Resistance to hematopoietic progenitor cell allografts is problematic, even after HLA-matched allogeneic BMT. The use of T cell depleted inoculum and the continuing efforts to diminish chemo / radiation preparative regimens to reduce post-BMT immunosuppression will increase the need to better understand the `barrier response' to engraftment. In the proposed studies, the cellular and effector pathways underlying resistance to engraftment following allogeneic BMT will be investigated using a model of MHC matched, minor H antigen (MiHA) mismatched BMT. To examine the kinetics and strength of the barrier response in differing host compartments immediately post-BMT, progenitor function will be directly assessed by CFU function. Stem cells representative of committed and multi potential populations will be examined by CFU assay to address for selective resistance against differing populations. MiHA recombinant inbred strains will be used as marrow donors /recipients to examine immunodominance in barrier responses. Studies will challenge the notion that cell-mediated cytotoxicity via the major pathways of perforin and FasL are the crucial molecular pathways used during host resistance by transplants into cytotoxic double deficient (cdd) recipients. Progenitor cells from TNF receptor 1 and/or 2 knock out donors transplanted to cdd recipients will create a novel `cytotoxic triple deficient' model to assess the role of these signaling pathways. Direct apoptotic killing of purified Lin-Sca-1+ pluripotential stem cell populations will be examined. If apoptosis is detected, expression of progenitor cell RNA for death receptors will be examined by RT-PCR If stem cell killing is not detected, functional inhibition will be examined by forward transplant to assess if the `resistance' is reversible and may be mediated by cytokines with demonstrable anti-hematopoietic activity. Differences from these studies in the types of progenitor cells affected as a consequence of differing functional deficits in transplant recipients would provide novel insights towards linking distinct effector pathways to the targeting of differing hematopoietic progenitor populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046689-04
Application #
6697442
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Kirkham, Perry M
Project Start
2001-02-01
Project End
2005-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$340,875
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
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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