Therapeutic targeting of human islets with recombinant regulatory T cells

项目概要/摘要 本申请加入作为人类胰岛研究一部分的靶向和再生联盟 网络（HIRN）寻求开发基于细胞的策略，以靶向胰岛，并克服两个核心问题。 1型糖尿病（T1 D）的问题，通过（1）靶向免疫调节胰岛和抑制免疫- 介导的破坏，而没有全身性免疫抑制，和（2）递送改善β细胞增殖的因子， 存活、功能和/或再生。T淋巴细胞遗传修饰的进展已经彻底改变了 肿瘤学等领域的治疗靶向。T细胞可以被工程化以表达嵌合抗原受体 (CAR)它将CAR T细胞导向肿瘤细胞表达的特异性抗原，从而它们被激活， 导致肿瘤消退和消除。这些成功促进了对CAR技术的探索， 调节性T细胞（T reg细胞）在非肿瘤性疾病的设置，包括T1 D。虽然这些研究 Treg细胞具有免疫调节和递送营养因子的能力， 支持胰岛细胞功能和存活-没有定位于可能需要它们的部位（如胰岛或 胰腺）。这项提议是基于我们团队最近的发现，即小鼠Treg细胞可以被修饰， 表达CAR，其结合修饰的抗体以指导Treg定位于胰岛，并促进同种异体移植物 体内耐受性我们已经鉴定了靶向人β细胞抗原的CAR，其指导人Treg细胞 体外和体内的人胰岛。我们假设，开发这些基于T细胞的靶向方法将 制定新的临床策略，以预防高危患者的T1 D，抑制自身免疫， 最近发作的T1 D患者的β细胞质量，并向胰岛递送治疗剂以保护β细胞， 功能改善或再生已建立的T1 D。我们的团队将为CTAR和HIRN带来大量 经验和新的工具，可以使HIRN使命及其成员受益。

Project Summary / Abstract This application to join the Consortium on Targeting And Regeneration as part of the Human Islet Research Network (HIRN) seeks to develop cell-based strategies to target pancreatic islets and overcome two central problems in type 1 diabetes (T1D) by (1) targeting immunoregulation to islets and suppressing immune- mediated destruction, without systemic immuno-suppression, and (2) delivering factors that improve β-cell survival, function and/or regeneration. Advances in genetic modification of T lymphocytes have revolutionized therapeutic targeting in fields like oncology. T cells can be engineered to express chimeric antigen receptors (CAR) that direct CAR T-cells to specific antigens expressed by neoplastic cells whereupon they activate and cause tumor regression and elimination. These successes have prompted exploration of CAR technology with regulatory T cells (T reg cells) in non-neoplastic disease settings, including T1D. While those studies demonstrated safety, Treg cells – which have the ability both to immunomodulate and deliver trophic factors supporting islet cell function and survival – did not localize to sites where they may be needed (like islets or pancreas). This proposal is based on recent discoveries by our team that mouse Treg cells can be modified to express CAR's which bind modified antibodies to direct Treg localization to islets, and promote allograft tolerance in vivo. We have identified CAR's targeting human β-cell antigens that direct human Treg cells to human islets in vitro and in vivo. We postulate that developing these T cell-based targeting methods will produce novel clinical strategies to prevent T1D in high risk patients, to suppress autoimmunity and preserve β-cell mass in patients with recent-onset T1D, and to deliver therapeutics to the islet for β-cell protection, functional improvement or regeneration in established T1D. Our team will bring to CTAR and HIRN substantial experience and new tools that could benefit the HIRN mission and its members.