Interferon-beta specific T cells are associated with the development of neutralizing antibodies in interferon-beta treated multiple sclerosis patients

J Autoimmun. 2018 Mar;88:83-90. doi: 10.1016/j.jaut.2017.10.003. Epub 2017 Oct 21.

Abstract

Beta-interferons are still among the most commonly used drugs to treat Multiple Sclerosis (MS). The use of beta-interferons is limited by the development of anti-drug antibodies (ADA), which may abrogate the treatment effect of the drug. Although the antibody response has been well studied, little is known about the T cell response to interferon-beta (IFN-β). We investigated T cell responses in four treatment naïve MS patients and twenty-three patients treated with IFN-β who had or had not developed ADA to IFN-β. T cell responses were determined by split-well and primary proliferation assays against different IFN-β protein preparations and a set of overlapping peptides covering the full sequence of IFN-β. T cell responses to IFN-β were observed in all donors. ADA positive patients showed higher T cell responses to IFN-β protein than ADA negative patients and untreated controls. We identified two immunodominant regions; T cell responses to IFN-β1-40 were observed in all patients independent of ADA status, while T cell responses to IFN-β125-159 were stronger in ADA positive than ADA negative patients. IFN-β specific T cell responses were HLA class II restricted and in ADA positive patients skewed towards a Th2 phenotype. In IFN-β treated patients we observed a correlation between IFN-β specific T cell responses, serum ADA titer and loss of biological activity of IFN-β treatment. Our studies demonstrate the occurrence of an antigen specific HLA class II restricted Th2 T cell response associated with the development of ADA in IFN-β treated patients.

Keywords: Anti-drug antibodies; Antigenic epitope; Interferon beta; Multiple sclerosis; Neutralizing antibodies; T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Neutralizing / therapeutic use
  • Antibody Formation
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • HLA Antigens / metabolism
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunodominant Epitopes / immunology
  • Immunotherapy / methods*
  • Interferon-beta / immunology
  • Male
  • Middle Aged
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / therapy*
  • Peptides / immunology
  • Th2 Cells / immunology*

Substances

  • Antibodies, Neutralizing
  • HLA Antigens
  • Histocompatibility Antigens Class II
  • Immunodominant Epitopes
  • Peptides
  • Interferon-beta