The critical role of Th1 cytokine polarization in murine primary biliary cirrhosis. (P4154)

Abstract

Abstract Primary biliary cirrhosis (PBC) is a female predominant organ specific autoimmune disease with specific destruction of intrahepatic small biliary epithelial cells (BECs). Patients develop a multilineage response to the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody. We previously reported that IL-12p40 deficiency eliminated biliary disease in dnTGFβRII mice, suggesting that IL-12 and IL-23 are important in the development of biliary disease. IL-12 induced Th1 and IL-23 induces Th17, which express both IFN-\#933; and IL-17, but the role of IL-12p40 in PBC remains unidentified. To further investigate the role of the IL-12p40 in this murine model of autoimmune biliary disease, we immunized IL-12p40-/-, IFN-\#933;-/- and IL-17-/- mice with a xenobiotic mimic of PDC-E2 , 2-octynoic acid (2-OA), coupled to bovine serum albumin. The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Importantly IL-12p40-/- and IFN-\#933;-/- mice immunized with 2-OA did not manifest autoimmune biliary disease. In contrast to IL-12p40-/- and IFN-\#933;-/- mice, IL-17-/- mice developed autoimmune biliary disease. These data suggest that signaling by way of Th1 polarizaion via IL-12p40 is an essential requirement for the development of autoimmune cholangitis. These data have implications for the biologic therapy of patients with primary biliary cirrhosis.