ANIMAL MODEL FOR VIRAL-INDUCED BMT COMPLICATIONS

Project: Research project

Description

The overall objective of the research in this proposal is the development
of an animal model which mimics the well documented association of DNA
virus with graft vs. host disease (GvHD) following clinical allogeneic
bone marrow transplantation (BMT). A previously well characterized BMT
model between major histocompatibility complex (MHC) matched non-MHC
mismatched donor - recipient strains will be utilized as a model for
transplants between HLA matched individuals. B10.D2 (H-2d) bone marrow
(depleted of T-cells) together with a number of T-cells determined to be
insufficient to induce graft vs. host disease (GvHD) will be used as the
donor inoculum transplanted into 7.5 Gy. irradiated allogeneic BALB/c (H-
2d) recipients. Murine cytomegalovirus (MCMV) will be administered one
week post BMT to these and control, including syngeneic BMT recipients.
Recipients who do not survive when receiving both allogeneic T-cells and
MCMV will be studied to determine the underlying basis for the
'synergistic' affects of the two pathogenic processes, i.e. GvH and viral
infection. Studies are proposed to investigate the properties of
infectious MCMV which are necessary with respect to its ability to induce
complications following BMT. Inactivated virus and other non-infectious
(including viral protein) immunogens which induce potent immune responses
will be examined. Experiments are designed to determine the location and
presence of infectious virus (plaque assay) and viral antigens (PCR) and
compare findings with syngeneic transplant (and normal) recipients. These
studies should provide novel findings as to whether the tissue
distribution of infectious virus is altered in recipients (i.e. BMT)
undergoing allogeneic immune (i.e. GvH) reactions. Examination of
clinical signs and histopathological changes (inflammatory tissue
infiltrates and tissue damage) will be compared to BMT recipients
undergoing GvHD in the absence of MCMV to begin to assess whether the
synergistic effect in the model system results in GvHD signs and changes.
In order to assess the immunological changes occurring in MCMV infected
allogeneic BMT recipients, phenotypic and functional studies will be
performed prior to and following viral inoculation. Phenotypic changes
which have previously been detected during GvH reactions and disease
involving T-cell populations, activation markers and T-cell receptor V-
beta usage will be analyzed by flow cytometric analysis. Functional
studies will determine viral-induced responses. i.e anti-MCMV antibody,
natural killer activity and specific T-cell mediated anti-viral responses.
In total, these studies will establish a new model system which will help
to elucidate the underlying mechanism whereby pathogens complicate
allogeneic BMT.
StatusFinished
Effective start/end date12/1/933/31/03

Funding

  • National Institutes of Health: $213,627.00
  • National Institutes of Health: $175,838.00
  • National Institutes of Health
  • National Institutes of Health: $205,430.00
  • National Institutes of Health
  • National Institutes of Health: $220,037.00
  • National Institutes of Health
  • National Institutes of Health: $184,749.00

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Muromegalovirus
Animal Models
T-Lymphocytes
Viruses
Transplants
Tissue Donors
Graft vs Host Disease
Bone Marrow
Bone Marrow Transplantation
Perforin
Population
Cytomegalovirus Infections
Polymerase Chain Reaction
Cytomegalovirus
Interferon-gamma
Major Histocompatibility Complex
Theoretical Models
Aptitude
Homologous Transplantation
Viral Antigens

ASJC

  • Medicine(all)