Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

BACKGROUND & AIMS: The NOD.c3c4 mouse model develops autoimmune biliary disease characterized by spontaneous granulomatous cholangitis, antimitochondrial antibodies and liver failure. This model for primary biliary cirrhosis (PBC) has evidence of biliary infection with mouse mammary tumour virus (MMTV), suggesting that the virus may have a role in cholangitis development and progression of liver disease in this mouse model. We tested the hypothesis that MMTV infection is associated with cholangitis in the NOD.c3c4 mouse model by investigating whether antiretroviral therapy impacts on viral levels and liver disease. METHODS: NOD.c3c4 mice were treated with combination antiretroviral therapy. Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score. RESULTS: Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice. Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model. CONCLUSIONS: The attenuation of cholangitis with regimens containing the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the protease inhibitors, lopinavir and ritonavir, suggests that retroviral infection may play a role in the development of cholangitis in this model.

Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models.

BACKGROUND & AIMS: A human betaretrovirus resembling the mouse mammary tumor virus (MMTV) has been characterized in primary biliary cirrhosis (PBC) and associated with aberrant pyruvate dehydrogenase complex (PDC)-E2-like expression. As MMTV is prevalent in mice as either an exogenous or endogenous infection, we tested the hypothesis that MMTV is linked with anti-mitochondrial antibody (AMA) production in models with severe immune dysfunction. METHODS: Evidence for MMTV was assessed in the liver and spleen of mice by PCR and immunochemistry and PDC-E2-like protein by immunochemistry. ELISA and Western blot were used to investigate AMA and anti-MMTV antibody production. RESULTS: Increased MMTV gag or env expression was detected in the livers of AMA producing mice including NOD.c3c4, CD4 directed dominant negative TGF-ß receptor II and IL-2 receptor α knockout mice as well as the NOD parental strain when compared to healthy strains and biliary disease control mice. The NOD.c3c4 mice expressed MMTV surface and capsid proteins and aberrant PDC-E2-like protein in the bile ducts, whereas IL-2 receptor α knockout mice, NOD.c3c4 and the NOD mice expressed MMTV proteins and aberrant PDC-E2-like protein in the spleen. A significant correlation between anti-MMTV antibody production and AMA production was observed in the sera of NOD and NOD.c3c4 mice (p<0.0001). CONCLUSIONS: The association of betaretroviral protein production and aberrant PDC-E2-like protein expression in the NOD.c3c4, NOD, and the IL-2 receptor α knockout mice is comparable to observations in patients with PBC. The correlation of AMA and anti-MMTV suggests the hypothesis that MMTV infection may trigger the production of AMA.

Effects of systemic 5-HT(1B) receptor compounds on ventral tegmental area intracranial self-stimulation thresholds in rats.

Serotonin 1B (5-HT(1B)) receptors may play a role in regulating motivation and reward-related behaviours. To date, no studies have investigated the effects of the highly selective 5-HT(1B) receptor agonist CP 94253, on the reward model of ventral tegmental area intracranial self-stimulation. The current study investigated the hypothesis that 5-HT(1B) receptors play an inhibitory role in ventral tegmental area ICSS. Using Sprague-Dawley rats, the effects of the selective 5-HT(1B) receptor agonist CP 94253 (0-5.0 mg/kg) and the 5-HT(1B/1D) receptor antagonist GR 127935 (10.0 mg/kg) were investigated in rats trained to respond for ventral tegmental area ICSS; results were compared using rate-frequency threshold analysis. The highest dose of CP 94253 (5.0 mg/kg) tested in ventral tegmental area ICSS produced an increase in rate-frequency thresholds without affecting maximal response rates. This effect was attenuated by GR 127935 which did not show any effects when administered alone. These results suggest that 5-HT(1B) receptors play an inhibitory role in regulating ventral tegmental area ICSS.