Insights into Gene Modulation by Therapeutic TNF and IFNγ Antibodies: TNF Regulates IFNγ Production by T Cells and TNF-Regulated Genes Linked to Psoriasis.

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Insights into Gene Modulation by Therapeutic TNF and IFNγ Antibodies: TNF Regulates IFNγ Production by T Cells and TNF-Regulated Genes Linked to Psoriasis Transcriptome Asifa S. Haider, Jules Cohen, Ji Fei, Lisa C. Zaba, Irma Cardinale, Kikuchi Toyoko, Jurg Ott, James G. Krueger Journal of Investigative Dermatology Volume 128, Issue 3, Pages 655-666 (March 2008) DOI: 10.1038/sj.jid.5701064 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 T-cell activation, apoptosis, detection of IFNγ on T cells, and effects on T cells, B cells, and NK cells. PBMC stimulation with anti-CD3/CD28 antibody (S) was compared with non-stimulated PBMCs (NS), activation in the presence of anti-IFNγ antibody (fontolizumab) and anti-TNF antibody (infliximab). Representative plots out of four individual experiments are presented. (a) T-cell activation: percentage of expression of CD3/CD69-positive T cells is indicated in the upper right-hand corner of dot plots. (b) Apoptosis: percentage of propidium iodide/annexinV-FITC-positive cells is indicated in the upper right-hand corner of the dot plots. (c) Intracellular IFNγ positive T-cell measurements: percentage of expression of CD3/IFNγ-positive T cells indicated in the upper right-hand corner of dot plots. (d) Effects on T cells, B cells, and NK cells: percentages of lymphocytes (CD3+ T cells, CD3−CD19+ B cells, and CD3−CD56+CD16+ NK cells) are presented as column bars. Journal of Investigative Dermatology 2008 128, 655-666DOI: (10.1038/sj.jid.5701064) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 mRNA analysis. (a) Heat maps of activation genes regulated by IFNγ, TNF. mRNA from cultured PBMCs was hybridized to individual oligonucleotide arrays containing ~12,000 human genes (Affymetrix HG-U95Av2 chips). Heat maps show unsupervised hierarchical clusters of genes regulated by TNF or IFNγ in PBMCs by >1.5-fold, using similarity measure, Pearson correlation. Gene lists were created after significance analysis as described in Materials and Methods. The mean expression levels of genes regulated by >1.5-fold are represented by red lines (upregulated) and green lines (downregulated). Genes in PBMCs activated with anti-CD3/CD28 (stimulated) are compared with non-stimulated, stimulated in the presence of control antibody (IgG1), TNF inhibitor infliximab and IFNγ inhibitor fontolizumab. Genes exclusively regulated by >1.5-fold by either infliximab or fontolizumab are listed in Table 2 and complete lists of genes, with fold changes and P-values, and confidence intervals in Table S4 and Table S5. (b) Real-time reverse transcription-PCR confirmation of IL-12Rβ2, IFNγ, and IL-8. mRNA from PBMCs stimulated with anti-CD3/CD28 antibody (S) was compared with non-stimulated PBMCs (NS), activation in the presence of anti-IFNγ antibody (fontolizumab, F), anti-TNF antibody (infliximab, I). Mean of relative mRNA expression normalized to human acidic ribosomal protein is plotted as column bars (n=3). Journal of Investigative Dermatology 2008 128, 655-666DOI: (10.1038/sj.jid.5701064) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Protein expression of IL-1α and IL-1β, IFNγ and TNF. Cytokine levels in the supernatant from PBMCs activated with anti-CD3/CD28 antibody (S) were compared with non-stimulated PBMCs (NS), activation in the presence of anti-IFNγ antibody (fontolizumab, F) or anti-TNF antibody (infliximab, I). Mean of cytokine expression is plotted as column bars (n=3). Journal of Investigative Dermatology 2008 128, 655-666DOI: (10.1038/sj.jid.5701064) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions