Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction.
METHODS
We have previously reported that CD4+ T cells induced primary biliary cirrhosis (PBC)-like hepatic lesions in mice with graft-versus-host reaction due to major histocompatibility complex class II disparity. To clarify the relationship between the cytokine profile produced by CD4+ T cells and the formation of hepatic lesions, we sorted CD4+ T cells from the liver by using flow cytometry and examined their cytokine mRNA expression at various times after GVHR induction. We also examined the associated changes in the serum levels of antimitochondrial antibodies (AMA).


RESULTS
Histologically, the infiltration of CD4+ T cells around the bile ducts was observed from day 5, and the lesions deteriorated gradually until day 14. On day 14, CD8+, B220+ and Mac-1+ cells, as well as CD4+ T cells were seen around the bile ducts. In the liver-infiltrating CD4+ T cells, the expression level of interferon-gamma (IFN-gamma) mRNA was observed to increase at an early phase (day 3), whereas that of interleukin (IL)-10 mRNA was elevated at a later phase (day 14). The elevation of IFN-gamma mRNA expression at an early phase before the appearance of non-suppurative destructive cholangitis suggests that IFN-gamma may be related to the pathogenesis of PBC in this model. Serum levels of AMA on day 14 were significantly higher than those on day 5. Interleukin-10 was considered to stimulate antibody production, to show an inhibitory effect upon the function of T helper 1 cells, and to inhibit fibrosis.


CONCLUSIONS
Interferon-gamma may play an important role in the pathogenesis of this model. Moreover, delayed expression of IL-10 mRNA may control PBC-like hepatic lesions.
Itoh
S
S
Division of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Matsuzaki
Y
Y
Kimura
T
T
Ikegami
T
T
Shoda
J
J
Fujiwara
M
M
Tanaka
N
N
D000818:Animals; D001323:Autoantibodies / Q000032:analysis; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D017690:Cell Transplantation / Q000009:adverse effects; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000150:complications* / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology
D001323:Autoantibodies; D015415:Biomarkers; D017931:DNA Primers; D012333:RNA, Messenger; D016753:Interleukin-10; D007371:Interferon-gamma