, Volume 2, Issue 1, pp 1–12 | Cite as

Enhancement of depressed lymphokine activated killer cell activity in patients with hepatocellular carcinoma

  • Toshiji Saibara
  • Saburo Onishi
  • Yasushi Matsuura
  • Masanao Fujikawa
  • Hiroshi Sakaeda
  • Youichi Matsunaga
  • Yasutake Yamamoto


Hepatocellular carcinoma (HCC) patients can be divided into two groups according to the degree of lymphokine activated killer (LAK) cell activity; a high LAK activity group (H-LAK-HCC) and a low LAK activity group (L-LAK-HCC). Interferon-gamma (IFN-gamma) production is severely defective in L-LAK-HCC but not defective in H-LAH-HCC. IFN-gamma production is suppressed with the addition of anti-Tac in dose dependent manner, though LAK activity is suppressed only in the presence of high concentration of anti-Tac. LAK activity is suppressed with the addition of anti-IFN-gamma, which is most prominent when the antibody is present during the first 12 hr of incubation. LAK generation is enhanced with the addition of recombinant IFN-gamma, which is most prominent when it is present during the first 12 hr of incubation. However, this enhancing effect is less prominent in L-LAK-HCC as compared to normals, liver cirrhosis, and H-LAK-HCC. This enhancement is regarded to depend on the presence of Leu7+ and Leu11+ subset, as this enhancement is abandoned and IFN-gamma production is inhibited when either of these subsets is deleted. These data suggest that IFN-gamma production and the participation of Leu7+ and Leu11+ subsets is important in sufficient LAK generation, and that poor IFN-gamma production and insufficient response to IFN-gamma may be the cause of severely defective LAK generation in L-LAK-HCC.

Key words

hepatocellular carcinoma gamma-interferon interleukin 2 lymphokine activated killer cell 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982; 155: 1823–41.PubMedGoogle Scholar
  2. 2.
    Grimm EA, Ramsey KM, Mazumder A, Wilson DJ, Djeu JYL, Rosenberg SA. Lymphokine activated killer cells phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med 1983; 157: 884.PubMedGoogle Scholar
  3. 3.
    Grimm EA, Robb RJ, Roth JA, Neckers LM, Lachman LB, Wilson DJ, Rosenberg SA. Lymphokine activated killer cells phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells. J Exp Med 1983; 158: 1356.PubMedGoogle Scholar
  4. 4.
    Rosenberg SA, Grimm EA, McGrogan M, Doyle M, Kawasaki E, Koths K, Mark DF. Biological activity of recombinant human interleukin-2 produced inEscherichia coli. Science 1984; 223: 1412.PubMedGoogle Scholar
  5. 5.
    Hsieh KH, Shu S Lee CS, Chu CT, Yang CS, Chang KJ. Lysis of primary hepatic tumours by lymphokine activated killer cells. Gut 1987; 28: 117–24.Google Scholar
  6. 6.
    Takasugi M, Mickey MR, Terasaki PI. Reactivity of lymphocytes from normal persons on cultured tumor cells. Cancer Res 1973; 33: 2898–2902.PubMedGoogle Scholar
  7. 7.
    Pross HF, Baines MG. Spontaneous human lymphocyte mediated cytotoxicity against tumor target cells. IV. A brief review. Cancer Immunol Immunother 1977; 3: 75–85.Google Scholar
  8. 8.
    Farrar WL, Johnson HM, Farrar JJ. Regulation of the production of immune interferon and cytotoxic T lymphocytes by interleukin 2. J. Immunol. 1981; 126: 1120.PubMedGoogle Scholar
  9. 9.
    Itoh K, Shiiba K, Shimizu Y, Suzuki R, Kumagai K. Generation of activated killer (AK) cells by recombinant interleukin 2(rIL 2) in collaboration with interferon-gamma (IFN-gamma). J Immunol 1985; 134: 3124–9.PubMedGoogle Scholar
  10. 10.
    Holdstock G, Chastenay BF, Krawitt. Studies on lymphocyte hyporesponse in cirrhosis. Am. J. Gastroenterol 1982; 82: 206.Google Scholar
  11. 11.
    Dilman RO, Koziol JA, Zavanelli MI. Immunoincompetence in cancer patients. Cancer 1984; 53: 144.Google Scholar
  12. 12.
    Son K, Kew M, Rabson MB. Depressed natural killer cell activity in patients with hepatocellular carcinoma. Cancer 1982; 50: 2820–25.PubMedGoogle Scholar
  13. 13.
    Saibara T, Onishi S, Sakaeda H, Yamamoto Y. Defective function of lymphokine activated killer cells and natural killer cells in patients with hepatocellular carcinoma. Hepatology 1989; 9: 471–6.PubMedGoogle Scholar
  14. 14.
    Naruo K, Hinuma S, Kato K. Comparison of the biological properties of purified natural and recombinant human interleukin-2. Biol Biophys Res Commun 1985; 128: 257–64.Google Scholar
  15. 15.
    Uchiyama T, Broder S, Waldmann TA. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac+ cells. J Immunol 1981; 126: 1393.PubMedGoogle Scholar
  16. 16.
    Itoh K, Tsuchikawa K, Awataguchi T, Shiiba K, Kumagai K. A case of chromic lymphocytic leukemia with properties characteristic of natural killer cells. Blood 1983; 61: 940.PubMedGoogle Scholar
  17. 17.
    Gerson JM. Systemic and in situ natural killer activity in tumor-bearing mice and patients with cancer. In: Herberman RB, ed. Natural cell-mediated immunity against tumors. New York: Academic Press, 1980; 1047–62.Google Scholar
  18. 18.
    Cannon GB, Bonnard GD, Djeu J, West WH, Herberman RB. Relationship of human natural lymphocyte-mediated cytotoxicity of breast-cancer derived target cells. Int J Cancer 1977; 19: 487–97.PubMedGoogle Scholar
  19. 19.
    Kawase I, Brooks CG, Kuribayashi K, Olabuenaga S, Newman W, Gills S, Henny C. Interleukin 2 induces gamma-interferon production: Participation of macrophages and NK-like cells. J Immunol 1983; 131: 288.PubMedGoogle Scholar
  20. 20.
    Itoh K, Tilden AB, Kumagai K, Balch CM. Leu-11+ lymphocytes with natural killer (NK) activity and precursors of recombinant interleukin 2(rIL 2)-induced activated killer(AK) cells. J Immunol 1985; 134: 802.PubMedGoogle Scholar
  21. 21.
    Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CAY, Custer MC, Rosenberg SA. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 1985; 135: 2865.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1990

Authors and Affiliations

  • Toshiji Saibara
    • 1
  • Saburo Onishi
    • 1
  • Yasushi Matsuura
    • 1
  • Masanao Fujikawa
    • 1
  • Hiroshi Sakaeda
    • 1
  • Youichi Matsunaga
    • 1
  • Yasutake Yamamoto
    • 1
  1. 1.First Department of MedicineKochi Medical SchoolKochiJapan

Personalised recommendations