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Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment
  1. Theresa Schwaiger1,
  2. Cindy van den Brandt1,
  3. Brit Fitzner2,
  4. Sarah Zaatreh2,
  5. Franziska Kraatz1,
  6. Annegret Dummer1,
  7. Horst Nizze3,
  8. Matthias Evert4,
  9. Barbara M Bröker5,
  10. Monika C Brunner-Weinzierl6,
  11. Thomas Wartmann7,
  12. Tareq Salem3,
  13. Markus M Lerch1,
  14. Robert Jaster2,
  15. Julia Mayerle1
  1. 1Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
  2. 2Department of Medicine II, Division of Gastroenterology, University of Medicine, University of Rostock, Rostock, Germany
  3. 3Institute of Pathology, University Medicine, University of Rostock, Rostock, Germany
  4. 4Institute of Pathology, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
  5. 5Division of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
  6. 6Department of Pediatrics, Division of Pediatric Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  7. 7Division of Experimental Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  1. Correspondence to Professor Julia Mayerle, Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Ferdinand-Sauerbruchstrasse, Greifswald 17475, Germany; mayerle{at}uni-greifswald.de

Abstract

Background Autoimmune pancreatitis (AIP) in humans invariably responds to steroid treatment, but little is known about the underlying pathogenesis and the benefits of alternative treatments.

Objective To study the pathogenesis, and the efficacy of alternative immunosuppressant agents in the MRL/Mp mouse model of AIP.

Design MRL/Mp mice were pretreated for 4 weeks with polyinosinic:polycytidylic acid to induce AIP. Pancreatic sections of mice genetically deleted for CTLA-4 were analysed. Blockage of CTLA-4 was achieved by intraperitoneal antibody treatment with 2 μg/g anti-mouse-CD152. Subsequent therapeutic studies were performed for a period of 4 weeks using cyclosporine A (40 μg/g), rapamycin (1 μg/g) or azathioprine (15 μg/g).

Results Blockage of CTLA-4 in MRL/Mp mice suppressed regulatory T cell (Treg) function and raised the effector T cell (Teff) response with subsequent histomorphological organ destruction, indicating that AIP is a T cell-driven disease. Using an established histopathological score, we found that dexamethasone, cyclosporine A and rapamycin, but less so azathioprine, reduced pancreatic damage. However, the beneficial effects of cyclosporine A and rapamycin were achieved via different mechanisms: cyclosporine A inhibited Teff activation and proliferation whereas rapamycin led to selective expansion of Tregs which subsequently suppressed the Teff response.

Conclusions The calcineurin inhibitor cyclosporine A and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, improve the course of AIP in MRL/Mp mice via different mechanisms. These findings further support the concept of autoreactive T cells as key players in the pathogenesis of AIP and suggest that cyclosporine A and rapamycin should be considered for treatment of AIP in humans.

  • MRL/Mp mice
  • Treg
  • CTLA-4
  • Teff
  • rapamycin
  • cyclosporine A
  • azathioprine

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