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Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis

ABSTRACT: The interleukin (IL)-23/T-helper type 17 cell axis is a target for psoriasis. The tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, PF 06700841, will directly suppress TYK2-dependent IL-12 and IL-23 signaling and JAK1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF 06700841 improves the clinical manifestations of psoriasis. Patients (n=30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n=14) or 100 mg (n=7) PF 06700841, or placebo (n=9) for 28 days. Biopsies were taken from non-lesional and lesional skin at baseline, weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and RT-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and ~70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF 06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of pro-inflammatory cytokines that require TYK2 and JAK1 for signal transduction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136757 | GEO | 2020/03/03

REPOSITORIES: GEO

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Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).

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Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis

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