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：
10450831
负责人：
Seung K Kim
金额：
$ 70.99万
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/10450831
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 Functional Regeneration Genetic Goals Graft Rejection Home Human Hybrids IL2RA gene Immune Immune mediated destruction Immune response Immunology Immunosuppression In Vitro Inflammation Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans L Cells Leukocytes Ligands 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 bioluminescence imaging 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.

项目摘要 /摘要作为人类胰岛研究的一部分，此应用程序加入靶向和再生联盟网络（HIRN）试图制定基于细胞的策略，以靶向胰岛并克服两个中心（1）针对胰岛免疫调节并抑制免疫 - 介导的破坏，没有全身免疫抑制，（2）提供改善β细胞的因素生存，功能和/或再生。 T淋巴细胞的遗传修饰的进步已革新肿瘤学等领域的治疗靶向。可以设计T细胞以表达嵌合抗原受体（CAR）将汽车T细胞引导至由肿瘤细胞表达的特定抗原，因此它们激活并引起肿瘤的消退和消除。这些成功促使探索汽车技术在包括T1D在内的非肿瘤性疾病环境中的调节性T细胞（T Reg细胞）。而这些研究证明安全性的Treg细胞 - 具有免疫调节和传递营养因子的能力支持胰岛细胞功能和生存 - 没有本地化到可能需要的站点（例如胰岛或胰腺）。该提案是基于我们团队最近发现的鼠标Treg细胞可以修改为表达汽车将修饰的抗体结合到将Treg定位与胰岛引导并促进同种异体移植体内耐受性。我们已经确定了汽车的靶向人β细胞抗原，该抗原将人treg细胞引导至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，以防止高风险患者的T1D，抑制自身免疫性并保存最近发作T1D患者的β细胞质量已建立的T1D的功能改进或再生。我们的团队将带给CTAR和HIRN大量可以使HIRN任务及其成员受益的经验和新工具。