Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis

Hajime Tanaka, Guo-Xiang Yang, Neal Iwakoshi, Stuart Knechtle, Kazuhito Kawata, Koichi Tsuneyama, Patrick S C Leung, Ross Leon Coppel, Aftab A Ansari, Takashi Joh, Christopher Bowlus, M Eric Gershwin

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Abstract

While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target auto-antigens in primary biliary cirrhosis (PBC), unfortunately, these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor beta receptor II (dnTGFbetaRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serologic features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four week old dnTGFbetaRII mice were injected intra-peritoneally with either anti-CD40L or control IgG at days 0, 2, 4, 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serologic and histologic features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L significantly reduced liver inflammation through 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial auto-antibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness, will be critical to determining whether such efforts can be applied to PBC.
Original languageEnglish
Pages (from-to)364 - 371
Number of pages8
JournalClinical and Experimental Immunology
Volume174
Issue number3
DOIs
Publication statusPublished - 2013

Cite this

Tanaka, H., Yang, G-X., Iwakoshi, N., Knechtle, S., Kawata, K., Tsuneyama, K., Leung, P. S. C., Coppel, R. L., Ansari, A. A., Joh, T., Bowlus, C., & Gershwin, M. E. (2013). Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clinical and Experimental Immunology, 174(3), 364 - 371. https://doi.org/10.1111/cei.12193