Abstract

As the field continues to move towards reduced intensity conditioning (RIC) to lower toxicity and immune difficiency, a major obstacle toward more successful allogeneic stem/progenitor cell transplantation is overcoming immune mediated resistance to hematopoietic engraftment in the recipient. During the prior grant period we identified a resistance pathway in recipients sensitized to donor antigens mediated by host CD8 T cells independent of perforin, fasl, TNF and other death receptor ligands. Experiments are designed in the present proposal to understand resistance pathways by effector cells derived from naive (TN) memory CD8 T (TM) cells. Identification and monitoring of an immunodominant tetramer+ host population will enable precise kinetic and compartmental analysis of these cells and studies are proposed to understand the antigen presentation pathway and regulation of resistance by CD4+CD25+ host T regulatory cells. Experiments will determine the relative survival, expansion and function of host TN and TM cells with respect to (RIC) and ablative conditioning protocols. Experiments will test the hypothesis that cytotoxicity plays an important role in T cell mediated resistance in unsensitized recipients but is not required for resistance in recipients previously sensitized to donor antigens. To test the hypothesis that T cells can directly eliminate HSC/PC, ex vivo studies will investigate T cells from cytotoxically normal and deficient recipients co-cultured with HSC and MPP enriched, (LSK FLK-2-),and HSC depleted committed progenitor cell enriched (LSK FLK-2+) populations. Experiments will investigate whether stem/PC are eliminated (i.e., via caspase dependent apoptosis) and/or can be suppressed (i.e., non-apoptotically) in their lineage commitment and differentiation to generate hematopoietic colonies. Overall, these studies will challenge the importance of cytotoxicity in resistance occuring in different transplant settings and generate findings which may discover non-lytic immune inhibition can occur against hematopoietic engraftment by allogeneic HSC/PC.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046689-07
Application #
7469400
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Rice, Jeffrey S
Project Start
1999-12-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
7
Fiscal Year
2008
Total Cost
$417,462
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146

  Publications

Ganguly, Sudipto; Ross, Duncan B; Panoskaltsis-Mortari, Angela et al. (2014) Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood 124:2131-41
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
Opiela, Shannon J; Levy, Robert B; Adkins, Becky (2008) Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens. Blood 112:1530-8

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