ANIMAL MODEL TO STUDY THE ROLE OF CYTOTOXICITY IN GVHD

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the applicant's abstract): 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.
StatusFinished
Effective start/end date9/30/968/31/05

Funding

  • National Center for Research Resources: $329,892.00
  • National Center for Research Resources: $338,899.00
  • National Center for Research Resources: $339,013.00
  • National Center for Research Resources
  • National Center for Research Resources
  • National Center for Research Resources
  • National Center for Research Resources: $338,957.00
  • National Center for Research Resources: $335,745.00
  • National Center for Research Resources

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