November 12, 2014
Notes: Scheen, Andre
Expert Opin Drug Saf. 2013 Jul;12(4):545-57. doi: 10.1517/14740338.2013.793671. Epub 2013 Apr 27.
Author Address: Chu Sart Tilman, Liege, Belgium. email@example.com
Reference Type: Journal Article
Record Number: 5337Author: Schwaiger, T., van den Brandt, C., Fitzner, B., Zaatreh, S., Kraatz, F., Dummer, A., Nizze, H., Evert, M., Broker, B. M., Brunner-Weinzierl, M. C., Wartmann, T., Salem, T., Lerch, M. M., Jaster, R. and Mayerle, J.
Title: Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment
Short Title: Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment
Alternate Journal: Gut
ISSN: 1468-3288 (Electronic)
Accession Number: 23564336
Autoimmune Diseases/chemically induced/*drug therapy/immunology/pathology
CTLA-4 Antigen/antagonists & inhibitors
Cell Proliferation/drug effects
Drug Administration Schedule
Immunosuppressive Agents/pharmacology/*therapeutic use
Lymphocyte Activation/drug effects
Mice, Inbred Strains
Pancreatitis, Chronic/chemically induced/*drug therapy/immunology/pathology
T-Lymphocyte Subsets/drug effects/*metabolism
T-Lymphocytes, Regulatory/drug effects/metabolism
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 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.