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Etude phénotypique et fonctionnelle des lymphocytes intra-hépatiques dans l'hépatite chronique virale C et le carcinome hépatocellulaire

Abstract : Chronic hepatitis C is associated with the failure of the immune system. We were interested to NK cells and Treg cells, partners in the innate immune response. The number of NK, particularly the CD56+dim, is significantly reduced in infected patients, in the liver more than in the blood, and increases during the process of fibrogenesis. The number of circulating CD3- CD56+brightNKG2A+ correlates with the severity of inflammation and fibrosis and that of CD3- CD56+dimNKG2A+ inversely correlates with viral load. The NK functional capacity to produce IFN-γ and initiate a process of cytolysis is maintened. The CD158 expression is significantly reduced on the surface of intrahepatic NK, whereas NKG2A,C,D expression in circulating and hepatic NK is identical to that of non-infected patients. The intrahepatic Treg FoxP3+ are almost exclusively CD4+ phenotype. In multivariate analysis, the number of FoxP3+ is independently associated with that of CD8+, especially in necroinflammatory lesions and a strong correlation is observed between CD8, FoxP3, IL-10 and TGF-β, suggesting that Treg could inhibit CD8 expansion and cytotoxicity by cell contact or through immunosuppressive cytokines. The balance between FoxP3 and CD8 is broken in the most severe stages of the disease (METAVIR A>2 and F>3), which results in a drop in the FoxP3/CD8 ratio. Chronic inflammation is accompanied by liver fibrosis, leading to cirrhosis, the main cause of HCC. In viral C cirrhosis with or without HCC, CD3+, CD4+, CD8+, CD20+, CD56+, TCR γδ+, FoxP3+ lymphocytes are more numerous in fibrosis than in parenchyma. The number of CD3+, CD4+, CD8+, CD20+ and the expression of IFN-γ and RANTES were higher in cirrhosis developing HCC. In multivariate analysis, CD8 is the only independent predictor of tumor recurrence and is associated with a significant decrease in the 5 years disease free survival. The CD3+, CD4+, CD8+, CD20+, CD56+, TCR γδ+, FoxP3+ tumor infiltrating lymphocytes were significantly lower than in distant cirrhosis. However, FoxP3+ are significantly higher and CD56+ significantly lower in HCC than in parenchymatous nodules, without LT changes, leading to an increase in the FoxP3/CD8 ratio into the tumor. The number of CD56+ decreases from cirrhosis to HCC. No correlation was found between the density of studied tumor infiltrating lymphocytes and HCC recurrence. Conclusion. A dense inflammatory infiltrate in viral C cirrhosis, particularly rich in CD8, promotes HCC development and/or recurrence.
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Submitted on : Thursday, December 8, 2011 - 9:57:36 AM
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Nathalie Sturm. Etude phénotypique et fonctionnelle des lymphocytes intra-hépatiques dans l'hépatite chronique virale C et le carcinome hépatocellulaire. Sciences agricoles. Université de Grenoble, 2011. Français. ⟨NNT : 2011GRENV056⟩. ⟨tel-00649495⟩

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