Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human moncyte derived dendritic cells grown with/without Etanercept TNF inhibitor

ABSTRACT: The process for making monocyte derived DCs (moDCs) has been previously described (46). All analysis was performed on âday 5â immature DCs. Etanercept 10mg/mL was added to experimental wells on days 0, 2, and 4. We chose this concentration of etanercept as it approximates the plasma concentration of drug when given 50mg BIW. Experiment Overall Design: 6 totoal samples. 3 control replicates paired with 3 experimental replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Lisa Caithleen Zaba

PROVIDER: E-GEOD-9239 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.

Zaba Lisa C LC Cardinale Irma I Gilleaudeau Patricia P Sullivan-Whalen Mary M Suárez-Fariñas Mayte M Fuentes-Duculan Judilyn J Novitskaya Inna I Khatcherian Artemis A Bluth Mark J MJ Lowes Michelle A MA Krueger James G JG

The Journal of experimental medicine 20071126 13

Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor-immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cel ...[more]

PMID: 18039949

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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).

Dataset Information

Transcription profiling of human moncyte derived dendritic cells grown with/without Etanercept TNF inhibitor

Publications

Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.

Similar Datasets

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