This work will examine the pathogenesis of chronic graft-versus-host (GVHD) in the rat. Bone marrow transplantation between the inbred AUG.2b (PVG) and AUG strains is associated with the appearance of a chronic, prolonged GVHD 4-6 months following transplantation. These two strains are congenic for a blood group antigen, RT2, and apparently differ for a histocompatibility locus identical to or closely linked to RT2. The experiments are designed to achieve three specific aims. The first is to characterize the cellular and humoral immunopathological changes present in the animals undergoing a chronic GVHD. The onset of clinical disease follows a period of stable chimerism and we are particularly interested in the immunological events that occur during the onset of the GVHD. Second, we intend to examine the pathogenesis of the cell-mediated lesions of the chronic GVHD by adoptive transfer, in vitro modification of the transplanted marrow, and the generation of alloreactive T-cell clones. The T-cell clones will be particularly useful for reconstitution experiments to establish the cell subpopulations and target specificity required to produce the GVHD. Third, the use of the congenic donor-recipient strain combination provides the opportunity to characterize the antigen(s) responsible for stimulating a chronic GVHD. We intend to use donor antihost antibody and T-cell clones to establish the tissue distribution, degree of polymorphism and structural characteristics of the target antigen. The importance of the proposed work is the opportunity to study an experimental model of chronic graft-versus-host disease that closely mimics the disease seen following bone marrow transplantation between HLA-identical siblings. The chronic GVHD seen in man and in our experimental model share important clinical and pathological features that allow for experimental investigation not possible in other experimental animals. The unique feature of the RT2 congenic model is a chronic GVHD in MHC matched animals directed against a single non-MHC background gene. The results obtained from these studies will greatly improve our understanding of the pathogenesis of chronic GVHD and should have direct application for donor-recipient selections and therapeutic applications of bone marrow transplantation in man. (TT)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038804-03
Application #
3177119
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-04-01
Project End
1988-09-30
Budget Start
1987-04-01
Budget End
1988-09-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Cramer, D V; Qian, S; Harnaha, J et al. (1989) Accelerated graft arteriosclerosis is enhanced by sensitization of the recipient to donor lymphocytes. Transplant Proc 21:3714-5
Cramer, D V; Qian, S Q; Harnaha, J et al. (1989) Cardiac transplantation in the rat. I. The effect of histocompatibility differences on graft arteriosclerosis. Transplantation 47:414-9
Cramer, D V; Harnaha, J B; Herberman, R B (1989) The use of 5-fluorouracil to enhance natural killer activity in rat bone marrow. Transplant Proc 21:3275-6
Uhteg, L C; Salomon, D R; Cohen, D J et al. (1987) Characterization of the Ia antigens involved in suppressor T cell generation in the rat. Immunogenetics 26:138-42
Cramer, D V (1987) Cardiac transplantation: immune mechanisms and alloantigens involved in graft rejection. Crit Rev Immunol 7:1-30