Memory CD8 T Cell Survival and Function Following Experimental BMT

T细胞可在非消融性T细胞移植(HSPCT)后存活 消融性预适应方案，例如抗辐射T细胞，介导了对造血移植物的抵抗 和感染。最近的发现表明，记忆性T细胞(TM)应该比幼稚的T细胞更有效地存活下来 这一亚群中增强的抗凋亡调节的结果和在这方面的新的初步发现 建议证明输注和内源性抗原特异性宿主TM后的存活和扩张 移植。该项目中的实验将解决验证现有CDS TM的假设的问题 移植时的预适应和TM输注将导致抗原特异性免疫增强 移植后早期(重建)免疫隔室实验将检查存活率， HSPCT后记忆群体的扩展和功能及其与初始T细胞的比较 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 (H60)抗原特异性TM，包括体外衍生的记忆种群。AIM I的实验针对的是 阐明移植参数，包括条件和宿主T细胞补充量或耗尽量 为跟踪这些TM种群而设计的模型中的记忆细胞存活。IL-15和IL-7在血管内皮细胞损伤中的作用 TM的维持和扩展将使用融合蛋白和敲除菌株以及 实验还将检验移植后记忆细胞对CD30-CD30L相互作用的作用。研究 在AIM II中，将检查在重组宿主中存在的被重新激活的存储单元的容量 淋巴小室。抗原传递将使用同基因宿主APC进行检查，并与 转代理抗原的同种异体肿瘤。Gp96-LG转染体作为一种新型基因工程载体的有效性 将研究抗原递送载体以及IL-15转基因肿瘤群体。功能性 对重新激活的TM的反应将使用免疫分析进行评估。最后，在AIM中进行研究 III旨在检测HSPCT后记忆群体对肿瘤抗原的反应能力。 将检查携带肿瘤的接受者将接种疫苗的模型，以尝试 在移植后早期增强抗肿瘤反应。

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.