B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice

Yuki Moritoki, Zhe-Xiong Lian, Keith Lindor, Joseph Tuscano, Koichi Tsuneyama, Weici Zhang, Yoshiyuki Ueno, Robert Dunn, Marilyn Kehry, Ross Leon Coppel, Ian R Mackay, M Eric Gershwin

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Abstract

The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of dnTGF-RII mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with IP injections of anti-CD20 every two weeks. We quantitated B cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of pro-inflammatory cytokines and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significant lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8+ T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of TNF, IL-6 and CCL2 (MCP-1). These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise the cautionary note regarding the use of anti-CD20 in IBD.
Original languageEnglish
Pages (from-to)1893 - 1903
Number of pages11
JournalHepatology
Volume50
Issue number6
DOIs
Publication statusPublished - 2009

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