title: Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, , Greifswald, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Schwaiger
authors.forename: Cindy
authors.initials: C
authors.lastname: van den Brandt
authors.forename: Brit
authors.initials: B
authors.lastname: Fitzner
authors.forename: Sarah
authors.initials: S
authors.lastname: Zaatreh
authors.forename: Franziska
authors.initials: F
authors.lastname: Kraatz
authors.forename: Annegret
authors.initials: A
authors.lastname: Dummer
authors.forename: Horst
authors.initials: H
authors.lastname: Nizze
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bröker
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.forename: Tareq
authors.initials: T
authors.lastname: Salem
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001379:Azathioprine / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010179:Pancreas / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011070:Poly I-C; D011897:Random Allocation; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D016572:Cyclosporine; D001379:Azathioprine; D011070:Poly I-C; D020123:Sirolimus
keywords: Keywords: MRL/Mp mice, Treg, CTLA-4, Teff, rapamycin, cyclosporine A, azathioprine