The overall focus of the proposed studies in this application is to determine how cytotoxic function following allogeneic bone marrow transplantation influences the outcome of the transplant. Experiments will address related questions utilizing cytotoxically defective donor strains of mice. Single (i.e., perforin or CD95L = csd) and double cytotoxic deficient (cdd) strains will be employed to assess the role of donor cytotoxic function in GVH responses contributing to progenitor cell engraftment and GVH disease using experimental BMT models involving MHC mismatched and minor histocompatibility antigen mismatch donor/recipient combinations. Studies are designed to generate mouse strains deficient in tumor necrosis factor receptor-1 and/or 2 expression to be used to establish an allogeneic BMT model lacking three major effector pathways mediating cytotoxicity. These models will be used to analyze GVHD induced weight loss, clinical signs, tissue damage and immune deficiency. The use of CD4+ and CD8+ T cell subsets in this model will be of interest to determine if the """"""""subtraction"""""""" of these effector pathways differentially affects their capacity to induce GVH responses. The """"""""triple deficient"""""""" model can subsequently be used for the design of experiments to address the potential contribution of additional cytotoxic pathways involving TWEAK and TRAIL dependent signaling. These approaches will permit further testing of the hypothesis that differing effector molecules play more and less important roles in differing GVHD target compartments. Finally, experiments are proposed to examine the potential application of infused recipient (i.e., syngeneic) populations to kill donor cells following BMT to inhibit or reverse ongoing GVHD. Cell populations to be examined will include cytotoxic T cells and antigen presenting cells transduced with death receptor ligands.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR011576-06
Application #
6394649
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Grieder, Franziska B
Project Start
1996-09-30
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$335,745
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Barao, Isabel; Hanash, Alan M; Hallett, William et al. (2006) Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells. Proc Natl Acad Sci U S A 103:5460-5
Zimmerman, Z F; Levy, R B (2006) MiHA reactive CD4 and CD8 T-cells effect resistance to hematopoietic engraftment following reduced intensity conditioning. Am J Transplant 6:2089-98
Zimmerman, Zachary; Shatry, Alwi; Deyev, Vadim et al. (2005) Effector cells derived from host CD8 memory T cells mediate rapid resistance against minor histocompatibility antigen-mismatched allogeneic marrow grafts without participation of perforin, Fas ligand, and the simultaneous inhibition of 3 tumor necrosis fa Biol Blood Marrow Transplant 11:576-86
Hanash, Alan M; Levy, Robert B (2005) Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 105:1828-36
Maeda, Yoshinobu; Levy, Robert B; Reddy, Pavan et al. (2005) Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease. Blood 105:2023-7
Mammolenti, Michele; Gajavelli, Shyam; Tsoulfas, Pantelis et al. (2004) Absence of major histocompatibility complex class I on neural stem cells does not permit natural killer cell killing and prevents recognition by alloreactive cytotoxic T lymphocytes in vitro. Stem Cells 22:1101-10
Shatry, Alwi M; Jones, Monica; Levy, Robert B (2004) The effect of the spleen on compartmental levels and distribution of donor progenitor cells after syngeneic and allogeneic bone marrow transplants. Stem Cells Dev 13:51-62
Marks, Lianne; Altman, Norman H; Podack, Eckhard R et al. (2004) Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients. Transplantation 77:804-12
Blazar, Bruce R; Levy, Robert B; Mak, Tak W et al. (2004) CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease. J Immunol 173:2933-41
Shatry, Alwi M; Levy, Robert B (2004) Engraftment of splenic tissue as a method to investigate repopulation by hematopoietic cells from host and donor marrow. Stem Cells Dev 13:390-9

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