24 Until recently, our understanding of PBC has been limited by the
absence of appropriate animal models. Based upon a rigorous quantitative analysis of the epitope of PDC-E2, our laboratory has identified several organic compounds that resemble the immunodominant epitope of PDC-E2. In particular, 2-octynoic acid (2OA), a compound found in perfumes, lipstick, and many common food flavorings, reacts equally or even better than lipoic acid to AMAs.25-26 Importantly, immunization with 2OA when coupled with bovine serum albumin (BSA), induces high-titer AMAs and portal inflammation strikingly selleck chemical similar to human PBC.27-29 We report herein that treatment of this xenobiotic induced murine model of human PBC with either anti-CD20 or anti-CD79
monoclonal antibodies (mAbs) exacerbates liver pathology, even though it successfully depletes B cells and diminishes the production of AMAs. These findings have important clinical implications for the treatment of PBC and other autoimmune diseases in which B cell regulatory function may be critical. 2OA, 2-octynoic acid; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; APC, antigen-presenting cell; AST, aspartate aminotransferase; BSA, bovine serum albumin; dnTGF-βRII, transforming growth factor β receptor II dominant negative; EAE, autoimmune encephalomyelitis; IFN-γ, interferon-γ; Ig, immunoglobulin; IL, interleukin; mAb, monoclonal PDK4 antibody; MCP-1, monocyte chemotactic protein-1; PBC, primary biliary selleckchem cirrhosis; PBS, phosphate-buffered
saline; PDC-E2, E2 subunit of the pyruvate dehydrogenase complex; TLR, Toll-like receptor. Female C57BL/6J (B6) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained in ventilated cages under specific pathogen-free conditions at the animal facilities of the University of California at Davis. The Animal Care and Use Committee in University of California Davis approved all studies. To deplete B cells in vivo, four independent groups of 6-week-old mice were injected intraperitoneally weekly with either sterile murine immunoglobulin (IgG) 2a anti-mouse CD20 antibody (n = 8) (250 μg/250 μL in phosphate-buffered saline [PBS]), hamster IgG2 anti-mouse CD79b antibody (n = 10) (1 mg/100 μL in PBS), or isotype-matched control mAbs. The anti-mouse CD20 IgG2a (Biogen Idec, San Diego, CA) and the Armenian hamster anti-mouse CD79b IgG used herein have been described elsewhere.30, 31 The non–cross-reactive mouse anti-human CD20 antibody (250 μg/250 μL in PBS) and an Armenian hamster normal IgG (1 mg/mL) (Innovative Research, Novi, MI) were used as controls. One week after the beginning of B cell depletion therapy, autoimmune cholangitis was induced as described.