Insights Into Gene Modulation By Therapeutic Tnf And Ifn Gamma Antibodies: Tnf Regulates Ifn Gamma Production By T Cells And Tnf-Regulated Genes Linked To Psoriasis Transcriptome

Therapeutic antibodies against tumor necrosis factor (TNF) (infliximab) and IFN gamma (fontolizumab) have been developed to treat autoimmune diseases. While the primary targets of these antibodies are clearly defined, the set of inflammatory molecules, which is altered by use of these inhibitors, is poorly understood. We elucidate the target genes of these antibodies in activated human peripheral blood mononuclear cells from healthy volunteers. While genes suppressed by fontolizumab overlap with known IFN gamma-induced genes, majority of genes suppressed by infliximab have previously not been traced to TNF signaling. With this approach we were able to extrapolate new TNF-associated genes to be upregulated in psoriasis vulgaris, an "autoimmune" disease effectively treated with TNF antagonists. These genes represent potential therapeutic targets of TNF antagonists in psoriasis. Furthermore, these data establish an unexpected effect of TNF blockade on IFN gamma synthesis by T cells. Synthesis of IFN gamma, a cytokine of Th1-polarized T cells, is suppressed by 8.1-fold (P<0.01) at the mRNA level, while synthesis of IFN gamma is eliminated in >60% of individual T cells. These data suggest that TNF blockade with infliximab can suppress a major pathway of the adaptive immune response and this observation provides a key rationale for targeting TNF in "Type-1" T-cell-mediated autoimmune diseases.