Abstract
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 CD44high 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 359-364 |
| Number of pages | 6 |
| Journal | Clinical and Experimental Immunology |
| Volume | 157 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2009 |
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Keywords
- CD8 T cells
- DnTGF-βRII mice
- Glucosylceramide
- Liver inflammation
- Primary biliary cirrhosis
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis. / Zhang, Weici; Moritoki, Y.; Tsuneyama, K.; Yang, G. X.; Ilan, Y.; Lian, Z. X.; Gershwin, M. Eric.
In: Clinical and Experimental Immunology, Vol. 157, No. 3, 09.2009, p. 359-364.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis
AU - Zhang, Weici
AU - Moritoki, Y.
AU - Tsuneyama, K.
AU - Yang, G. X.
AU - Ilan, Y.
AU - Lian, Z. X.
AU - Gershwin, M. Eric
PY - 2009/9
Y1 - 2009/9
N2 - 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 CD44high 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.
AB - 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 CD44high 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.
KW - CD8 T cells
KW - DnTGF-βRII mice
KW - Glucosylceramide
KW - Liver inflammation
KW - Primary biliary cirrhosis
UR - http://www.scopus.com/inward/record.url?scp=67651214208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651214208&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2249.2009.03971.x
DO - 10.1111/j.1365-2249.2009.03971.x
M3 - Article
C2 - 19664143
AN - SCOPUS:67651214208
VL - 157
SP - 359
EP - 364
JO - Clinical and Experimental Immunology
JF - Clinical and Experimental Immunology
SN - 0009-9104
IS - 3
ER -