Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo.
Treating activated CD4+ T cells with DNA methyltransferase inhibitors modifies gene expression and induces autoreactivity. Adoptive transfer of viable polyclonal autoreactive cells causes a lupus-like disease, most likely because of one or more effector functions expressed by the autoreactive cells. However, the number of potential effector mechanisms expressed by polyclonal cells is large. To more readily identify responsible mechanisms, we asked if autoimmunity can be induced by using the conalbumin-reactive, cloned Th2 cell line D10.G4.1, treated with 5-azacytidine (5-azaC) or procainamide (Pca). Treated, but not untreated, cells responded to syngeneic APCs without Ag, overexpressed LFA-1, spontaneously lysed syngeneic macrophages, and secreted relatively large amounts of IL-6, small amounts of IL-4, and no detectable IL-2 nor IFN-gamma. Adoptive transfer of treated, but not untreated, cells induced a severe immune complex glomerulonephritis, pulmonary alveolitis, central nervous system abnormalities including fibrinoid necrosis, karyorrhexis, and meningitis, and bile duct proliferation with periportal inflammatory cell infiltration resembling primary biliary cirrhosis. Anti-ssDNA, anti-dsDNA, and anti-histone Abs were also found. These experiments demonstrate that modification of this cloned T cell line with DNA methyltransferase inhibitors is sufficient to cause an autoimmune disease, with features of lupus as well as autoimmune liver disease. The results also raise the possibility that macrophage lysis, IL-6 secretion, and LFA-1 overexpression could contribute to the disease process. This system may be useful in testing the role of these and other pathologic mechanisms in the development of specific autoimmune lesions.
Yung
R L
RL
Department of Internal Medicine, University of Michigan, Ann Arbor.
Quddus
J
J
Chrisp
C E
CE
Johnson
K J
KJ
Richardson
B C
BC
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001374:Azacitidine / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016219:Immunotherapy, Adoptive; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008806:Mice, Inbred AKR; D008814:Mice, Inbred NZB; D011342:Procainamide / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*
D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D004247:DNA; D011342:Procainamide; D001374:Azacitidine