iSTAR Tregs

iSTAR Tregs

• 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
• 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

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.

摘要 调节性T细胞（Regulatory T cells，TCFs）是一小部分T细胞，对免疫自身耐受至关重要。他们 通过控制其他免疫细胞的活动来发挥作用。在1型糖尿病小鼠模型中 (T1D)，单次输注胰岛特异性TdR可预防并稳定逆转自身免疫性糖尿病。在这些 在小鼠模型中，输注的睾酮在胰岛中积累，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细胞疗法在T1 D患者中的早期临床试验表明， 数十亿患者自己输注THBE，并且该疗法耐受性良好且安全。这些开创性 这些努力为开发下一代Treg疗法铺平了道路， 功效本提案中描述的研究计划侧重于对战略的迫切需要， 通过将人THBE靶向胰岛来提高有效性，并监测靶向 患者的疗效。 所提出的策略是由一个总体假设指导的，即共享的，占主导地位的免疫肽 在β细胞的表面上是用于胰岛靶向的高度特异性锚。可以将TSTK设计为 靶向这些锚以在胰岛中局部地传递它们的免疫调节功能。此外，成功 可以使用释放到细胞中的工程化生物标志物来监测TcB与β细胞的接合。 外周血 目的1：明确胰腺β细胞的免疫肽组。AIM 2将开发一种细胞工程学 有效和安全地靶向胰岛的策略。Aim 3将开发一种条形码生物标志物 由活化的TdR释放到外周血中。这些项目共同致力于开发岛- 特定TCR激活继电器（iSTAR）TcR。我们已经建立了一个由三名调查员组成的团队， 免疫学、β细胞生物学和技术开发方面的互补专业知识。拟议 该计划协同我们的专业知识，以应对精确靶向胰岛的挑战， T1 D中β细胞群的保存。