Related Experiment Video

Updated: May 8, 2026

Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
16:07

Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method

Published on: September 16, 2017

A clinical conundrum: the detrimental effect of TNF antagonists in multiple sclerosis

Calliope A Dendrou1, John I Bell, Lars Fugger

  • 1Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK.

Pharmacogenomics
|September 13, 2013
PubMed

Insights

Tumor necrosis factor (TNF) antagonists worsen multiple sclerosis (MS), yet genetic studies reveal TNF signaling is protective in MS. This suggests a re-evaluation of TNF

Area of Science:

  • Immunology and Neuroscience
  • Autoimmune Disease Pathogenesis
  • Demyelinating Diseases

Background:

  • Tumor necrosis factor (TNF) antagonists are effective for autoimmune conditions but paradoxically exacerbate multiple sclerosis (MS).
  • The role of TNF signaling in MS development has been debated for over a decade due to conflicting clinical and experimental observations.

Purpose of the Study:

  • To investigate the functional consequences of genetic variations in the TNFR1 gene associated with MS.
  • To reconcile the clinical observation of TNF antagonist exacerbation of MS with the underlying biological mechanisms.
  • To re-evaluate the role of TNF signaling in neuroprotection and inflammation within the context of MS.

Main Methods:

  • Investigated genetic variations in the gene encoding TNFR1 (TNF receptor 1) in individuals with MS.
  • Analyzed the functional impact of these MS-associated genetic variations on TNF signaling pathways.
  • Correlated genetic findings with existing clinical data on TNF antagonist treatment in MS patients.

Main Results:

  • MS-associated genetic variation in the TNFR1 gene leads to the production of a novel, endogenous TNF antagonist.
  • This endogenous antagonist mirrors the effects of therapeutic TNF antagonists, explaining their detrimental impact on MS.
  • The findings indicate that net TNF function is protective in the development of MS.

Conclusions:

  • The study provides a biological explanation for why TNF antagonists worsen MS, highlighting a protective role for TNF signaling.
  • Re-evaluation of existing research on TNF signaling in inflammation, immunoregulation, and neuroprotection is warranted.
  • Future therapeutic strategies may involve targeting the TNF pathway differently to achieve beneficial outcomes in MS.

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