T cells can survive hematopoietic stem/progenitor cell transplants (HSPCT) following non-ablative andablative conditioning regimens, for example radioresistant T cells mediate resistance to hematopoietic graftsand infection. Recent findings suggest that memory T cells (TM) should survive more effectively vs. naivecells as a result of enhanced anti-apoptotic regulation in this subset and new preliminary findings in thisproposal demonstrate survival and expansion of host TM post-transplant. The experiments in this project willaddress questions testing the hypothesis that CD8 TM pre-conditioning and/or infused at transplant will resultin increased host T cell survival and enhanced antigen-specific immunity in the early (reconstituting) post-transplant immune compartment. Experiments will examine the survival, expansion and function of memorypopulations in the post-HSPCT recipient. To accomplish these studies we will utilize and compare transgenic(OT-I) and non-transgenic (HBO)antigen specific TM including in vitro derived populations as developed inProject 2. Experiments in aim I are directed to elucidating the transplant parameters including conditioningand T cell replete or depleted inoculum on host memory cell survival in transplant models designed to trackthese TMpopulations. The involvement of IL-15and IL-7 in the maintenance and expansion of TM will beexamined using fusion proteins (Core B) and knock-out strains (Core D) and experiments will also examinethe role of CD30-CD30L interaction by memory cells post-transplant together with Project! Studies in aim IIwill examine the capacity of memory cells present to be reactivated in the reconstituting host=s lymphoidcompartment. Antigen delivery will be examined using syngeneic host APC and compared to syngeneictumors transfected with surrogate antigen. The effectiveness of gp96-lg transfectants as an antigen deliveryvehicle will be investigated together with Project 1 as well as IL-15 transfected tumor populations with Project2. Functional evaluation of responses by reactivated TM will be carried out using immune analysis (Core C).Finally, studies in aim III are designed to examine the ability of memory populations to respond to tumorantigens post-HSPCT. Models will be examined in which recipients bearing tumors will be administeredvaccines in attempts to augment anti-tumor responses in the early post-transplant period and collaborativestudies with Project 3 will examine effects of B cell deficiency in these responses.
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