Engineered Immune Cells for T1D

项目总结/摘要 本申请是为了响应一个具体的要求，建议发展免疫细胞工程， 1型糖尿病（T1 D）的治疗。我们建议评估免疫T细胞的基因工程方法， 通过整合嵌合抗原受体（CAR）蛋白，调节性细胞（Treg），所述嵌合抗原受体（CAR）蛋白被工程化， 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 具有提高的特异性和T细胞作用的有效性的治疗。我们和其他人已经找到证据表明 CAR Treg可以帮助介导胰岛的免疫保护，甚至可以作用于胰岛本身，以减少胰岛细胞的增殖。 压力和细胞死亡。我们建议（a）确定如何增强Treg对人的靶向和激活 胰岛可以改善胰岛功能和局部免疫调节以保护胰岛，（B）评估用于 通过开发和测试双重靶向CAR系统增强胰岛靶向， 下游T细胞受体信号传导分子，其先前未被评估，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 我们建议的一个重要组成部分是，我们怀疑来自T1 D患者的CAR Treg可能不 功能以及来自正常个体的CAR Treg。事实上，没有这方面的数据。我们认为 来自一些T1 D患者的一些CAR Treg可能更具细胞毒性，更不有效或更具炎症性， 我们建议从统计学上评估这是否正确，并开发一种方法来引入和过度表达 一组已知对Treg功能很重要的基因，作为确保所有情况下所有Treg 发挥想要的效果。我们假设，开发这些Treg方法将产生新的临床应用。 在高危患者中预防T1 D以及在高危患者中抑制自身免疫和保护β细胞群的策略 最近发作的T1 D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.