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Gut 60:1345-1353 doi:10.1136/gut.2010.217117
  • Inflammatory bowel disease

Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFα treatment

  1. Heike Bantel2
  1. 1Department of Gastroenterology, Hepatology and Infectious Diseases, Ruprecht-Karls-University, Heidelberg, Germany
  2. 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  3. 3Institute of Pathology, Hannover Medical School, Hannover, Germany
  4. 4Interfaculty Institute for Biochemistry, Eberhard-Karls-University, Tübingen, Germany
  1. Correspondence to Professor Dr Heike Bantel, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; bantel.heike{at}mh-hannover.de
  1. Contributors CV, MA, KV, SM, SG, OB, MHW and FL were involved in the acquisition and analysis of data; CV, WS, MPM, KSO and HB contributed to the conceptual design of the study, interpretation of data and writing of the manuscript.

  • Revised 22 February 2011
  • Accepted 23 February 2011
  • Published Online First 1 April 2011

Abstract

Background and aims Inappropriate immune responses contribute to the continuous stimulation of the intestinal immune system in chronic inflammatory bowel disease (IBD). Among several pathogenic factors, a numerical deficiency of regulatory T (Treg) cells has been suggested to lead to an insufficient compensation of chronically activated T lymphocytes. This study was conducted to investigate whether increased apoptosis contributes to Treg cell deficiency in IBD and whether successful treatment with antitumour necrosis factor α (TNFα) is achieved by reducing of Treg cell apoptosis.

Methods Apoptosis of CD4+Foxp3+ Treg cells in tissue sections of patients with active IBD was analysed by immunohistochemistry and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling) staining. Apoptosis of peripheral blood CD4+CD25+Foxp3+ Treg cells was investigated by flow cytometry and annexin-V staining. In addition, caspase activity and apoptosis were measured in sera of patients with IBD treated with anti-TNFα by a luminometric caspase enzyme assay.

Results It is demonstrated that patients with active IBD revealed increased apoptosis of local CD4+Foxp3+ Treg cells in the inflamed mucosa compared with non-inflamed control colon tissue. Moreover, in peripheral blood a reduced frequency and increased apoptosis of Treg cells were found and accompanied by elevated caspase activity in the serum. During anti-TNFα treatment, Treg cell apoptosis declined in close correlation with elevated peripheral Treg cell numbers and a decrease of caspase activation and disease activity.

Conclusions These data suggest that increased apoptosis of Treg cells plays a potentially important role in the pathogenesis of IBD and can be reversed by anti-TNFα treatment. Measurement of Treg cell apoptosis and serum caspase activity might therefore represent promising tools for monitoring disease activity and treatment response in patients with IBD.

Footnotes

  • CV and MA contributed equally to this work.

  • Funding This study was supported by the Deutsche Forschungsgemeinschaft (SFB773, SFB685, TRR77, GRK1302, BA 2092/2-1, BA 2092/9-1) and the Federal Ministry of Education and Research (BMBF, No. 01FP09104B and AID-Net project).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Hannover Medical School and University of Heidelberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.