iSTAR Tregs

摘要 调节性T细胞(Tregs)是T细胞的一小部分，对免疫自我耐受至关重要。他们 主要通过控制其他免疫细胞的活动来发挥作用。在1型糖尿病小鼠模型中 (T1D)，单次输注胰岛特异性Tregs可预防并稳定逆转自身免疫性糖尿病。在这些 小鼠模型，输注Tregs在胰岛积聚并阻止自身免疫攻击 胰岛β细胞通过局部表达免疫抑制功能。 T1D患者Treg细胞疗法的早期临床试验表明，生产 数十亿患者自己的Tregs输液，治疗耐受性好，安全。这些开创性的 努力为下一代Treg疗法的发展铺平了道路，旨在建立 功效。本提案中描述的研究计划侧重于战略的迫切需要，以 通过将人树突状细胞靶向胰岛并监测靶向来提高有效性 对患者的疗效。 所提出的策略是由共同的、占主导地位的免疫多肽的总体假设指导的。 在β细胞表面有高度特异性的胰岛靶向锚定。Tregs可以被设计成 以这些锚为靶点，在胰岛局部发挥免疫调节功能。此外，还成功地 可以使用释放到β细胞中的工程生物标记物来监测Tregs与β细胞的结合 外周血液。 目的1定义胰岛β细胞的免疫表位。AIM 2将开发一种细胞工程 有效和安全地将Tregs靶向胰岛的策略。AIM 3将开发一种条形码生物标记 由激活的Tregs释放到外周血液中。这些项目共同致力于开发小岛- 特定的TCR激活继电器(ISTAR)树。我们已经建立了一个由三名调查人员组成的团队， 在免疫学、β细胞生物学和技术开发方面的互补专业知识。建议数 该计划与我们的专业知识相结合，以应对精确定位胰岛方面的挑战 T1D时β细胞团的保存情况。

ABSTRACT Regulatory T cells (Tregs) are a small subset of T cells that are vital to immune self-tolerance. They function by dominantly controlling the activities of other immune cells. In mouse models of type 1 diabetes (T1D), a single infusion of islet-specific Tregs prevents and stably reverses autoimmune diabetes. In these mouse models, infused Tregs accumulate in pancreatic islets and arrest autoimmune aggression against islet beta cells by expressing immune suppressive functions locally. Early-phase clinical trials of Treg cell therapy in patients with T1D have shown that it is feasible to produce billions of patients’ own Tregs for infusion and the therapy is well tolerated and safe. These pioneering efforts have paved the way for the development of next-generation Treg therapy aiming at establishing efficacy. The research program described in this proposal focuses on a critical need for a strategy to increase effectiveness by targeting human Tregs to the pancreatic islets and to monitor the targeting efficacy in patients. The proposed strategy is guided by the overarching hypothesis that shared, dominant immunopeptides on the surface of beta cells are highly specific anchors for islet targeting. Tregs can be engineered to target these anchors to deliver their immune regulatory function locally in the islets. Moreover, successful engagement of Tregs with beta cells can be monitored using an engineered biomarker released into the peripheral blood. Aim 1 will define the immunopeptidome of pancreatic beta cells. Aim 2 will develop a cellular engineering strategy to target Tregs efficiently and safely to pancreatic islets. Aim 3 will develop a barcode biomarker that is released by activated Tregs into the peripheral blood. These projects together aim to develop islet- specific TCR activation relay (iSTAR) Tregs. We have built a team of three investigators with complementary expertise in immunology, beta cell biology, and technology development. The proposed program synergizes our expertise to tackle the challenges in precision targeting of pancreatic islets for the preservation of beta cell mass in T1D.