权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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/摘要申请加入目标和再生联盟作为人类岛屿研究的一部分网络(Hirn)寻求开发基于细胞的策略来瞄准胰岛并克服两个中央 1型糖尿病(T1D)的问题：(1)针对胰岛的免疫调节和抑制免疫- 介导性破坏，没有系统性免疫抑制，以及(2)提供改善β细胞的因子生存、功能和/或再生。T淋巴细胞基因修饰的进展带来了革命性的变化肿瘤学等领域的治疗靶向。T细胞可以被改造成表达嵌合抗原受体 (CAR)将CAR T细胞定向到肿瘤细胞表达的特定抗原，然后它们激活并导致肿瘤消退和消除。这些成功推动了汽车技术的探索，非肿瘤性疾病环境中的调节性T细胞(T reg细胞)，包括T1D。虽然这些研究证明安全，Treg细胞--既有免疫调节能力，又有运送营养因子的能力支持胰岛细胞功能和存活--不局限于可能需要它们的部位(如胰岛或胰腺)。这一建议是基于我们团队最近的发现，即小鼠Treg细胞可以被修改为表达结合修饰抗体将Treg定位于胰岛并促进同种异体移植的CAR‘s 体内耐受性。我们已经确定了CAR的靶向人类β细胞抗原，将人类Treg细胞定向到人胰岛的体外和活体实验。我们推测，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新近发病的T1D患者中的β细胞群，并将治疗药物输送到胰岛以保护β细胞，已建立的T1D的功能改善或再生。我们的团队将为ctar和hirn带来实质性的可使赫恩特派团及其成员受益的经验和新工具。