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Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response

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Abstract

Purpose

The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60 % of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure.

Methods

The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed.

Results

IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients.

Conclusions

RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients’ inflammatory status.

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Acknowledgments

We would like to thank Dr. Donata Dell’Acqua for her technical support and all residents and consultants for their kind collaboration.

This study was supported by FIRA (Italian Foundation focused on Rheumatoid Arthritis Research), which did not play any role in conducting the study, deciding on the analyses, or writing the manuscript. The authors declare no competing interest

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Author notes

    Authors and Affiliations

    1. Rheumatology Unit, Department of Internal Medicine, L. Sacco University Hospital, Milan, Italy

      Rossella Talotta, Fabiola Atzeni, Alberto Batticciotto & Piercarlo Sarzi-Puttini

    2. L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Via GB Grassi 74, 20157, Milan, Italy

      Angela Berzi & Daria Trabattoni

    3. Department of Physiopathology and Transplantation, University of Milan, Milan, Italy

      Mario Clerici

    4. Don C. Gnocchi Foundation, IRCCS, Milan, Italy

      Mario Clerici

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    1. Rossella Talotta
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    Correspondence to Daria Trabattoni.

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    Rossella Talotta and Angela Berzi contributed equally to this work.

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    Talotta, R., Berzi, A., Atzeni, F. et al. Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response. J Clin Immunol 35, 550–557 (2015). https://doi.org/10.1007/s10875-015-0182-0

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