法是不顾一切的 需要的。目前，由于缺乏安全有效的方法，预防或逆转自身免疫性疾病的努力受到限制。 免疫疗法。考虑到这一挑战，我们认为诱导免疫耐受是一个根本的 对任何有效治疗的要求。之前的研究，包括我们的ACES小组和 其他人则专注于使用调节性T细胞(Tregs)作为恢复自身免疫耐受性的一种手段。这 理念基于核心原则，即使用Tregs治疗将导致长期耐受的诱导。 值得注意的是，有强有力的证据表明，自身抗原特异性树突状细胞对治疗各种自身免疫疾病最有效。 疾病。然而，由于缺乏有效的方法，这些细胞的鉴定和应用受到了影响 这些低频小区的隔离和扩展协议。因此，需要新的方法来解决这一问题 需要。具体地说，这项申请建议开发新的方法来产生足够数量的抗原性 能够恢复耐受和避免自身免疫的树突状细胞。这些研究将作为 阿巴斯和蓝石实验室之间的合作努力，其中已经建立了多个小鼠模型，并将 用于快速测试理论单元格操作。这些努力将提供信息并加强#年的大量研究工作。 他的建议发展到人类Treg研究和开发既可用于研究的生成Treg Tregs的谎言生物学，并有可能开发为临床应用。要解决这些关键问题，请执行以下操作 提出了具体的目标。目的1.通过引入自身反应性T细胞开发基因工程抗原特异性树突状细胞 受体(TCR)和其他治疗基因。目的2.评估细胞治疗的机制和安全性 工程兵特雷格。目的3.产生大量能够抑制自身反应的工程树 致病的自身反应性T细胞反应。

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.