Summary
Defective natural killer (NK) cell populations from patients with chronic myelogenous leukemia (CML), that reacted with both HNK-1+ and B73.1+ antibodies, were obtained by a flluorescence-activated cell sorter (FACS). These fractions, along with NK fractions from normal donors which reacted with both antibodies, were expanded as bulk cultures or clones by limiting dilution, for 4 weeks in the presence of 10% interleukin 2 (IL 2), human type AB plasma, and irradiated human allogeneic mononuclear cells. Successfully established clones from patients with CML, with lytic activity against autologous and more differentiated neoplastic granulocytes, were generated more efficiently from B73.1+ than from HNK-1+ subsets. However, there were no significant differences among the generations of B73.1+ and HNK-1+ clones for both patients and normal donors with lytic activity against NK susceptible K-562 targets. Fresh myeloblast preparations from a blast crisis were found to be more susceptible to lysis by IL 2-proliferative B73.1+ and HNK-1+ clones than were fresh myelocyte preparations from a chronic phase CML patient, which were lytically susceptible to only B73.1+ clones. B73.1+ and HNK-1+ subsets from CML patients demonstrated major histocompatibility complex nonrestricted killing, and showed the following predominant phenotypes: B73.1+T3+T8+ or B73.1+T3+T8− from B73.1+ subsets; and HNK-1−T3+T8+ (initially HNK-1+) from HNK-1+ subsets. In contrast, B73.1+ and HNK-1+ clones from normal donors showed the following predominant phenotypes: B73.1+T3−T8−; and HNK-1−T3−T8− or HNK-1−T3−T8+ (initially all HNK-1+). Short-term in vitro IL 2 or interferon treatment of fresh NK defective subsets from CML patients resulted in minimal cytotoxic augmentation. In contrast, defective NK cells from CML patients, whether HNK-1+ or B73.1+ subsets, proliferated with complete regeneration of cytolytic activity after a 3–4 week exposure to IL 2, but differed in phenotypic profiles as compared to those of normal donors. These observations imply that not only fresh defective NK cells but also the cytotoxically restored clones from CML patients are derived from different NK subsets and may represent undifferentiated forms of NK cells that may be arrested at an early stage of development by yet unknown mechanism(s). In vitro substantiation of autologous leukemia cell killing by IL 2-proliferative NK cell clones is encouraging and may allow for new in vivo immunotherapeutic modalities in CML patients.
Similar content being viewed by others
References
Abo T, Balch CM (1981) A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK—1). J Immunol 127:1024
Abo T, Balch CM (1983) In vitro propagation of cultured human natural killer cells expressing the HNK-1 differentiation antigen and spontaneous cytotoxic function. Eur J Immunol 13:383
Brunda MJ, Rosenbaum D (1983) Modulation of murine natural killer cell activity in vitro and vivo by recombinant human interferons. Cancer Res 44:597
Christopher SH, Kuribayashi K, Kern DE, Gillis S (1981) Interleukin 2 augments natural killer cell activity. Nature 291:335
Dempsey RA, Dinarello CA, Mier JW, Rosenwasser LJ, Allegretta M, Brown TE, Parkinson DR (1982) The differential effects of human leukocytic pyrogen/lymphocyte-activating factor, T cell growth factors, and interferon on human natural killer activity. J Immunol 129:2504
Edwards BS, Hawkins MJ, Borden EC (1983) Correlation between in vitro and systemic effects of native and recombinant interferon on human natural killer cell cytotoxicity. J Biol Response Mod 2:409
Edwards BS, Hawkins MJ, Borden EC (1984) Comparative in vivo and in vitro activation of human natural killer cells by two recombinant interferons-gamma differing in antiviral activity. Cancer Res 44:3135
Fujimiya Y, Bakke A, Chang WC, Linker-Islaeri M, Udis B, Horwitz D, Pattengale PK (1986) Natural killer cell immunodeficiency in patients with chronic myelogenous leukemia. I. Analysis of the defect using the monoclonal antibodies HNK-1 (Leu 7) and B73.1 (Leu 11c). Int J Cancer 37:639
Gastle G, Niederwieser D, Marth C, Huber H, Egg D, Schuler G, Margrieter R, Braunsteiner H, Huber C (1984) Human large granular lymphocytes and their relationship to natural killer activity in various disease states. Blood 64:288
Gidlund M, Orn A, Pattengale PK, Jansson M, Wigzell H, Nilsson K (1981) Natural killer cells kill tumour cells at a given stage of differentiation. Nature 292:848
Golightely MG, D'Amore P, Golub SH (1982) Studies on cytotoxicity generated in human mixed lymphocyte cultures. II. Natural killer-like cytotoxicity mediated by human lymphocytes with receptors for IgM. Cell Immunol 70:219
Grimm EA, Mazumder A, Zhang HA, Rosenberg SA (1982) 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 155:1823
Gronovik KO, Anderson J, Alm G, Stern P (1983) T-cell growth factors contain activity that supports natural killer activity in vitro. Scand J Immunol 18:307
Herberman RB, Holden HT (1978) Natural cell-mediated immunity. Adv Cancer Res 27:305
Herzenberg LA, Herzenberg LA (1977) Analysis and separation using the fluorescence activated cell sorter (FACS). In: Weir DM (ed) Handbook of experimental immunology, vol 3. Blackwell Publications, Oxford, p 1
Itoh D, Tsuchikawa K, Awataguchi T, Shiiba K, Kumagai K (1983) A case of chronic lymphocytic leukemia with properties characteristic of natural killer cells. Blood 61:940
Jannossay G, Roberts MM, Capellaro D, Greaves MF, Francis GE (1978) Use of the fluorescence activated cell sorter in human leukemia. In: Knapp W, Holabar K, Wiock G (eds) Immunofluorescence and related staining techniques. Elservier/North Holland Biochemical Press, Amsterdam, p 111
Kasai M, Leclerc JC, MaVay-Boudreu L, Shen FH, Cantor H (1979) Direct evidence that NK cells in nonimmune cell populations prevent tumour growth in vivo. J Exp Med 149:1260
Kay NE, Zarling JM (1984) Impaired natural killer activity in patients with chronic lymphocytic leukemia is associated with a deficiency of azurophilic cytoplasmic granules in putative NK cells. Blood 63:305
Lanier LL, Benike CJ, Phillips JH, Engleman EG (1985) Recombinant interleukin 2 enhanced natural killer cell-mediated cytotoxicity in human lymphocyte subpopulations expressing the leu 7 and leu 11 antigens. J Immunol 134:794
London L, Perussia B, Trinchieri G (1985) Induction of proliferation in vitro of resting human natural killer cells: expression of surface activation antigens. J Immunol 134:718
Lotzova E, McCredie KB, Maroun JA, Dicke KA, Freireich EJ (1979) Some studies on natural killer cells in man. Transplant Proc 11:1390
Lotzova E, Savary CA, Gutterman JU, Hersh EH (1982) Modulation of natural killer cell-mediated cytotoxicity by partially purified and cloned interferon-gamma. Cancer Res 42:2480
Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood 45:321
Lozzio BB, Lozzio CB (1979) Properties and usefulness of the original K562 human myelogenous leukemia cell line. Leuk Res 3:363
Lozzio CB, Lozzio BB, Yang WK, Ichiki A, Bamberger EG (1976) Absence of T-derived lymphocyte markers in a myelogenous leukemia (Ph1+) cell line K562. Cancer Res 36:4657
Lozzio BB, Lozzio CB, Krauss S, Wust CJ (1977) Leukemia associated antigens detected by a nonhuman primate antiserum to a Ph1+ myelogenous leukemia cell line. Blood 50:115
Marks SM, Baltimore D, McCaffrey R (1978) Terminal transferase as a predictor of initial responsiveness to vincristine and prednisone in blastic myelogenous leukemia. N Engl J Med 298:812
Mazumder A, Rosenberg SA (1984) Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2. J Exp Med 159:495
Mule JJ, Shu S, Rosenberg SA (1985) The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo. J Immunol 135:646
Nowell PC, Hungerford DA (1960) Minute chromosome in human chronic granulocytic leukemia. Science 132:1497
Ortaldo JR, Oldham RK, Cannon GC, Herberman RB (1977) Specificity of natural cytotoxic reactivity of normal human lymphocytes against a myeloid leukemia cell line. J Natl Cancer Inst 59:77
Palutke M, Kaplan J, Hussain M, Kithier K, Tabaczka P, Mirchandani I, Tanenbaum D (1983) Natural killer and suppressor T-cell chronic lymphocytic leukemia. Blood 62:627
Pattengale PK, Gidlund M, Nilsson K, Sundstrom C, Orn A, Wigzell H (1981) Lysis of human B-lymphocyte-derived lymphoma/leukemia cells of established cell lines by interferon-activated natural killer (NK) cells. Int J Cancer 28:459
Pattengale PK, Sundstrom C, Yu AL, Levine A (1984) Lysis of fresh leukemic blasts by interferon-activated human natural killer cells. Nat Immunol Cell Growth Regul 3:165
Persussia B, Starr S, Abraham S, Fanning V, Trinchieri G (1983) Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. I. Characterization of the lymphocyte subset reactive with B73.1. J Immunol 130:2133
Perussia B, Acuto O, Terhorst C, Faust J, Lazarus R, Fanning V, Trinchieri G (1983) Human natural killer cells analysed by B73.1, a monoclonal antibody blocking Fc receptor function. J Immunol 130:2142
Platsoucas CD, Fernandes G, Gupta SL, Kempin S, Clarkson B, Good RA, Gupta S (1980) Defective spontaneous and antibody-dependent cytotoxicity mediated by E-rosette-positive and E-rosette-negative cells in untreated patients with chronic lymphocytic leukemia: augmentation by in vitro treatment with interferon. J Immunol 125:1216
Pross HF, Jonda M (1975) Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes. Clin Exp Immunol 21:226
Rowley JD (1973) A new consistent chromosome abnormality in chronic myelogenous leukemia identified by quinicrine fluorescence and German staining. Nature 343:290
Schmidt RE, Hercent T, Fox DA, Bensusan A, Bartley G, Daley JE, Schlossman SF, Reinherz EL, Ritz J (1985) The role of interleukin 2 and T 11 E rosette antigen in activation and proliferation of human NK clones. J Immunol 135:672
Stainhauer EH, Doyle AT, Kadish AS (1985) Human natural killer cytotoxic factor (NKCF): role of IFN-gamma. J Immunol 133:714
Svedersky LP, Shepard HM, Spencer SA, Shalady MR, Palladin MA (1984) Augmentation of human natural killer-mediated cytotoxicity by recombinant human interleukin 2. J Immunol 133:714
Timonens T, Ortald JR, Herberman RB (1981) Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J Exp Med 153:569
Timonen T, Ortaldo JR, Stadler BU, Bonnard GD, Sharrow SO, Herberman RB (1982) Cultures of purified human natural killer cells: growth in the presence of IL-2. Cell Immunol 72:178
Ting CC, Yang SY, Hargrove ME (1982) Effect of interleukin 2 on cytotoxic effectors. II. Long-term culture of NK cells. Cell Immunol 73:279
Toten M, Sidell N, Golub SH (1982) Interleukin 2 and stimulator lymphoid cells induce thymocytes to bind and kill K562 targets. J Exp Med 156:1545
Trinchieri G, Santoli D, Grano D, Perussia B (1981) Antagonistic effects of interferons on the cytotoxicity mediated by natural killer cells. Fed Proc 40:2705
Van de Griend RJ, Bolhuis RLH (1985) In vitro expansion and analysis of cloned cytotoxic T cells derived from patients with chronic T gammalymphoproliferative disorders. Blood 65:1002
Van de Griend RJ, Van Krimpken BA, Ronteltap GPM, Bolhuis RLH (1984) Rapidly expanded human killer cell clones have strong antitumor cell activity and have the surface phenotype of either T gamma, T-non gamma, or null cells. J Immunol 132:3185
Vose BM (1981a) Expansion of autorecognitive cytotoxic effectors in human cancer by T cell growth factor (interleukin 2). Arch Geschwulstforsch 51:317
Vose BM, Moore M (1981b) Cultured human T-cell lines kill autologous solid tumours. Immunol Lett 3:237
Vose Bm, Bonnard GD (1983b) Limiting dilution analysis of the frequency of human T cells and large granular lymphocytes proliferating in response to interleukin 2. I. The effect of lectin on the proliferative frequency and cytotoxic activity of cultured lymphoid cells. J Immunol 130:687
Warner JF, Dennert G (1982) Effects of a cloned cell line with NK activity on bone marrow transplants, tumour development and metastases in vivo. Nature 300:31
Ziegler HW, Kay NE, Zarling JM (1981) Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia. Int J Cancer 27:321
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fujimiya, Y., Chang, WC., Bakke, A. et al. Natural killer (NK) cell immunodeficiency in patients with chronic myelogenous leukemia. Cancer Immunol Immunother 24, 213–220 (1987). https://doi.org/10.1007/BF00205632
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00205632