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: 7215140
• 负责人: Robert Benjamin Levy
• 金额: $ 29.81万
• 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/7215140
• 关键词: Address; Affect; Antigens; Apoptotic; Autologous; B-Lymphocytes; Blood; CD8B1 gene; Cancer Vaccines; Cell Survival; Cells; Chimeric Proteins; Condition; 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; Numbers; Outcome; Output; Patients; Peptides; Physiologic pulse; Population; Pulse taking; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：T细胞可以在非消融性和消融性预处理方案后在造血干/祖细胞移植（HSPCT）中存活，例如抗辐射T细胞介导对造血移植物和感染的抗性。最近的研究结果表明，记忆T细胞（TM）应该更有效地生存与幼稚细胞作为增强的抗凋亡调节在这个子集和新的初步发现，在这个建议证明移植后输注和内源性抗原特异性宿主TM的生存和扩增。本项目中的实验将解决以下假设的检验问题：现有CDS TM预处理和移植时输注的TM将导致移植后早期（重建）免疫区室中抗原特异性免疫增强。实验将检查记忆群体的存活、扩增和功能，并将其与HSPCT后受体中的幼稚T细胞进行比较。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（H60）抗原特异性TM，包括体外衍生的记忆群体。目的I中的实验涉及阐明移植参数，包括在设计用于跟踪这些TM群体的模型中调节和T细胞充满或耗尽的接种物对宿主记忆细胞存活的影响。将使用融合蛋白和敲除菌株检查IL-15和IL-7在TM的维持和扩增中的参与，并且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。目的II的研究将检查记忆细胞在重建宿主淋巴区室中重新激活的能力。将使用同系宿主APC检查抗原递送，并与用替代抗原转染的同系肿瘤进行比较。将研究gp 96-lg转染子作为抗原递送载体的有效性以及IL-15转染的肿瘤群体。将使用免疫分析对再活化TM的反应进行功能评价。最后，目的III中的研究旨在检查记忆人群对HSPCT后肿瘤抗原的反应能力。将检查模型，其中携带肿瘤的受体将被施用疫苗以试图在移植后早期增强抗肿瘤应答。