Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohn's disease

Authors

  • Rebeca Santaolalla PhD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Josep Mañé PhD,

    1. Gastroenterology & Nutrition Research Unit, Health Sciences Research Institute, Germans Trias i Pujol Foundation, Badalona, Barcelona, Catalonia, Spain; and CIBERehd, Barcelona, Catalonia, Spain
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  • Elisabet Pedrosa PhD,

    1. Gastroenterology & Nutrition Research Unit, Health Sciences Research Institute, Germans Trias i Pujol Foundation, Badalona, Barcelona, Catalonia, Spain; and CIBERehd, Barcelona, Catalonia, Spain
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  • Violeta Lorén BSc,

    1. Gastroenterology & Nutrition Research Unit, Health Sciences Research Institute, Germans Trias i Pujol Foundation, Badalona, Barcelona, Catalonia, Spain; and CIBERehd, Barcelona, Catalonia, Spain
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  • Fernando Fernández-Bañares MD, PhD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Josefa Mallolas PhD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Anna Carrasco BSc,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Antonio Salas MD, PhD,

    1. Department of Pathology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Mercè Rosinach MD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Montserrat Forné MD, PhD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Jorge C. Espinós MD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Carme Loras MD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Michael Donovan MD, PhD,

    1. Althia, Advanced Laboratories of Translational Health, Barcelona, Catalonia, Spain
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  • Pere Puig PhD,

    1. Althia, Advanced Laboratories of Translational Health, Barcelona, Catalonia, Spain
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  • Miriam Mañosa MD,

    1. Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Foundation, Badalona, Barcelona, Catalonia, Spain; and CIBERehd, Barcelona, Catalonia, Spain
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  • Miquel A. Gassull MD, PhD,

    1. Health Sciences Research Institute, Germans Trias i Pujol Foundation, Badalona, Barcelona, Catalonia, Spain
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  • Josep M. Viver MD, PhD,

    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
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  • Maria Esteve MD, PhD

    Corresponding author
    1. Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona, Research Foundation Mútua de Terrassa, Terrassa, Barcelona, Catalonia, Spain
    • Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, University of Barcelona; Pl. Dr. Robert 5, 08221 Terrassa, Barcelona, Catalonia, Spain
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  • Supported by La Marató de TV3 Foundation; ref 03/1810 Ferring International; GETECCU-Otsuka; and the Spanish Ministry of Science and Innovation. BFU 200764887.

Abstract

Background:

Apoptosis resistance of T-cells is considered an abnormality of immune pathways in Crohn's disease (CD). It has been previously shown that corticosteroids induce apoptosis of cells involved in inflammation. Thus, our aim was to assess the apoptosis of mononuclear cells and pro/antiinflammatory cytokines in the intestinal mucosa of patients with active CD, related to steroid response, and identify cellular and molecular factors that may predict this response to therapy.

Methods:

Patients with CD (n = 26), ulcerative colitis (UC) (n = 32), and controls (n = 10) were prospectively studied with mucosal biopsies before and 7–10 days after corticosteroid treatment. Immunophenotype and apoptosis of T and B lymphocytes, plasma cells, and macrophages were assessed by flow cytometry, immunohistochemistry, and immunofluorescence. The cytokine expression pattern was evaluated by quantitative polymerase chain reaction (PCR).

Results:

Apoptosis resistance of T and B lymphocytes was observed only in steroid-refractory and -dependent CD patients as compared to responsive patients (P = 0.032; P = 0.004, respectively), being evident after steroid treatment. Interleukin (IL)-10 was markedly increased at baseline in steroid-responsive patients compared to the nonresponders (P = 0.006; sensitivity: 88.8%; specificity: 66.6% to predict steroid response).

Conclusions:

Apoptosis resistance of mucosal T and B cells in steroid-refractory and -dependent CD patients appears during the evolution of the acute phase, limiting its clinical application as a predictor marker. In contrast, increased expression of IL-10 at an early stage of active steroid-sensitive CD patients supports its usefulness at predicting a good steroid response. Steroid-dependent and -refractory CD patients share similar molecular and cellular pathophysiological mechanisms. (Inflamm Bowel Dis 2010;)

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