Cyclosporine (CsA) is a potent immunosuppressive drug that paradoxically elicits a T-lymphocyte dependent autoimmune disease when administered after syngeneic/autologous bone marrow transplantation (BMT). This autoaggression syndrome which develops after withdrawal of CsA treatment was termed syngeneic graft-vs-host disease (SGVHD) because of its similarity (histologically, target organs) to GVHD occurring after allogeneic BMT. Two important factors responsible for the pathogenesis of this autoimmune syndrome have been identified: the enhanced production of CD4+ and CD8+ MHC class II specific autoreactive T cells by the thymus and the elimination of a T-lymphocyte dependent peripheral host resistance mechanism. Both CD8+ and CD4+ SGVHD autoreactive T lymphocytes promiscuously recognize MHC class II antigens and express the V beta 8.5 T-cell receptor determinant. Preliminary studies reveal that the peptide from the invariant chain plays a critical role in the recognition of MHC class II antigens in SGVHD. The studies proposed in this application plan to characterize the autoreactive and regulatory effector T cells. The T-cell receptor repertoire with respect to a Valpha and Vbeta gene usage and the cytokine profile of the autoreactive T-cell subsets will be assessed in vitro by the reverse transcriptase polymerase chain reaction in clones from limiting dilution cultures. These results will be confirmed by in situ hybridization and immunoperoxidase analysis of the target tissue and by adoptive transfer studies with established autoclones. Structure function studies with modified CLIP peptides will be evaluated in order to identify the regions that allow autoimmune recognition in SGVHD. Thirdly, mechanisms by which CsA inhibits the clonal deletion or promotes selection of these autoreactive T cells in the thymus will be defined assessing if CsA inhibits clonal deletion of the MHC class II reactive T cells. Finally, studies will be performed to evaluate the mechanism by which the regulatory T cells recognize and inactivate the autoreactive T cells. Specifically, the ability of the autoregulatory T cells to recognize V beta T-cell receptor peptides presented by MHC class II determinants will be assessed. These studies will define some of the immunobiological mechanisms involved in this unique autoaggression syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024319-13
Application #
2886535
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Prasad, Shiv A
Project Start
1986-12-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
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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