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CD1D-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells in interferon-gamma independent manner and induces the activation of acquired immunity against murine hepatocellular carcinoma



CD1D-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells in interferon-gamma independent manner and induces the activation of acquired immunity against murine hepatocellular carcinoma



Hepatology 38(4 Suppl 1): 771A



Background and Aim: Since hepatocellular carcinomas (HCCs) develop from transformed hepatocytes, sometimes in a multicentrical manner, immunological deletion of such small intrahepatic regions should be an important strategy to prevent HCC development. The liver contains abundant innate cell lineages including natural killer (NK) cells and natural killer T (NKT) cells, the latter of which become activated in a CD1d-restricted manner by alpha-galactosylceramide (alpha-GalCer). In the previous meeting, we reported that CD1d-mediated stimulation of NKT cells by alpha-GalCer administration selectively activated hepatic NK cells to eliminate experimentally disseminated hepatoma cells in murine liver. The aim of the present study is to investigate the mechanism underlying this anti-tumor effect, especially in terms of the involvement of interferon-gamma (IFN-gamma) and adaptive immunity. Methods: BNL 1MEA.7R.1 (BNL) hepatoma cells were injected into the liver via spleen of syngenic wild type BALB/c mice or IFN-gamma-deficient mice. After the tumor injection, the alpha-GalCer treatment or the control treatment started as previously reported. Three weeks after the tumor injection, the mice were sacrificed for the examination of tumor formation in the liver. Mononuclear cells were isolated from the liver of alpha-GalCer-treated or vehicle-treated IFN-gamma-deficient mice as well as wild type mice, and analyzed for the surface phenotype by flow cytometry and the cytotoxic activity by 51Cr release assay. The survival periods of BNL-bearing wild type mice were observed. Mice surviving more than two months, when all of the mice in the control treatment group had been dead, were judged as cured. Cured mice in the alpha-GalCer treatment group and age-matched no-treatment mice were subcutaneously inoculated with BNL cells and the control tumor cells, Colon 26 cells, on the right flank and the left flank of their backs, respectively. After the tumor inoculation, tumor volume of each mouse was observed. Results: alpha-GalCer administration completely abolished growth of hepatoma cells in the liver of IFN-gamma-deficient mice as well as wild type mice. Flow cytometric analysis revealed that hepatic NKT cells were rapidly activated after alpha-GalCer administration and that hepatic NK cells substantially increased their population in the IFN-gamma-deficient mice as well as wild type mice. 51Cr release assay demonstrated that hepatic NK cells augmented their cytotoxic activity against BNL cells after alpha-GalCer administration in the IFN-gamma-deficient mice as well as wild type mice. These results demonstrated that the anti-tumor effect was independent of IFN-gamma. The control tumor cells, Colon 26 cells, grew at the almost same degree in both cured mice and age-matched mice. In contrast, the rechallenged BNL cells were completely rejected in all cured mice, while in all age-matched mice inoculated BNL cells grew. These results suggested that the cured mice had acquired BNL-specific immunity. Conclusion: The present study showed that CD1d-mediated stimulation of NKT cells by alpha-GalCer administration not only activated hepatic NK cells in IFN-gamma-independent manner but also induced the activation of acquired immunity, which could efficiently kill transformed hepatocytes in vitro and in vivo. We propose that sequential activation of these innate immune cell lineages in the liver, leading to the activation of adaptive immune cell lineages, may be an attractive strategy for controlling hepatocarcinogenesis.

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Accession: 034513583

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DOI: 10.1016/s0270-9139(03)81306-x


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