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Therapeutic targeting of human islets with recombinant regulatory T cells

用重组调节性 T 细胞治疗人类胰岛

基本信息

批准号：
10018894
负责人：
Seung K Kim
金额：
$ 73.56万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018894
关键词：
Allograft Tolerance Antibodies Antigens Autoimmunity Autologous Beta Cell Binding Biology C-Peptide CD28 gene Cell Survival Cell Therapy Cell physiology Cells Clinical Clinical Trials Communities Community Networks Cytoprotection Data Diabetes Mellitus Disease Engineering Environment FOXP3 gene Genetic Goals Graft Rejection Home environment Human Hybrids IL2RA gene Image Immune Immune response Immunology Immunosuppression In Vitro Inflammation Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans L Cells Leukocytes Ligands Mediating Methods Mission Modification Molecular Analysis Monoclonal Antibodies Mus Natural regeneration Oncology Outcome Pancreas Patients Phase I/II Trial Pre-Clinical Model Reagent Recombinants Regulatory T-Lymphocyte Research Research Personnel Safety Signal Transduction Site Skin graft Specificity Surface T-Lymphocyte Technology Testing Therapeutic Transplantation antigen binding base chimeric antigen receptor chimeric antigen receptor T cells combinatorial experience extracellular flexibility functional improvement graft vs host disease high risk immunoregulation improved in vivo in vivo evaluation insulin dependent diabetes mellitus onset islet islet allograft member neoplastic cell novel preclinical study preservation prevent receptor receptor binding reconstitution success targeted treatment therapeutic target tool translational approach tumor

项目摘要

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.

项目概要/摘要该应用程序将加入靶向和再生联盟，作为人类胰岛研究的一部分 Network (HIRN) 寻求开发基于细胞的策略来靶向胰岛并克服两个中枢 1 型糖尿病 (T1D) 问题的解决方法是 (1) 针对胰岛的免疫调节并抑制免疫介导的破坏，无需全身免疫抑制，以及 (2) 传递改善 β 细胞的因子生存、功能和/或再生。 T淋巴细胞基因改造的进展彻底改变了肿瘤学等领域的治疗靶向。 T细胞可以被改造来表达嵌合抗原受体 (CAR) 将 CAR T 细胞引导至肿瘤细胞表达的特定抗原，然后激活并导致肿瘤消退和消除。这些成功促使人们对 CAR 技术进行探索非肿瘤性疾病（包括 T1D）中的调节性 T 细胞（T reg 细胞）。虽然那些研究 Treg 细胞具有免疫调节和传递营养因子的能力，已证明安全性支持胰岛细胞功能和生存——没有定位到可能需要它们的部位（如胰岛或胰腺）。该提议基于我们团队最近的发现，即小鼠 Treg 细胞可以被修饰为表达结合修饰抗体的 CAR，引导 Treg 定位至胰岛，并促进同种异体移植体内耐受性。我们已经确定了针对人类 β 细胞抗原的 CAR，可引导人类 Treg 细胞体外和体内的人类胰岛。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来预防高危患者的 T1D、抑制自身免疫并保护检测新近发病的 T1D 患者的 β 细胞量，并向胰岛输送治疗剂以保护 β 细胞，已确诊的 T1D 的功能改善或再生。我们的团队将为 CTAR 和 HIRN 带来实质性成果可以使 HIRN 使命及其成员受益的经验和新工具。