Beta-glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis.
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-beta receptor (dnTGF-betaRII) 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 beta-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-betaRII 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.
Zhang
W
W
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Moritoki
Y
Y
Tsuneyama
K
K
Yang
G-X
GX
Ilan
Y
Y
Lian
Z-X
ZX
Gershwin
M E
ME
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002761:Cholangitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D005963:Glucosylceramides / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics
D005963:Glucosylceramides; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II