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051

HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) WITH COMBIVIR AND KALETRA ABROGATES CHOLANGITIS IN THE NOD.c3c4 MOUSE MODEL OF PRIMARY BILIARY CIRRHOSIS (PBC)

M Chen, D Graham, S Girgis, G Zhang, S Wasilenko, C McDougall, M Kneteman, Y Li, A Mason
Department of Medicine and Pathology, University of Alberta

A human betaretrovirus resembling the mouse mammary tumor virus (MMTV) has been characterized in patients with PBC. The NOD.c3c4 mouse develops AMA, autoimmune biliary disease and liver failure. We have shown that NOD.c3c4 mice have a significantly higher burden of MMTV infection in the liver compared to control mice without immune deficiency and that the virus is predominantly localized to bile ducts. The goal of this study was to investigate whether antiviral therapy can impact on the development of autoimmune biliary disease in the NOD.c3c4 mouse.
METHODS: Twenty 5 to 8 week old NOD.c3c4 (Taconic) were randomized to either placebo (n=10), Combivir (n=10), or HAART with Combivir and Kaletra (n=10). Mice were sacrificed at 20 weeks of age and a liver pathologist ranked coded liver samples using the Ishak score. Percentage of liver demonstrating biliary cyst formation was measured in 5 low magnification sections using MetaVue software analysis. Hepatic RNA was assessed for viral burden using real-time RT-PCR with MMTV gag and pol primers normalized to beta-actin.
RESULTS: Anti-viral therapy had little impact on bile duct cyst formation. Histological evaluation showed a significant decrease in histological scores with increasing potency of antiviral regimen (table), cholangitis (p<0.001), portal inflammation (p<0.003) and necroinflammatory score (p<0.002). When compared to mice receiving placebo, Combivir therapy reduced viral burden by 26% to 47% as measured by the pol and gag gene RT-PCR, respectively.
                        

	Placebo Mean (SEM)	Combivir Mean (SEM)	Combivir and Kaletra Mean (SEM)
Cholangitis	1.0 (0.21)	0.3 (0.15)	0 (0)
Portal inflammation	1.5 (0.17)	0.8 (0.2)	0.4 (0.17)
Necroinflammatory	1.6 (0.16)	0.6 (0.2)	0.4 (0.16)

CONCLUSIONS: Combivir treatment positively impacted on inflammation and bile duct damage in the NOD.c3c4 mouse, as previously reported for patients with PBC. Even though Combivir therapy lacked potency in inhibiting MMTV, the bile duct damage and inflammation was attenuated suggesting a central role for MMTV in the autoimmune biliary disease. In contrast, the HAART abrogated cholangitis completely in the NOD.c3c4 mouse. As Combivir treatment is insufficient to halt disease in PBC patients, the NOD.c3c4 mouse model can be used for testing HAART regimens for further clinical trials.

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