Engineering CAR Tregs for type 1 diabetes

摘要 1型糖尿病(T1D)是由于免疫耐受性的崩溃和由此产生的T细胞- 介导对胰腺中产生胰岛素的β细胞的破坏。这是由缺陷引起的 “调节性”T细胞(或Tregs)，通常会抑制有害的免疫反应。在T1D，Tregs停止 保护贝塔细胞。来自T1D动物模型的研究表明，Tregs的治疗性修复可以 预防疾病进展，临床研究表明这种方法在人类身上是安全的。 尽管取得了初步的成功，但在T1D的长期和全球Treg治疗方面仍存在重大障碍。 目前的方法是注入大量未被选作抗原的多克隆树。 特异性，因此它们存在非特异性免疫抑制的风险。此外，它还很难扩大 足够的这些多克隆Tregs用于治疗，即使这样，也只有一小部分细胞 实际上抑制了自身免疫力。这些挑战可以通过创建符合以下条件的“设计者”树来解决 为特异性而设计，并有最好的机会重置免疫耐受。如果成功，这将是 技术将带来更个性化和更有效的T1D免疫疗法。我们最近开发了 一种利用嵌合抗原重定向抗原特异性Tregs的方法 感受器或汽车。在这个应用中，我们将测试多肽特异性MHC-CAR-Tregs是否可以预防和/或 逆转NOD小鼠T1D。我们假设小鼠Tregs表达一种混合胰岛素肽-MHCII- 特定的CAR通过恢复免疫耐受性和抑制自身反应性效应CD4+来预防T1D 和CD8+T细胞的功能，以限制它们在胰腺中的积聚。

Summary Type 1 diabetes (T1D) results from a breakdown in immunological tolerance and the resulting T cell- mediated destruction of insulin producing beta cells in the pancreas. This is caused by defective “regulatory” T cells (or Tregs), which normally suppress harmful immune responses. In T1D, Tregs stop protecting beta cells. Work from T1D animal models has shown that therapeutic restoration of Tregs can prevent disease progression, and clinical studies have shown the safety of this approach in humans. Despite this initial success, there are significant hurdles for long term and global Treg therapy in T1D. Current methods infuse large numbers of polyclonal Tregs that have not been selected for antigen specificity, so they carry the risk of non-specific immunosuppression. Furthermore, it is difficult to expand enough of these polyclonal Tregs required for therapy, and even then, only a small fraction of the cells actually suppress autoimmunity. These challenges can be solved by creating “designer” Tregs that are engineered for specificity and have the best chance of resetting immune tolerance. If successful, this technology would lead to a more personalized and effective T1D immunotherapy. We recently developed an approach to engineer antigen-specific Tregs by re-directing their specificity using chimeric antigen receptors, or CARs. In this application, we will test if peptide specific MHC-CAR-Tregs prevent and/or reverse T1D in NOD mice. We hypothesize that mouse Tregs expressing a hybrid insulin peptide-MHCII- specific CAR will prevent T1D by restoring immune tolerance and suppressing autoreactive effector CD4+ and CD8+ T cell function to limit their accumulation in the pancreas.