Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFα treatment
- Claudia Veltkamp1,
- Matthias Anstaett2,
- Kristin Wahl2,
- Sarah Möller2,
- Saskia Gangl2,
- Oliver Bachmann2,
- Matthias Hardtke-Wolenski2,
- Florian Länger3,
- Wolfgang Stremmel1,
- Michael P Manns2,
- Klaus Schulze-Osthoff4,
- Heike Bantel2
- 1Department of Gastroenterology, Hepatology and Infectious Diseases, Ruprecht-Karls-University, Heidelberg, Germany
- 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- 3Institute of Pathology, Hannover Medical School, Hannover, Germany
- 4Interfaculty Institute for Biochemistry, Eberhard-Karls-University, Tübingen, Germany
- Correspondence to Professor Dr Heike Bantel, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
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
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.
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.