Anti‐ CD 40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis

Summary While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target autoantigens 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 β receptor II (dn TGF β RII ), under the control of the CD 4 promoter, develop an intense autoimmune cholangitis associated with serological features similar to human PBC . CD 40‐ CD 40 ligand ( CD 40 L ) 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‐ CD 40 L antibody (anti‐ CD 40 L ; MR ‐1). Four‐week‐old dn TGF β RII mice were injected intraperitoneally with either anti‐ CD 40 L or control immunoglobulin ( Ig)G at days 0, 2, 4 and 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serological and histological features of PBC , including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti‐ CD 40 L reduced liver inflammation significantly to 12 weeks of age. In addition, anti‐ CD 40 L initially lowered the levels of anti‐mitochondrial autoantibodies ( AMA ), but these reductions were not sustained. These data indicate that anti‐ CD 40 L 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 .