Opposite role for the chemokines CCL5 (RANTES) and CXCL3 (IP-10) in the development of autoimmune liver disease in the CYP2D6 mouse model

The etiology of autoimmune hepatitis (AIH) is poorly understood although the major autoantigen, cytochrome P450 2D6 (CYP2D6), has been identified and immunodominant epitopes mapped. We generated a mouse model for AIH using the natural human autoantigen CYP2D6 as a triggering molecule. Wildtype C57BL/6 mice are infected with an adenovirus expressing the human CYP2D6 (Ad-2D6) in order to break self-tolerance to the mouse CYP2D6 homologues (molecular mimicry). Such mice display persistent features characteristic for liver damage associated with AIH (fibrosis, 'fused' lobules, cellular infiltrations and necrosis). Ad-2D6-infected mice generated anti-CYP2D6 antibodies recognizing the identical immunodominant epitope as LKM-1 antibodies from AIH patients and mount a robust CYP2D6-specific T cell response.

Here we investigated the role of chemokines during the pathogenesis of AIH in the CYP2D6 mouse model and found that among others the chemokines CCL5 (RANTES) and CXCL10 (IP-10) were strongly induced after Ad-2D6 infection. Interestingly, CXCL10 has been found previously to be increased in the serum of AIH patients. We therefore infected CCL5-/-, CXCL10-/- and wildtype C57BL/6 mice with Ad-2D6. CXCL10 deficient mice showed a reduced acute virus-induced liver damage (AST/ALT levels) and a diminished chronic autoimmune hepatitis. Cellular infiltrations were reduced and the frequency of CYP2D6-specific T cells was lower than in wildtype mice. In contrast, CCL5 deficient mice displayed similar serum aminotransferase levels than wildtype mice. In addition, chronic autoimmune hepatitis was slightly enhanced in CCL5 deficient mice.

Conclusion: Our data indicate an opposite effect of the early expressed chemokines CCL5 and CXCL10 on the acute virus-induced damage to hepatocytes as well as on the chronic autoimmune hepatitis.