β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

Summary We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-β receptor (dnTGF-βRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8⁺ T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8⁺ T cells, we have determined herein whether administration of β-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8⁺ T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-βRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver-infiltrating CD8⁺ T cells, accompanied by a significant decrease in activated CD44^high CD8⁺ T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4⁺ T cells, CD19⁺ B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver-infiltrating CD8⁺ T cells. These data suggest that further work on GC in models of CD8⁺ T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.