Engineered Immune Cells for T1D

项目摘要/摘要 这项申请是为了回应一项关于发展免疫细胞工程的建议的具体要求 1型糖尿病(T1D)的治疗。我们建议评估免疫T细胞中的基因工程方法 通过整合嵌合抗原受体(CAR)蛋白来调节细胞(Treg)，这些蛋白与 外部靶向结构域(ScFv)和内部刺激结构域。这种方法彻底改变了癌细胞。 提高T细胞作用的特异性和有效性的治疗。我们和其他人已经发现了证据 CAR Treg可以帮助调节胰岛的免疫保护，甚至可能作用于胰岛本身以减少 压力和细胞死亡。我们建议(A)确定如何增强Treg对人类的靶向和激活 胰岛可以改善胰岛功能和局部免疫调节以保护胰岛，(B)评估一种方法 通过开发和测试双目标汽车系统来增强小岛目标定位 未经评估的下游T细胞受体信号分子和(C)确定 如何增强Treg对人单核细胞的靶向和激活可能导致更多的免疫调节 单核细胞可以帮助改变对胰岛自身抗原的反应，防止免疫破坏。一个非常棒的 我们建议的重要组成部分是，我们怀疑来自T1D患者的CAR Treg可能不会 功能和正常人的汽车Treg一样好。事实上，目前还没有关于这方面的数据。我们认为 一些T1D患者的某些CAR Treg可能更具细胞毒性，效果较差，或更具炎症性 我们建议从统计学上评估这是否属实，并开发一种引入和过度表达的方法 一组已知对Treg很重要的基因的功能是确保所有Treg在所有情况下都 发挥想要的效果。我们推测，开发这些Treg方法将产生新的临床应用。 预防高危患者T1D、抑制自身免疫和保存β细胞团的策略 新发的T1D患者。

Project Summary / Abstract This application is in response to a specific request for proposals to develop immune cell engineering towards the treatment of type 1 diabetes (T1D). We propose to evaluate genetic engineering approaches in immune T regulatory cells (Treg) by integrating chimeric antigen receptor (CAR) proteins that are engineered with an external targeting domain (scFv) and internal stimulatory domain. This approach has revolutionized cancer cell therapy with heightened specificity and effectiveness of T cell action. We and others have found evidence that CAR Treg can help mediate immune protection of islets and may even act upon islets themselves to reduce stress and cell death. We propose to (a) determine how enhanced targeting and activation of Treg to human islets might improve islet function and local immune modulation to protect islets, (b) evaluate a method for enhanced islet targeting through the development and testing of a dual-targeting CAR system that exploits downstream T cell receptor signaling molecules that have not been previously evaluated and (c) determine how enhanced targeting and activation of Treg to human monocytes might result in more immunoregulatory monocytes that could help to alter response to islet autoantigens and prevent immune destruction. One very important component of our proposal is that we suspect that CAR Treg from patients with T1D may not function as well as CAR Treg from normal individuals. In fact, there is no data about this available. We think that some CAR Treg from some T1D patients might be more cytotoxic, less effective or more inflammatory and we propose to evaluate if this is true statistically and also to develop an approach to introduce and overexpress a set of genes known to be important for Treg function as a way of making sure that all Treg in all cases will exert effects that are wanted. We postulate that developing these Treg methods will produce novel clinical strategies to prevent T1D in high risk patients and to suppress autoimmunity and preserve β-cell mass in patients with recent-onset T1D.