Clinical allogeneic 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. However, the usefulness of marrow transplantation continues to be 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 risk of GVHD can be reduced by HLA matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, the risk of GVHD is still quite high due to disparity of non-HLA multiple minor histocompatibility antigens (miHA). In previous years we have clearly defined, in murine models, the relative etiological and pathological roles of both CD4+ and CD8+ T cell subsets in GVHD directed to miHA barriers. We have also found evidence for the oligoclonal, yet heterogeneous, nature of both T cell subset responses to miHA in vivo. The general aim of this current proposal is to continue our investigation of the immunobiology of lethal GVHD, with a focus on multiple miHA differences and how donor T cells develop the specific response to them. In this regard we will concentrate our efforts on the following specific aims: (1) the molecular and immunological analyses of the CD4+ T cell repertoire response to multiple miHA responsible for GVHD; (2) the molecular and immunological analyses of the CD8+ T cell repertoire response to multiple miHA responsible for GVHD; and (3) the utilization of the repertoire information to avoid GVHD and to retain optimal graft-versus-leukemia (GVL) responses. Insights generated from these studies on GVHD to miHA will hopefully lead to new approaches for overcoming one of the major obstacles for improved and expanded use of clinical allogeneic bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055593-18
Application #
6530685
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Jensen, Lee Ann
Project Start
1988-01-01
Project End
2004-09-30
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
18
Fiscal Year
2002
Total Cost
$320,472
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Fanning, Stacey L; Zilberberg, Jenny; Stein, Johann et al. (2013) Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR V? spectratype analysis in a murine bone marrow transplantation model. J Immunol 190:447-57
Zhan, Qian; Korngold, Robert; Lezcano, Cecilia et al. (2012) Graft-versus-host disease-related cytokine-driven apoptosis depends on p73 in cytokeratin 15-positive target cells. Biol Blood Marrow Transplant 18:841-51
Fanning, Stacey L; Appel, Michael Y; Berger, Stephanie A et al. (2009) The immunological impact of genetic drift in the B10.BR congenic inbred mouse strain. J Immunol 183:4261-72
Korngold, Robert; Antin, Joseph H (2009) Biology and management of acute graft-versus-host disease. Cancer Treat Res 144:257-75
Sportes, Claude; Hakim, Frances T; Memon, Sarfraz A et al. (2008) Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 205:1701-14
Zilberberg, Jenny; McElhaugh, Danielle; Gichuru, Loise N et al. (2008) Inter-strain tissue-infiltrating T cell responses to minor histocompatibility antigens involved in graft-versus-host disease as determined by Vbeta spectratype analysis. J Immunol 180:5352-9
DiRienzo, Christine G; Murphy, George F; Friedman, Thea M et al. (2007) T-cell receptor V(alpha) usage by effector CD4+Vbeta11+ T cells mediating graft-versus-host disease directed to minor histocompatibility antigens. Biol Blood Marrow Transplant 13:265-76
Zhan, Qian; Signoretti, Sabina; Whitaker-Menezes, Diana et al. (2007) Cytokeratin15-positive basal epithelial cells targeted in graft-versus-host disease express a constitutive antiapoptotic phenotype. J Invest Dermatol 127:106-15
DiRienzo, Christine G; Murphy, George F; Jones, Stephen C et al. (2006) T-cell receptor Valpha spectratype analysis of a CD4-mediated T-cell response against minor histocompatibility antigens involved in severe graft-versus-host disease. Biol Blood Marrow Transplant 12:818-27
Reddy, Pavan; Maeda, Yoshinobu; Liu, Chen et al. (2005) A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med 11:1244-9

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