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: 7579040
• 负责人: Robert Benjamin Levy
• 金额: $ 31.04万
• 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/7579040
• 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; Regulation; Relative (related person); Research Personnel; Resistance; Role; Stem cells; T memory cell; T-Lymphocyte; Testing; Time; Transgenic Organisms; Transplant Recipients; Transplantation; Treatment Protocols; 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细胞可以在非消融性和移植后的造血干/祖细胞移植（HSPCT）中存活。 消融性预处理方案，例如抗辐射T细胞介导对造血移植物的抗性 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。 细胞作为增强的抗凋亡调节的结果，在这个子集和新的初步发现， 建议证明输注和内源性抗原特异性宿主TM在 移植在这个项目中的实验将解决问题测试的假设，现有的CDS TM 预处理和移植时输注TM将导致增强的抗原特异性免疫， 移植后早期（重建）免疫区室实验将检查存活率， 记忆群体的扩增和功能，并将其与HSPCT后的初始T细胞进行比较。 收件人。为了完成这些研究，我们将利用和比较TCR转基因（OT-I）和非转基因（OT-I）。 (H60)抗原特异性TM，包括体外衍生的记忆群体。目的I中的实验针对 阐明移植参数，包括宿主上的条件化和T细胞充满或耗尽的接种物 记忆细胞存活率的模型设计来跟踪这些TM群体。IL-15和IL-7参与了 将使用融合蛋白和敲除菌株来检查TM的维持和扩增， 实验还将检查移植后记忆细胞的CD 30-CD 30 L相互作用的作用。研究 在目标II中，将检查在重建宿主中存在的被重新激活的记忆细胞的能力。 淋巴区室将使用同基因宿主APC检查抗原递送，并与 用替代抗原转染的同源肿瘤。gp 96-lg转染子作为抗肿瘤细胞的有效性 将研究抗原递送载体以及IL-15转染的肿瘤群体。功能 将使用免疫分析来评价再活化TM的应答。最后，对aim III旨在检查记忆群体对HSPCT后肿瘤抗原的应答能力。 将检查模型，其中携带肿瘤的受体将被施用疫苗，以试图 增强移植后早期的抗肿瘤反应。