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Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy

Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy
Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

Journal Article
1664-3224
Byng-Maddick, Rachel
bae8a42b-4bf0-49c9-8e12-b2f81189b4d7
Turner, Carolin T
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Pollara, Gabriele
e1c9f947-db4f-41c3-9b81-5bd4531cf007
Ellis, Matthew
afbca752-ced4-40dd-b0af-d9ecffbd5b63
Guppy, Naomi J
85f075ce-0155-4eda-ab71-91059f5ed571
Bell, Lucy C K
81acab61-493b-4ce2-8b80-a239335cc2dd
Ehrenstein, Michael R
134fea33-0940-4426-9207-981398161827
Noursadeghi, Mahdad
c86534b2-c59d-4f43-8af4-48ecba03b5ee
Byng-Maddick, Rachel
bae8a42b-4bf0-49c9-8e12-b2f81189b4d7
Turner, Carolin T
6de35528-8aee-4aac-8be2-490c75f5a0ae
Pollara, Gabriele
e1c9f947-db4f-41c3-9b81-5bd4531cf007
Ellis, Matthew
afbca752-ced4-40dd-b0af-d9ecffbd5b63
Guppy, Naomi J
85f075ce-0155-4eda-ab71-91059f5ed571
Bell, Lucy C K
81acab61-493b-4ce2-8b80-a239335cc2dd
Ehrenstein, Michael R
134fea33-0940-4426-9207-981398161827
Noursadeghi, Mahdad
c86534b2-c59d-4f43-8af4-48ecba03b5ee

Byng-Maddick, Rachel, Turner, Carolin T, Pollara, Gabriele, Ellis, Matthew, Guppy, Naomi J, Bell, Lucy C K, Ehrenstein, Michael R and Noursadeghi, Mahdad (2017) Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy. Frontiers in Immunology, 8. (doi:10.3389/fimmu.2017.00932).

Record type: Article

Abstract

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

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fimmu-08-00932 - Version of Record
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Accepted/In Press date: 21 July 2017
e-pub ahead of print date: 4 August 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 428035
URI: http://eprints.soton.ac.uk/id/eprint/428035
ISSN: 1664-3224
PURE UUID: 8666fe51-f168-4588-a187-0c6fd5f4d001

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Date deposited: 07 Feb 2019 17:30
Last modified: 15 Jan 2020 17:47

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Contributors

Author: Rachel Byng-Maddick
Author: Carolin T Turner
Author: Gabriele Pollara
Author: Matthew Ellis
Author: Naomi J Guppy
Author: Lucy C K Bell
Author: Michael R Ehrenstein
Author: Mahdad Noursadeghi

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