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050

BILIARY INFECTION WITH MOUSE MAMMARY TUMOR VIRUS IN THE NOD.c3c4 MOUSE AND OTHER MOUSE MODELS OF PRIMARY BILIARY CIRRHOSIS (PBC)

M Chen, D Graham, G Zhang, S Wasilenko, C McDougall, M Kneteman, A Mason
Dept. Medicine, University of Alberta

Three mouse models with immune defects have been reported that develop spontaneous AMA and biliary lesions. Endogenous mouse mammary tumor virus (MMTV) is found in the genome of most mouse strains and this germline virus can be expressed to form infectious viral particles in mice. A human betaretrovirus resembling MMTV has been linked with PBC. Our aim was to assess whether MMTV expression is associated with the PBC mouse models.
METHODS: Livers were isolated from female 12 week-old mice. The immune deficient models, NOD.c3c4, CD4 directed dominant negative TGF-beta receptor II (dnTGF-betaRII) and IL-2 receptor alpha knockout (IL-2Ralpha–/–) were compared with control mice, BALB/c, C57/bl, SJL and the Pera/Eij mouse lacking endogenous MMTV. Anti-gp52Su and anti-p27Ca were used to localize MMTV using immunohistochemistry and AMA to assess the aberrant expression of mitochondrial antigens. Hepatic RNA was assessed by real-time RT-PCR to quantify MMTV using gag and pol primers normalized to beta-actin.
RESULTS: MMTV gag and pol gene expression was detected in all mice except for the Pera/Eij that lacks endogenous MMTV. Viral burden was found to be 4 to 25 fold higher in all three autoimmune biliary disease models, NOD.c3c4, dnTGF-betaRII and IL-2Ralpha–/– as compared to control mice (Table, p<0.0001). Immuno-histochemistry localized AMA and MMTV Capsid and Surface proteins to biliary epithelium of the NOD.c3c4 mice.
                                        

	MMTV Gag mean (SEM)	MMTV pol mean (SEM)
NOD.c3c4 (n=5)	50 (10)	7.2 (1.5)
IL-2Ralpha -/- (n=3)	35 (7.0)	7.4 (3.2)
dnTGF-betaRII (n=3)	116 (8.1)	37.5 (3.2)
Balb/c (n=4)	4.1 (2.7)	1.3 (0.9)
C57bl (n=3)	9.3 (3.1)	1.5 (0.6)
SJL (n=3)	2.0 (0.7)	0.3 (0.1)
Pera/Eij (n=5)	0 (0)	0 (0)

CONCLUSIONS: In the NOD.c3c4 mouse liver, MMTV predominantly replicates in the biliary epithelium, where abnormal mitochondrial protein expression was also observed, similar to that observed in patients with PBC. The viral burden of MMTV was much higher in mice with immune deficiency and autoimmune biliary disease, providing a model to investigate the viral and autoimmune pathogenesis of cholangitis and AMA production. These findings also provide additional support for the association of a human betaretrovirus with PBC.

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