Designer Tregs for restoring tolerance in patients with type 1 diabetes

摘要 在I型糖尿病中，胰岛被自身免疫反应破坏。因此，总的战略目标 预防胰岛损失的方法是局部抑制这种自身免疫反应，同时避免全身免疫反应， 镇压表达FoxP 3的调节性T细胞（TCFs）是在局部免疫反应中发挥核心作用的免疫细胞。 因此，可以作为细胞疗法的潜在平台，以防止胰岛损失。特什哈韦 作为抑制性细胞疗法的许多有吸引力的属性：它们可以发挥主要的免疫抑制作用， 通过细胞-细胞相互作用或产生抑制性细胞因子;原则上它们可以是长寿命的;和 由Tactobacillus诱导的耐受性可以通过赋予耐受原性特性而通过感染耐受性持续存在， 相邻的细胞。在小鼠模型中，单次输注TdR可以无限期地预防和逆转糖尿病。 在小鼠模型中令人鼓舞的初步数据已经让正在进行的临床试验的发展， 人类Treg细胞疗法。尽管如此，Treg细胞疗法仍然存在几个关键挑战： 如果它们特异性地将它们靶向胰岛并避免系统性抑制，它们很难在足够大的范围内扩增， 数量（特别是相对于常规效应T细胞），它们的细胞命运可以改变，特别是在 特别是炎症微环境。然而，在过去的几年里， 使用常规T细胞进行癌症治疗（例如CAR T细胞）的进展，包括新的 合成生物学工具，可用于精确靶向T细胞到疾病组织，以控制它们的命运， 扩散，甚至使它们能够在当地提供非天然的治疗有效载荷。这里我们的 我们的目标是利用这些新工具来解决工程改进胰岛特异性治疗的问题， 抑制细胞我们的目标是： 1)用改进的胰岛靶向和识别工程化天然THBE 2)开发工具以选择性地在体内扩增治疗性TdR并增强其稳定性 3)设计合成抑制细胞，解除效应器，抑制炎症，促进胰岛修复 这些方法将尖端的合成生物学与开发治疗药物的多种策略结合在一起。 抑制细胞我们将使用自身免疫性糖尿病的小鼠模型建立概念验证数据， 使用人源化小鼠模型，将它们应用于测试靶向人胰岛的工程化人TCLs， 自身免疫性胰岛炎本研究的成功完成将为未来的研究提供临床前数据。 在临床试验中实施这些策略。

ABSTRACT In type I diabetes, pancreatic islets are destroyed by an autoimmune reaction. Thus, a general strategic goal for preventing islet loss is to locally suppress this autoimmune response, while avoiding systemic immune suppression. FoxP3-expressing T regulatory cells (Tregs) are immune cells that play a central role in local tolerance, and therefore could serve as a potential platform for a cell therapy to prevent islet loss. Tregs have many attractive attributes as a suppressive cell therapy: they can exert dominant immunosuppressive actions, through cell-cell interactions or production of suppressive cytokines; they can in principle be long lived; and tolerance induced by Tregs can persist through infectious tolerance by conferring tolerogenic properties to neighboring cells. In mouse models, single infusion of Tregs can prevent and reverse diabetes indefinitely. The encouraging preliminary data in mouse models have let to the development of ongoing clinical trials of Treg cell therapies in humans. Nonetheless, Treg cell therapy presents several key challenges: it is hard to specifically target them to the islets and avoid systemic suppression, they are hard to expand in sufficient numbers (especially relative to conventional effector T cells), and their cell fate can be changed, especially in particular inflammatory microenvironments. In the past few years, however, there have been remarkable advances in using conventional T cells for cancer therapy (e.g. CAR T cells), including an explosion of new synthetic biology tools that can be used to precisely target T cells to disease tissues, to control their fate and proliferation, and to even give them the capability to locally deliver non-natural therapeutic payloads. Here our goal is to bring these new tools to bear on the problem of engineering improved islet-specific therapeutic suppressive cells. Our aims are to: 1) engineer natural Tregs with improved targeting and recognition of islets 2) develop tools to selectively expand therapeutic Tregs in vivo and enhance their stability 3) design synthetic suppressor cells that disarm effectors, dampen inflammation and promote islet repair These approaches wed cutting-edge synthetic biology with multiple strategies for developing therapeutic suppressor cells. We will establish proof-of-concept data using mouse model of autoimmune diabetes and apply them to test engineered human Tregs targeted to human islets using a humanized mouse model of autoimmune islet inflammation. Successful completion of this study will provide preclinical data for future implementation of these strategies in clinical trials.