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

摘要

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-beta). We investigated T cell responses in four treatment naive MS patients and twenty-three patients treated with IFN-beta who had or had not developed ADA to IFN-beta. T cell responses were determined by split-well and primary proliferation assays against different IFN-beta protein preparations and a set of overlapping peptides covering the full sequence of IFN-beta. T cell responses to IFN-beta were observed in all donors. ADA positive patients showed higher T cell responses to IFN-beta protein than ADA negative patients and untreated controls. We identified two immunodominant regions; T cell responses to IFN-beta(1-40) were observed in all patients independent of ADA status, while T cell responses to IFN-beta(125-159) were stronger in ADA positive than ADA negative patients. IFN-beta specific T cell responses were HLA class II restricted and in ADA positive patients skewed towards a Th2 phenotype. In IFN-beta treated patients we observed a correlation between IFN-beta specific T cell responses, serum ADA titer and loss of biological activity of IFN-beta 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-beta treated patients. (C) 2017 Elsevier Ltd. All rights reserved.