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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA120776-01
Application #
7082399
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2006-04-01
Project End
2011-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$296,829
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Newman, Robert G; Dee, Michael J; Malek, Thomas R et al. (2014) Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice. Blood 123:3045-55
Ross, Duncan; Jones, Monica; Komanduri, Krishna et al. (2013) Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:1430-8
Newman, Robert G; Ross, Duncan B; Barreras, Henry et al. (2013) The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success. Immunol Res 57:125-39
Bayer, Allison L; Chirinos, Jackeline; Cabello, Cecilia et al. (2011) Expansion of a restricted residual host T reg-cell repertoire is dependent on IL-2 following experimental autologous hematopoietic stem transplantation. Eur J Immunol 41:3467-78
Urbieta, Maite; Barao, Isabel; Jones, Monica et al. (2010) Hematopoietic progenitor cell regulation by CD4+CD25+ T cells. Blood 115:4934-43
Shatry, Alwi; Chirinos, Jackeline; Gorin, Michael A et al. (2009) Targeting Treg cells in situ: emerging expansion strategies for (CD4(+)CD25(+)) regulatory T cells. Biol Blood Marrow Transplant 15:1239-43
Shatry, Alwi; Levy, Robert B (2009) In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 15:785-94
Bayer, Allison L; Jones, Monica; Chirinos, Jackeline et al. (2009) Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT. Blood 113:733-43
Shatry, Alwi M; Roopenian, Derry C; Levy, Robert B (2007) Survival and function of MiHA epitope-specific host CD8 TM cells following ablative conditioning and HCT. Biol Blood Marrow Transplant 13:293-8
Keith, Melinda Roskos; Levy, Robert B (2007) Transplant conditions determine the contribution of homeostatically expanded donor CD8 memory cells to host lymphoid reconstitution following syngeneic HCT. Exp Hematol 35:1303-15