Clear Suppression of Th1 Responses but Marginal Amelioration of Autoimmune Manifestations by IL-12p40 Transgene in MRL-Faslprcg/Faslprcg Mice

To investigate the effects of overproduction of IL-12p40, a potent antagonist against IL-12, on lupus-like autoimmune disease in vivo, we generated p40 transgenic MRL-Faslprcg/Faslprcg mice. Serum p40 and IL-12 levels were 600- to 8000-fold and 3- to 20-fold higher in transgenic (p40-lprcg) than nontransgenic (lprcg) mice, respectively. Serum IFN-γ levels increased after 3 months of age in lprcg and this age-related increase was completely abrogated in p40-lprcg. Serum IL-4 levels were the same in both mice. Production of IgM and IgG anti-double-stranded DNA (dsDNA) antibodies was significantly lower in p40-lprcg. Anti-dsDNA antibodies decreased in Th1-dependent IgG2a but increased in the Th2-dependent IgG1 subclass significantly in p40-lprcg. Proteinuria, glomerulonephritis, and survival were only marginally ameliorated in p40-lprcg. The results suggest that excess p40 production in vivo may suppress Th1 responses in autoantibody and IFN-γ production but lead to minimal improvement of clinical manifestations of autoimmune disease in this mouse model.