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
| Autor: | Jules A. Cohen, Lisa C. Zaba, Jurg Ott, Kikuchi Toyoko, James G. Krueger, Ji Fei, Irma Cardinale, Asifa Haider |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_treatment
Gene Expression Dermatology In Vitro Techniques Antibodies Monoclonal Humanized Peripheral blood mononuclear cell Biochemistry Interferon-gamma Psoriasis medicine Humans Interferon gamma Molecular Biology B-Lymphocytes biology business.industry Tumor Necrosis Factor-alpha Gene Expression Profiling Antibodies Monoclonal Cell Biology Th1 Cells Acquired immune system medicine.disease Infliximab Killer Cells Natural Cytokine Immunology biology.protein Tumor necrosis factor alpha Dermatologic Agents Antibody business medicine.drug |
| Zdroj: | The Journal of investigative dermatology. 128(3) |
| ISSN: | 1523-1747 |
| Popis: | 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 (P0.01) at the mRNA level, while synthesis of IFNgamma is eliminated in60% 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. |
| Databáze: | OpenAIRE |
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