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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：
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