Previous studies demonstrated that cloned antigen specific CD4+ T cells treated with an inhibitor of DNA methylation, 5- azacytidine (5-azaC), lost the requirement for antigen and could be activated by autologous HLA-D molecules alone, thus becoming autoreactive. Evidence from murine models suggests that these autoreactive cells could produce an autoimmune disease resembling lupus erythematosus (LE). To test whether autoimmune disease may be caused by inhibiting DNA methylation, we asked whether drugs which cause LE affect T cells like 5-azaC. In preliminary experiments we demonstrated that procainamide, hydralazine and 5-azaC all induced autoreactivity in cloned antigen specific T cells, and inhibited 3H- methyl incorporation into newly synthesized T cell DNA. All 3 drugs also induced expression of the same 5 new proteins as measured by 2D gel analysis. These results suggest that two drugs which induce an autoimmune disease may mimic the effects of 5- azaC by inhibiting DNA methylation, inducing new gene expression and inducing autoreactivity in T cells. We therefore hypothesize that some forms of autoimmunity may be cause by agents which activate certain genes, allowing T cell autoreactivity. The experiments described in this proposal are designed to test this hypothesis by 1) confirming that agents which induce autoimmunity also induce T cell autoreactivity and induce gene expression similar to that observed following 5-azaC treatment, 2) testing whether T cells made autoreactive by these agents are capable of activating B cells and macrophages in such a fashion that tissue damage could result, and 3) testing for expression of these genes in autoimmune disease. These studies may help elucidate the pathogenesis of some forms of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025526-03
Application #
3138932
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Richardson, B; Powers, D; Hooper, F et al. (1994) Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity. Arthritis Rheum 37:1363-72
Quddus, J; Kaplan, A; Richardson, B C (1994) Anti-CD11a prevents deletion of self-reactive T cells in neonatal C57BR mice. Immunology 82:301-5
Richardson, B C; Buckmaster, T; Keren, D F et al. (1993) Evidence that macrophages are programmed to die after activating autologous, cloned, antigen-specific, CD4+ T cells. Eur J Immunol 23:1450-5
Quddus, J; Johnson, K J; Gavalchin, J et al. (1993) Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest 92:38-53
Richardson, B C; Strahler, J R; Pivirotto, T S et al. (1992) Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus. Arthritis Rheum 35:647-62
Scheinbart, L S; Johnson, M A; Gross, L A et al. (1991) Procainamide inhibits DNA methyltransferase in a human T cell line. J Rheumatol 18:530-4
Golbus, J; Palella, T D; Richardson, B C (1990) Quantitative changes in T cell DNA methylation occur during differentiation and ageing. Eur J Immunol 20:1869-72
Richardson, B; Scheinbart, L; Strahler, J et al. (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665-73