Insights into gene modulation by therapeutic TNF and IFNgamma antibodies: TNF regulates IFNgamma production by T cells and TNF-regulated genes linked to psoriasis transcriptome.
Therapeutic antibodies against tumor necrosis factor (TNF) (infliximab) and IFNgamma (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 IFNgamma-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 IFNgamma synthesis by T cells. Synthesis of IFNgamma, a cytokine of Th1-polarized T cells, is suppressed by 8.1-fold (P<0.01) at the mRNA level, while synthesis of IFNgamma 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.
Haider
Asifa S
AS
Department of Investigative Dermatology, Laboratory of Investigative Dermatology, The Rockefeller University, New York, New York 10021, USA.
Cohen
Jules
J
Fei
Ji
J
Zaba
Lisa C
LC
Cardinale
Irma
I
Toyoko
Kikuchi
K
Ott
Jurg
J
Krueger
James G
JG
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D003879:Dermatologic Agents / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D000069285:Infliximab; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D014409:Tumor Necrosis Factor-alpha; C505731:fontolizumab; D007371:Interferon-gamma; D000069285:Infliximab