MECHANISMS OF DRUG-INDUCED LUPUS .1. CLONED TH2 CELLS MODIFIED WITH DNA METHYLATION INHIBITORS IN-VITRO CAUSE AUTOIMMUNITY IN-VIVO

Treating activated CD4(+) T cells with DNA methyltransferase inhibitor s modifies gene expression and induces autoreactivity. Adoptive transf er of viable polyclonal autoreactive cells causes a lupus-like disease , most likely because of one or more effector functions expressed by t he autoreactive cells. However, the number of potential effector mecha nisms expressed by polyclonal cells is large. To more readily identify responsible mechanisms, we asked if autoimmunity can be induced by us ing the conalbumin-reactive, cloned Th2 cell line D10.G4.1, treated wi th 5-azacytidine (5-azaC) or procainamide (Pca). Treated, but not untr eated, 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 alveolit is, central nervous system abnormalities including fibrinoid necrosis, karyorrhexis, and meningitis, and bile duct proliferation with peripo rtal inflammatory cell infiltration resembling primary biliary cirrhos is. Anti-ssDNA, anti-dsDNA, and anti-histone Abs were also found. Thes e experiments demonstrate that modification of this cloned T cell line with DNA methyltransferase inhibitors is sufficient to cause an autoi mmune disease, with features of lupus as well as autoimmune liver dise ase. 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 ot her pathologic mechanisms in the development of specific autoimmune le sions.