2007 Fiscal Year Final Research Report Summary
A bepatitis aggravation instruction mechanism of the CDld natural killer T cell in the Wilson's disease
| Project/Area Number |
17590360
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Fujita Health University |
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Principal Investigator |
KINEBUCHI Miyuki Fujita Health University, School of medicine, Associate professor (30244346)
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| Project Period (FY) |
2005 – 2007
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| Keywords | copper / Wilson's disease / fulminant hepatitis / CDld / natural killer T cells / Lipid peroxidation |
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| Research Abstract |
Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. There is no evidence that the WD patient's immune system attacks copper accumulated hepatocytes. Here we describe that the frequency and absolute number of Va24+Vb11+natural killer T (NKT) cells were significantly increased in 3 cases of WD, whereas those of CD3+CD161+NKT cells were within the normal range. Patients no. 1 and 2 had a presymptomatic form of WD. Their tissue specimens showed pathological changes of mild degeneration of hepatocytes with a few infiltrating mononuclear cells and a low degree of fatty change. Patient no. 3 displayed fulminant hepatitis with Coombs-negative haemolytic anaemia. The tissue specimens of patient no. 3 showed macronodular cirrhosis with thick fibrosis, inflammatory infiltrates and spotty necrosis. Human Va24+Vb11+NKT cells are almost equal to CDld-restricted NKT cells. Therefore we investigated CDld-restricted NKT cells in the LEC rat as an animal model of WD. In LEC rats before hepatitis onset, the number and phenotype of liver NKT cells were normal. At about 4 months of age all LEC rats developed acute hepatitis accompanied by acute jaundice, and CD161high NKT cells developed in their livers. CD161highabTCRbright NKT cells developed in some of them. Their hepatitis was severe. CD161highabTCRbright NKT cells expressed an invariant rat Va14-Ja281 chain, which is CDld-restricted. Furthermore, liver lymphocytes in the acute jaundiced LEC rats with CD161highabTCRbright NKT cells had significant and CDld-specific cytotoxic activity. However, the CD161highabTCRbright NKT cells were not able to induce the hepatitis fulminant to put them into the preclinical LEC rats. Furthermore, the membrane lipid fraction of LEC rat liver at the time of the hepatitis fulminant onset and the membrane lipid fraction of copper loaded hepatocytes were not able to stimulate CDld-NKT cells significantly.
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