PMID- 23564336
OWN - NLM
STAT- MEDLINE
DCOM- 20140414
LR  - 20191210
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Linking)
VI  - 63
IP  - 3
DP  - 2014 Mar
TI  - Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to 
      cyclosporine A and rapamycin treatment.
PG  - 494-505
LID - 10.1136/gutjnl-2012-303635 [doi]
AB  - 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 mug/g anti-mouse-CD152. Subsequent 
      therapeutic studies were performed for a period of 4 weeks using cyclosporine A 
      (40 mug/g), rapamycin (1 mug/g) or azathioprine (15 mug/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.
FAU - Schwaiger, Theresa
AU  - Schwaiger T
AD  - Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University 
      Greifswald, , Greifswald, Germany.
FAU - van den Brandt, Cindy
AU  - van den Brandt C
FAU - Fitzner, Brit
AU  - Fitzner B
FAU - Zaatreh, Sarah
AU  - Zaatreh S
FAU - Kraatz, Franziska
AU  - Kraatz F
FAU - Dummer, Annegret
AU  - Dummer A
FAU - Nizze, Horst
AU  - Nizze H
FAU - Evert, Matthias
AU  - Evert M
FAU - Broker, Barbara M
AU  - Broker BM
FAU - Brunner-Weinzierl, Monika C
AU  - Brunner-Weinzierl MC
FAU - Wartmann, Thomas
AU  - Wartmann T
FAU - Salem, Tareq
AU  - Salem T
FAU - Lerch, Markus M
AU  - Lerch MM
FAU - Jaster, Robert
AU  - Jaster R
FAU - Mayerle, Julia
AU  - Mayerle J
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130405
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Biomarkers)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Ctla4 protein, mouse)
RN  - 0 (Immunosuppressive Agents)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - MRK240IY2L (Azathioprine)
RN  - O84C90HH2L (Poly I-C)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):321. PMID: 23609468
CIN - Gut. 2014 Mar;63(3):376-7. PMID: 23633291
MH  - Animals
MH  - Autoimmune Diseases/chemically induced/*drug therapy/immunology/pathology
MH  - Azathioprine/therapeutic use
MH  - Biomarkers/metabolism
MH  - CTLA-4 Antigen/antagonists & inhibitors
MH  - Cell Proliferation/drug effects
MH  - Cyclosporine/pharmacology/*therapeutic use
MH  - Dexamethasone/therapeutic use
MH  - Drug Administration Schedule
MH  - Female
MH  - Flow Cytometry
MH  - Immunosuppressive Agents/pharmacology/*therapeutic use
MH  - Lymphocyte Activation/drug effects
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Pancreas/drug effects/*immunology/pathology
MH  - Pancreatitis, Chronic/chemically induced/*drug therapy/immunology/pathology
MH  - Poly I-C
MH  - Random Allocation
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - T-Lymphocyte Subsets/drug effects/*metabolism
MH  - T-Lymphocytes, Regulatory/drug effects/metabolism
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Keywords: MRL/Mp mice, Treg, CTLA-4, Teff, rapamycin, cyclosporine A, 
      azathioprine
EDAT- 2013/04/09 06:00
MHDA- 2014/04/15 06:00
CRDT- 2013/04/09 06:00
PHST- 2013/04/09 06:00 [entrez]
PHST- 2013/04/09 06:00 [pubmed]
PHST- 2014/04/15 06:00 [medline]
AID - gutjnl-2012-303635 [pii]
AID - 10.1136/gutjnl-2012-303635 [doi]
PST - ppublish
SO  - Gut. 2014 Mar;63(3):494-505. doi: 10.1136/gutjnl-2012-303635. Epub 2013 Apr 5.