iSTAR Tregs

基本信息

批准号：
10731341
负责人：
MICHAEL T MCMANUS
金额：
$ 96.9万
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：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731341
关键词：
Address Aggressive behavior Antigen Presentation Antigens Autoimmune Autoimmune Diabetes Bar Codes Beta Cell Biological Markers Blood Cell Therapy Cells Cellular biology Clinical Development Diabetes Mellitus Effectiveness Engineering Frequencies HLA-A2 Antigen Homeostasis Human Immune Immunology Immunosuppression Immunotherapy In Vitro Individual Inflammation Infusion procedures Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Maps Mass Spectrum Analysis Molecular Monitor Pancreas Patients Peptides Process Program Description RNA Regulatory T-Lymphocyte Research Research Personnel Safety Specificity Structure of beta Cell of islet Surface T cell therapy T-Cell Immunologic Specificity T-Lymphocyte Subsets TCR Activation Technology Testing Tissues cellular engineering early phase clinical trial efficacy evaluation endocrine pancreas development experience extracellular vesicles human pluripotent stem cell humanized mouse immune self tolerance improved in vivo islet lymph nodes mouse model next generation peripheral blood preproinsulin preservation prevent programs selective expression stem cells synergism technology development therapeutic target therapy development

项目摘要

ABSTRACT Regulatory T cells (Tregs) are a small subset of T cells that are vital to immune self-tolerance. They function by dominantly controlling the activities of other immune cells. In mouse models of type 1 diabetes (T1D), a single infusion of islet-specific Tregs prevents and stably reverses autoimmune diabetes. In these mouse models, infused Tregs accumulate in pancreatic islets and arrest autoimmune aggression against islet beta cells by expressing immune suppressive functions locally. Early-phase clinical trials of Treg cell therapy in patients with T1D have shown that it is feasible to produce billions of patients’ own Tregs for infusion and the therapy is well tolerated and safe. These pioneering efforts have paved the way for the development of next-generation Treg therapy aiming at establishing efficacy. The research program described in this proposal focuses on a critical need for a strategy to increase effectiveness by targeting human Tregs to the pancreatic islets and to monitor the targeting efficacy in patients. The proposed strategy is guided by the overarching hypothesis that shared, dominant immunopeptides on the surface of beta cells are highly specific anchors for islet targeting. Tregs can be engineered to target these anchors to deliver their immune regulatory function locally in the islets. Moreover, successful engagement of Tregs with beta cells can be monitored using an engineered biomarker released into the peripheral blood. Aim 1 will define the immunopeptidome of pancreatic beta cells. Aim 2 will develop a cellular engineering strategy to target Tregs efficiently and safely to pancreatic islets. Aim 3 will develop a barcode biomarker that is released by activated Tregs into the peripheral blood. These projects together aim to develop islet- specific TCR activation relay (iSTAR) Tregs. We have built a team of three investigators with complementary expertise in immunology, beta cell biology, and technology development. The proposed program synergizes our expertise to tackle the challenges in precision targeting of pancreatic islets for the preservation of beta cell mass in T1D.

抽象的调节性 T 细胞 (Treg) 是 T 细胞的一小部分，对免疫自我耐受至关重要。在 1 型糖尿病小鼠模型中，它通过显着控制其他免疫细胞的活动来发挥作用。 (T1D)，单次输注胰岛特异性 Tregs 可以预防并稳定逆转自身免疫性糖尿病。小鼠模型中，注入的 Tregs 在胰岛中积聚并阻止自身免疫攻击胰岛β细胞通过局部表达免疫抑制功能。 Treg细胞治疗T1D患者的早期临床试验表明，生产Treg细胞是可行的数十亿患者自己的Tregs用于输注，并且该疗法具有良好的耐受性和安全性。为下一代 Treg 疗法的开发铺平了道路，旨在建立本提案中描述的研究计划重点关注对战略的迫切需求。通过将人类 Tregs 靶向胰岛并监测靶向来提高有效性对患者的疗效。所提出的策略以共享的、占主导地位的免疫肽的总体假设为指导 β 细胞表面是胰岛靶向的高度特异性锚定点，可通过基因工程改造。靶向这些锚点以在胰岛局部发挥其免疫调节功能。可以使用释放到细胞中的工程生物标志物来监测 Tregs 与 β 细胞的结合。外周血。目标 1 将定义胰腺 β 细胞的免疫肽组，目标 2 将开发细胞工程。有效、安全地将 Tregs 靶向胰岛的策略 Aim 3 将开发一种条形码生物标记物。这些项目共同旨在开发胰岛细胞。特定 TCR 激活中继 (iSTAR) Tregs 我们建立了一个由三名研究人员组成的团队。免疫学、β细胞生物学和技术开发方面的互补专业知识。计划协同我们的专业知识来应对胰岛精确靶向的挑战 T1D 中 β 细胞团的保存。