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Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with Crohn’s disease

  • Original Article—Alimentary Tract
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Abstract

Background

Anti-TNF-α therapies interact with the tolerogenic response in patients with Crohn’s disease, modulating inflammation. However, drug levels and the genetic background may affect this interaction.

Methods

Patients with Crohn’s disease in remission on biologic monotherapy were enrolled in this study. FoxP3+ lymphocytes, NOD2 genotype, serum cytokine, anti-TNF-α levels, and anti-drug antibodies were evaluated. Regulatory T cell response to infliximab was evaluated in vitro.

Results

Fifty-seven patients were included. Thirty-nine patients (68.4 %) were receiving non-intensified biologic therapy whereas 18 patients (31.6 %) were under an intensified biologic schedule due to loss of response. Eleven intensified patients (61.1 %) showed a variant NOD2 genotype vs 9 on non-intensified biologics (23 %, p < 0.01). Percentage of FoxP3+ T cells and serum free anti-TNF-α levels were significantly higher in patients with a wild-type vs variant NOD2 genotype, either under non-intensified or intensified schedule. Increasing amounts of infliximab significantly increased the expression of FoxP3+ T cells and anti-TNF-α levels in the supernatant from wild-type NOD2 patients cultured cells whereas the induction of FoxP3+ T cells and anti-TNF-α levels in the supernatant from variant NOD2 patients cultured cells were significantly lower. TNF-α and IL-10 showed a correlation with the FoxP3+ T cell population percentage and serum levels of anti-TNF-α, irrespective of NOD2 genotype. Eight variant NOD2 patients (66.6 %) vs 4 wild-type NOD2 patients (8.8 %) showed a perianal phenotype (p = 0.01). A significant reduction of the percentage of FoxP3+ T cells and serum levels of anti-TNF-α was observed in patients with the associated perianal disease.

Conclusion

Anti-TNF-α loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with CD.

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Acknowledgments

This work has been partially supported by Grant PI13/1443 from the Instituto de Salud Carlos III, Madrid, Spain.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

    Oriol Juanola, Alba Moratalla, Pedro Zapater, Paula Giménez, José M. González-Navajas, José F. Such & Rubén Francés

  2. Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Avda. Pintor Baeza 12, 03010, Alicante, Spain

    Oriol Juanola, Alba Moratalla, Ana Gutiérrez, Laura Sempere, Paula Giménez, Isabel Almenta, José M. González-Navajas & Rubén Francés

  3. Servicio de Farmacología Clínica, Hospital General Universitario de Alicante, Alicante, Spain

    Pedro Zapater

  4. Servicio de Anatomía Patológica, Hospital General Universitario de Alicante, Alicante, Spain

    Gloria Peiró

  5. Dpto. Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain

    Rubén Francés

  6. Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE

    José F. Such

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  1. Oriol Juanola
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Correspondence to Rubén Francés.

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Juanola, O., Moratalla, A., Gutiérrez, A. et al. Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with Crohn’s disease. J Gastroenterol 50, 758–768 (2015). https://doi.org/10.1007/s00535-014-1020-5

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  • DOI: https://doi.org/10.1007/s00535-014-1020-5

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