sirolimus and Pancreatitis--Chronic

Autoimmune pancreatitis (AIP) in humans invariably responds to steroid treatment, but little is known about the underlying pathogenesis and the benefits of alternative treatments.. To study the pathogenesis, and the efficacy of alternative immunosuppressant agents in the MRL/Mp mouse model of AIP.. 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).. 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.. 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.

Topics: Animals; Autoimmune Diseases; Azathioprine; Biomarkers; Cell Proliferation; CTLA-4 Antigen; Cyclosporine; Dexamethasone; Drug Administration Schedule; Female; Flow Cytometry; Immunosuppressive Agents; Lymphocyte Activation; Mice; Mice, Inbred Strains; Pancreas; Pancreatitis, Chronic; Poly I-C; Random Allocation; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Treatment Outcome

Topics: Animals; Autoimmune Diseases; Cyclosporine; Female; Immunosuppressive Agents; Pancreas; Pancreatitis, Chronic; Sirolimus; T-Lymphocyte Subsets

Topics: Animals; Autoimmune Diseases; Cyclosporine; Female; Immunosuppressive Agents; Pancreas; Pancreatitis, Chronic; Sirolimus; T-Lymphocyte Subsets

Chronic pancreatitis is a disease that involves the lymphocytic inflammation of the pancreatic gland, the destruction and fibrous transformation of the endocrine and ductal structures. An involvement of the immune system in the disease progression is assumed and possibly allows immune modulation as a novel treatment strategy. We used a new model of experimental chronic pancreatitis to examine the effect of immune modulation with the mTOR-inhibitor rapamycin on clinical, chemical and histological parameters of chronic pancreatitis. Pancreatitis was induced by injecting 8 mg/kg bodyweight DBTC intravenously in male Sprague Dawley rats. 24 and 72 hours later, 20 µg/kg bodyweight cerulein was injected intraperitoneally to simulate recurrent attacks of pancreatitis typical for the clinical course. 48 hours after the DBTC injection, rats were randomly allocated to placebo or sirolimus (1.5 mg/kg bw i.p.). The treatment was repeated every 24hours for 5 days. The rats were sacrificed 7, 14, 21 and 35 days after DBTC injection. Histologic examination revealed a reduced acute pancreatic damage in the treatment group in the first week and less chronic changes in the further course. ALT and amylase increased in Placebo animals over the observation period and was lower in sirolimus treated animals. Oral glucose tolerance test showed that all placebo animals were diabetic four weeks after DBTC while sirolimus treated animals were normoglycemic. An early, limited treatment with immunomodulatory and antifibrotic agents like sirolimus can positively influence the detrimental course of experimental chronic pancreatitis and may offer a treatment alternative in humans.

Topics: Animals; Disease Models, Animal; Disease Progression; Glucose Tolerance Test; Immunomodulation; Immunosuppressive Agents; Male; Pancreatitis, Chronic; Random Allocation; Rats; Rats, Sprague-Dawley; Sirolimus; Treatment Outcome