Clinical bone marrow transplantation is an important therapeutic treatment for several diseases including high risk leukemia, aplastic anemia, and severe combined immunodeficiency. In addition there is a wide range of metabolic and genetic disorders that can potentially be corrected by this approach. Recently, based on preliminary data, it has also been suggested that marrow transplantation may be a very effective tool in acquired immunodeficiency syndrome (AIDS) therapy. However, the usefulness of marrow transplantation is currently limited by several important risk factors, the principal one being graft-versus-host disease (GVHD), an oftentimes lethal complication which occurs in a high proportion of transplants. The general aim of this proposal is to continue our study of the immunobiology of lethal GVHD in murine models. In recent years we have clearly defined the relative etiological roles of both CD4+ and CD8+ T cell subsets in GVHD directed across both major histocompatibility complex (MHC) (class I and II) and non-MHC (multiple minor H) genetic barriers. We now intend to focus on the characteristics of GVHD pathogenesis mediated by each of these subsets and to define involved mechanisms, particularly across multiple minor H antigen differences. In this regard we will concentrate our efforts specifically on the following areas: 1) the features of T cell subsets mediating GVHD directed to minor H antigens including the functional characteristics and related differences in pathogenesis of the T cell subsets involved, the tissue expression of minor H antigens and recognition sites for T cell subsets, and the role of tumor necrosis factor (TNF) in development of GVHD; (2) the role of immunodominance in GVHD responses to multiple minor H antigens by which responses are directed to only a few select antigens, why in vivo results differ from in vitro, tissue distribution of minor H antigens, and mechanisms of immunodominance; and (3) the use of selective CD8+ T cell depletion of allogeneic donor inoculum to avoid GVHD directed to minor H antigens in irradiated recipients and allow for either enhanced resistance to cytomegalovirus (CMV) challenge or graft-versus-leukemia effects. In all, we feel that the projects designed in this proposal will add significant understanding to the mechanism and pathogenesis of GVHD as mediated by T cell subsets in MHC-matched transplantation situations. Insights generated from these studies will hopefully lead to new approaches for overcoming some of the major obstacles for improved and expanded use of clinical bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA038951-08
Application #
3177473
Study Section
Immunobiology Study Section (IMB)
Project Start
1988-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Meeker, N D; Hickey, W F; Korngold, R et al. (1995) Multiple loci govern the bone marrow-derived immunoregulatory mechanism controlling dominant resistance to autoimmune orchitis. Proc Natl Acad Sci U S A 92:5684-8
Korngold, R; Leighton, C; Manser, T (1994) Graft-versus-myeloid leukemia responses following syngeneic and allogeneic bone marrow transplantation. Transplantation 58:278-87
Berger, M; Wettstein, P J; Korngold, R (1994) T cell subsets involved in lethal graft-versus-host disease directed to immunodominant minor histocompatibility antigens. Transplantation 57:1095-102
Murphy, G F; Sueki, H; Teuscher, C et al. (1994) Role of mast cells in early epithelial target cell injury in experimental acute graft-versus-host disease. J Invest Dermatol 102:451-61
Hill, L L; Perussia, B; McCue, P A et al. (1994) Effect of human natural killer cells on the metastatic growth of human melanoma xenografts in mice with severe combined immunodeficiency. Cancer Res 54:763-70
Korngold, R (1993) Biology of graft-vs.-host disease. Am J Pediatr Hematol Oncol 15:18-27
Shanley, J D; Korngold, R; Forman, S J (1993) The effect of graft-versus-host disease in response to minor histocompatibility antigens on acute murine cytomegalovirus infection. Transplantation 56:487-9
Korngold, R (1992) Lethal graft-versus-host disease in mice directed to multiple minor histocompatibility antigens: features of CD8+ and CD4+ T cell responses. Bone Marrow Transplant 9:355-64
Wettstein, P J; Korngold, R (1992) T cell subsets required for in vivo and in vitro responses to single and multiple minor histocompatibility antigens. Transplantation 54:296-307
Murphy, G F; Whitaker, D; Sprent, J et al. (1991) Characterization of target injury of murine acute graft-versus-host disease directed to multiple minor histocompatibility antigens elicited by either CD4+ or CD8+ effector cells. Am J Pathol 138:983-90

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