Severe systemic autoimmunity occurs after syngeneic or autologous bone marrow transplantation (BMT) and treatment with cyclosporine (CsA) and has been termed syngeneic graft-versus-host disease (GVHD). Preliminary studies in syngeneic BMT recipients suggest that CsA alters T-cell differentiation in the thymus as indicated by changes in phenotypic cell surface markers and by a germ line configuration of the T-cell receptor gene. In addition, subsets of cells with phenotypic markers characteristic of early thymocytes with an apparent germ line configuration of the T-cell receptor gene can be detected in the peripheral blood of syngeneic BMT recepients treated with CsA. These data suggest that syngeneic GVHD is the result of altered thymic differentiation. A host autoregulatory system also appears to be essential for the induction of this systemic autoimmune syndrome. The general aim of this proposal is to define the immunological mechanisms which account for syngeneic GVHD. Specifically, determine if the syngeneic GVHD syndrome is the result of altered T-cell differentiation, augmentation of a normal component of T-cell differentiation and/or a loss of autoregulatory mechanisms. Adoptive transfer experiments will be performed in an attempt to identify the precursor effector cell and the mature effector cell of syngeneic GVHD. To demonstrate if there is host autoregulatory mechanisms which control the development of autogression, putative regulatory suppressor T-cells will be adoptively transferred together with the precursor and/or mature effector cell of syngeneic GVHD. Furthermore, the role of the cytotoxic T-cell recognizing Class II major histocompatibility (MHC) determinants associated with syngeneic GVHD will be assessed by adoptive transfer experiments, and in vitro using an organ explant system. In addition, T-cell receptor gene rearrangement will be assessed in thymocytes, the peripheral blood immature T-cells and the Class II specific cytotoxic T-cells in an effort to determine if CsA inhibits normal T-cell differentiation at the molecular level. If CsA results in the inhibition of T-cell differentation with the subsequent release of early thymocytes into the peripheral blood, we will attempt to determine if these cells can be induced to differentiate in vitro upon exposure to Class II MHC antigens utilizing thymic epithelial cultures. Such studies will increase our understanding of self versus non-self discrimination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024319-03
Application #
3137245
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1986-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hess, Allan D (2010) Reconstitution of self-tolerance after hematopoietic stem cell transplantation. Immunol Res 47:143-52
Miura, Yuji; Thoburn, Christopher J; Bright, Emilie C et al. (2002) Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD. Blood 100:2650-8
Chen, W; Thoburn, C J; Miura, Y et al. (2001) Autoimmune-mediated vasculopathy. Clin Immunol 100:57-70
Hess, A; Thoburn, C; Chen, W et al. (2001) Autoreactive T-Cell subsets in acute and chronic syngeneic graft-versus-host disease. Transplant Proc 33:1754-6
Hess, A D; Thoburn, C; Chen, W et al. (2001) The N-terminal flanking region of the invariant chain peptide augments the immunogenicity of a cryptic ""self"" epitope from a tumor-associated antigen. Clin Immunol 101:67-76
Miura, Y; Thoburn, C J; Bright, E C et al. (2001) Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD. Blood 98:868-76
Hess, A D; Thoburn, C J; Chen, W et al. (2000) Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. Biol Blood Marrow Transplant 6:13-24
Thoburn, C; Chen, W; Horwitz, L et al. (1999) Pathogenic specificity of effector T lymphocytes in syngeneic graft-versus-host disease. Transplant Proc 31:684-6
Hess, A; Horwitz, L; Thoburn, C (1999) Immune tolerance to self-MHC class II antigens after bone marrow transplantation. Transplant Proc 31:688-9
Chen, W; Thoburn, C; Hess, A D (1998) Characterization of the pathogenic autoreactive T cells in cyclosporine-induced syngeneic graft-versus-host disease. J Immunol 161:7040-6

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