Designer Tregs for restoring tolerance in patients with type 1 diabetes

用于恢复 1 型糖尿病患者耐受性的设计 Tregs

基本信息

批准号：
9459191
负责人：
JEFFREY A BLUESTONE
金额：
$ 335.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9459191
关键词：
Affinity Alpha Cell Animal Model Antigen Targeting Antigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmune Responses Beta Cell Biological Availability CD4 Positive T Lymphocytes Cell Communication Cell Therapy Cells Clinical Trials Data Development Diabetes Mellitus Disease Dose Engineering Ensure Environment Explosion FOXP3 gene Frequencies Future Goals Grant Human Human Engineering IL2RA gene Immune Immune Tolerance Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents In Vitro Inflammation Inflammatory Infusion procedures Insulin-Dependent Diabetes Mellitus Interleukin 2 Receptor Interleukin-2 Islets of Langerhans Knowledge Malignant Neoplasms Modality Modeling Mus Natural Killer Cells Normal tissue morphology Patients Play Population Prevention Process Production Property Protein Engineering Reaction Regulatory T-Lymphocyte Research Risk Role Safety Self-control as a personality trait Specificity Structure of beta Cell of islet Suppressor-Effector T-Lymphocytes Surface Antigens T-Lymphocyte Testing Therapeutic Tissues Ursidae Family autocrine base cancer therapy cellular engineering chimeric antigen receptor clinical development cytokine design genome wide association study humanized mouse improved in vivo islet mouse model next generation novel pre-clinical prevent programs receptor expression repaired response synthetic biology tissue repair tool

项目摘要

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.

抽象的在I型糖尿病中，胰岛被自身免疫反应破坏。因此，一个一般的战略目标为了防止胰岛损失，是在局部抑制这种自身免疫反应，同时避免全身免疫抑制。表达FOXP3的T调节细胞（TREG）是免疫细胞，在局部起着核心作用耐受性，因此可以作为预防胰岛损失的细胞疗法的潜在平台。 Tregs有许多有吸引力的属性作为一种抑制性细胞疗法：它们可以发挥主导性免疫抑制作用，通过细胞 - 细胞相互作用或抑制细胞因子的产生；他们原则上可以长期以来的生活；和 Treg诱导的耐受性可以通过传染性来持续存在，通过赋予耐受性特性相邻的细胞。在小鼠模型中，单次输注Treg可以无限期预防和反向糖尿病。小鼠模型中令人鼓舞的初步数据已使正在进行的临床试验的发展人类中的Treg细胞疗法。尽管如此，Treg细胞疗法提出了几个关键挑战：很难特别针对胰岛并避免全身抑制，它们很难足够扩展数字（尤其是相对于常规效应T细胞），并且可以更改其细胞命运，尤其是在特定的炎症微环境。然而，在过去的几年中，有很棒的使用常规T细胞进行癌症治疗（例如CAR T细胞）的进步，包括新的合成生物学工具可用于精确靶向T细胞以疾病组织，控制其命运和扩散，甚至赋予他们当地提供非天然治疗有效载荷的能力。这是我们的目标是将这些新工具带入工程改进的胰岛特异性治疗问题抑制细胞。我们的目标是： 1）工程师天然tregs具有改进的靶向和识别 2）开发工具以选择性地扩展体内治疗性Treg并增强其稳定性 3）设计合成抑制器细胞，解除效应子，抑制炎症和促进胰岛修复这些方法将尖端的合成生物学与多种策略相结合抑制细胞。我们将使用自身免疫性糖尿病的鼠标模型建立概念验证数据和将它们应用于针对人类胰岛的测试工程的人脉，使用人源化的鼠标模型自身免疫性胰岛炎症。这项研究的成功完成将为未来提供临床前数据在临床试验中实施这些策略。