Memory CD8 T Cell Survival and Function Following Experimental BMT

实验性 BMT 后记忆 CD8 T 细胞的存活和功能

• 批准号: 7777348
• 负责人: Robert Benjamin Levy
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777348
• 关键词: Address; Affect; Antigens; Apoptotic; Autologous; B-Lymphocytes; Blood; CD8B1 gene; Cancer Vaccines; Cell Survival; Cell Transplants; Cells; Chimeric Proteins; Cytotoxic Chemotherapy; Defect; Dose; Effectiveness; Effector Cell; Engraftment; Evaluation; Generations; Goals; Heat shock proteins; Hematopoietic; Immune; Immune response; Immunity; In Vitro; Infection; Infection Control; Interleukin-15; Interleukin-7; Investigation; Kinetics; Knock-out; Lymphoid; Maintenance; Marrow; Mediating; Memory; Modeling; Monitor; Morbidity - disease rate; Mus; Outcome; Output; Patients; Peptides; Physiologic pulse; Population; Recovery; Regimen; Regulation; Relative (related person); Research Personnel; Resistance; Role; Stem cells; T memory cell; T-Lymphocyte; Testing; Time; Transgenic Organisms; Transplant Recipients; Transplantation; Tumor Antigens; Tumor Burden; Tumor Immunity; Vaccination; Vaccines; Viral; conditioning; design; immune function; in vivo; insight; interest; minor H antigen H60; model design; mortality; neoplastic cell; programs; reconstitution; research study; response; stem; tumor; tumor progression

T cells can survive hematopoietic stem/progenitor cell transplants (HSPCT) following non-ablative and ablative conditioning regimens, for example radioresistant T cells mediate resistance to hematopoietic grafts and infection. Recent findings suggest that memory T cells (TM) should survive more effectively vs. naive cells as a result of enhanced anti-apoptotic regulation in this subset and new preliminary findings in this proposal demonstrate survival and expansion of infused and endogenous antigen specific host TM post- transplant. The experiments in this project will address questions testing the hypothesis that existing CDS TM pre-conditioning and TM infused at the time of transplant will result in enhanced antigen-specific immunity in the early (reconstituting) post-transplant immune compartment Experiments will examine the survival, expansion and function of memory populations and compare them to naive T cells in the post-HSPCT recipient. To accomplish these studies we will utilize and compare TCR transgenic (OT-I) and non-transgenic (H60) antigen specific TM including in vitro derived memory populations. Experiments in aim I are directed to elucidating the transplant parameters including conditioning and T cell replete or depleted inoculum on host memory cell survival in models designed to track these TM populations. The involvement of IL-15 and IL-7 in the maintenance and expansion of TM will be examined using fusion proteins and knock-out strains and experiments will also examine the role of CD30-CD30L interaction by memory cells post-transplant. Studies in aim II will examine the capacity of memory cells present to be reactivated in the reconstituting host's lymphoid compartment. Antigen delivery will be examined using syngeneic host APC and compared to syngeneic tumors transfected with surrogate antigen. The effectiveness of gp96-lg transfectants as an antigen delivery vehicle will be investigated as well as IL-15 transfected tumor populations. Functional evaluation of responses by reactivated TM will be carried out using immune analyses. Finally, studies in aim III are designed to examine the ability of memory populations to respond to tumor antigens post-HSPCT. Models will be examined in which recipients bearing tumors will be administered vaccines in attempts to augment anti-tumor responses in the early post-transplant period.

T 细胞可以在非剥脱性和非剥脱性造血干细胞/祖细胞移植 (HSPCT) 后存活 消融性调理方案，例如抗辐射 T 细胞介导对造血移植物的抵抗力 和感染。最近的研究结果表明，记忆 T 细胞 (TM) 应该比幼稚 T 细胞更有效地存活 由于该亚群抗凋亡调节增强以及该亚群新的初步发现 该提案证明了输注和内源性抗原特异性宿主 TM 后的存活和扩增 移植。该项目中的实验将解决测试现有 CDS TM 假设的问题 移植时的预处理和 TM 输注将导致抗原特异性免疫增强 早期（重建）移植后免疫区室实验将检查存活率， 记忆群体的扩展和功能，并将其与 HSPCT 后的初始 T 细胞进行比较 接受者。为了完成这些研究，我们将利用并比较 TCR 转基因 (OT-I) 和非转基因 (H60) 抗原特异性 TM，包括体外衍生的记忆群体。我的实验目的是 阐明移植参数，包括宿主上的条件调节和 T 细胞充满或耗尽的接种物 旨在追踪这些 TM 群体的模型中记忆细胞的存活率。 IL-15 和 IL-7 参与 将使用融合蛋白和敲除菌株来检查 TM 的维持和扩展， 实验还将检查移植后记忆细胞 CD30-CD30L 相互作用的作用。研究 目标 II 将检查重建宿主细胞中存在的记忆细胞被重新激活的能力 淋巴室。将使用同源宿主 APC 检查抗原递送，并与 用替代抗原转染的同基因肿瘤。 gp96-lg 转染子的有效性 将研究抗原递送载体以及 IL-15 转染的肿瘤群体。功能性 将使用免疫分析来评估重新激活的 TM 的反应。最后，针对目标进行研究 III 旨在检查 HSPCT 后记忆群体对肿瘤抗原的反应能力。 将检查模型，在模型中，携带肿瘤的接受者将被注射疫苗，以试图 增强移植后早期的抗肿瘤反应。