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Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment.
- Source :
-
Gut [Gut] 2014 Mar; Vol. 63 (3), pp. 494-505. Date of Electronic Publication: 2013 Apr 05. - Publication Year :
- 2014
-
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.<br />Objective: To study the pathogenesis, and the efficacy of alternative immunosuppressant agents in the MRL/Mp mouse model of AIP.<br />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).<br />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.<br />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.
- Subjects :
- Animals
Autoimmune Diseases chemically induced
Autoimmune Diseases immunology
Autoimmune Diseases pathology
Azathioprine therapeutic use
Biomarkers metabolism
CTLA-4 Antigen antagonists & inhibitors
Cell Proliferation drug effects
Cyclosporine pharmacology
Dexamethasone therapeutic use
Drug Administration Schedule
Female
Flow Cytometry
Immunosuppressive Agents pharmacology
Lymphocyte Activation drug effects
Mice
Mice, Inbred Strains
Pancreas drug effects
Pancreas pathology
Pancreatitis, Chronic chemically induced
Pancreatitis, Chronic immunology
Pancreatitis, Chronic pathology
Poly I-C
Random Allocation
Sirolimus pharmacology
T-Lymphocyte Subsets drug effects
T-Lymphocytes, Regulatory drug effects
T-Lymphocytes, Regulatory metabolism
Treatment Outcome
Autoimmune Diseases drug therapy
Cyclosporine therapeutic use
Immunosuppressive Agents therapeutic use
Pancreas immunology
Pancreatitis, Chronic drug therapy
Sirolimus therapeutic use
T-Lymphocyte Subsets metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 63
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 23564336
- Full Text :
- https://doi.org/10.1136/gutjnl-2012-303635