The studies proposed in this application will generate a new experimental mouse model for the investigation of questions concerning the clinical association of cytomegalovirus (CMV) and graft-versus-host disease (GVHD). Mice will be infected with murine cytomegalovirus (MCMV) and monitored until infectious virus is no longer detectable (chronically infected). These animals will subsequently receive an allogeneic bone marrow transplant. The major objective of the study is to investigate how donor T-cells effect the outcome of an allogeneic bone marrow transplant in recipients previously infected target tissues including the lung. Virus expression will be assessed by cellular (plaque) and molecular (PCR) assay and examined with respect to donor effector function. Clinical signs and histopathology of GVHD and MCMV target issues will be assessed to correlate the presence and levels of virus with the pathogenesis occurring following allogeneic BMT. In tissues where viral expression precedes or coincides with cellular infiltrates, CD3+ T-cells will be isolated and characterized by phenotype to identify the infiltrating populations and compare to populations identified in non-infected recipients. The infiltrates will be assessed functionally for anti-host and anti-viral reactivity. To address how donor cells can affect virus expression following transplant, functionally defective T-cells for the production of interferon-gamma and mediation of cytotoxicity via perforin and/or FasL will be transplanted. Finally, bone marrow transplants utilizing donor T-cells specific for non-self ('host') MHC plus MCMV will be performed to test the hypothesis that such cells can control MCMV infection and diminish GVHD post-transplant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052461-08
Application #
6389363
Study Section
Immunobiology Study Section (IMB)
Program Officer
Thomas, John
Project Start
1993-12-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
8
Fiscal Year
2001
Total Cost
$220,037
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
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
Komatsu, Masanobu; Mammolenti, Michele; Jones, Monica et al. (2003) Antigen-primed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the simultaneous absence of perforin-, CD95L-, TNFR1-, and TRAIL-dependent killing. Blood 101:3991-9
Yu, Aixin; Zhou, Jiehao; Marten, Norman et al. (2003) Efficient induction of primary and secondary T cell-dependent immune responses in vivo in the absence of functional IL-2 and IL-15 receptors. J Immunol 170:236-42
Jiang, Zhe; Adams, Gregor B; Hanash, Alan M et al. (2002) The contribution of cytotoxic and noncytotoxic function by donor T-cells that support engraftment after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 8:588-96
Jiang, Z; Podack, E; Levy, R B (2001) Major histocompatibility complex-mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4(+) donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenes Blood 98:390-7
Jones, M; Komatsu, M; Levy, R B (2000) Cytotoxically impaired transplant recipients can efficiently resist major histocompatibility complex--matched bone marrow allografts. Biol Blood Marrow Transplant 6:456-64
Levy, R B; Jones, M; Hamilton, B L et al. (1995) IL-7 drives donor T cell proliferation and can costimulate cytokine secretion after MHC-matched allogeneic bone marrow transplantation. J Immunol 154:106-15