Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1985 Apr;19(2):130–135. doi: 10.1007/BF00199721

Development of hyporesponsiveness of natural killer cells to augmentation of activity after multiple treatments with biological response modifiers

Tohru Saito 1, Ralf Ruffmann 1, Roy D Welker 1, Ronald B Herberman 1, Michael A Chirigos 1,✉
PMCID: PMC11039149  PMID: 3845849

Abstract

Four biological response modifiers (BRMs), MVE-2 (maleic anhydride divinyl ether), Corynebacterium parvum (C. Parvum), PolyICLC (polyinosinic:polycytidylic acid stabilized with poly-l-lysine), and mouse αβ-interferon (αβ-IFN), were tested to assess whether repeated treatments would repeatedly induce or sustain augmented levels of natural killer (NK) cell activity and/or macrophage (M0)-mediated inhibition of tumor cell growth. In contrast to a significant increase in splenic NK activity obtained with a single treatment with each of the agents, multiple treatments with these BRMs led to a progressive decrease in the degree of augmentation of NK activity. In contrast, multiple injections with these agents resulted in sustained augmentation of M0-mediated reactivity. Separation of the spleen cells by Percoll discontinuous density gradient centrifugation indicated that with mice treated once with each BRM high levels of NK activity were detected in the lower density fractions and that these fractions contained a higher percentage of large granular lymphocytes (LGLs) than that found in comparable fractions from normal mice. In contrast, cells in the lower density fractions from mice that received multiple treatments had decreased NK activity and an appreciably lower proportion of LGLs. These results indicate that the development of hyporesponsiveness to augmentation of splenic NK-cell activity following multiple treatments with BRMs may be attributable to a decreased percentage of LGLs, the effector cell population responsible for NK cell-mediated cytotoxicity.

Keywords: Multiple Treatment, Maleic Anhydride, Divinyl, Natural Killer Activity, Biological Response Modifier

Footnotes

Abbreviations used in this paper: BRMs, biological response modifiers; MVE-2, maleic anhydride divinyl ether of molecular weight 15,500; C. parvum, Corynebacterium parvum; PolyICLC, polyinosinic-polycytidylic acid stabilized with poly-l-lysine in carboxymethylcellulose; IFN, interferon; NK cells, natural killer cells; M0, macrophage; LGLs, large granular lymphocytes; PGE, prostaglandin E; FBS, fetal bovine serum; PBS, phosphate-buffer saline composed of 4.86 g NaCl, 0.306 g KH2PO4, and 2,417 g NaHPO4 in 100 ml H2O adjusted to pH 7.2; LPS, lipopolysaccharide

References

  • 1.Bartocci A, Papademetriou V, Chirigos MA. Enhanced macrophage and natural killer cell antitumor activity by various molecular weight maleic anhydride divinyl ethers. J Immunopharmacol. 1980;2:149. doi: 10.3109/08923978009026394. [DOI] [PubMed] [Google Scholar]
  • 2.Biron CA, Welsh RM. Blastogenesis of natural killer cells during viral infection in vivo. J Immunol. 1982;129:2788. [PubMed] [Google Scholar]
  • 3.Bruley-Rosset M, Rappaport H. Natural killer cell activity and spontaneous lymphoma development. Effects of single and multiple injections of interferon in young and aged C57B1/6 mice. Int J Cancer. 1983;31:381. doi: 10.1002/ijc.2910310320. [DOI] [PubMed] [Google Scholar]
  • 4.Brunda MJ, Herberman RB, Holden HT. Inhibition of murine natural killer cell activity by prostaglandin. J Immunol. 1980;124:2682. [PubMed] [Google Scholar]
  • 5.Chirigos MA, Papademetriou V, Bartocci A, Read A, Levy HB. Immune response modifying activity in mice of polyinosinic-polycytidylic acid stabilized with poly-l-lysine in carboxymethyl-cellulase [Poly-ICLC] Int J Immunopharmacol. 1981;3:329. doi: 10.1016/0192-0561(81)90028-x. [DOI] [PubMed] [Google Scholar]
  • 6.Chirigos MA, Saito T, Schlick E, Ruffmann R (1984) Cellular regulation by immunomodifiers MVE-2 and PolyICLC and their therapeutic application. Cancer Treat Symp (in press)
  • 7.De Landazuri MO, Herberman RB. Immune response to gross virus-induced lymphoma: III. Characterization of the cellular immune response. J Natl Cancer Inst. 1972;49:147. [PubMed] [Google Scholar]
  • 8.Herberman RB, Nunn MF, Lavin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors: I. Distribution, reactivity, and specificity. Int J Cancer. 1975;16:216. doi: 10.1002/ijc.2910160204. [DOI] [PubMed] [Google Scholar]
  • 9.Herberman RB, Brunda MJ, Cannon GB, Djeu JY, Nunn-Hargrove ME, Jett JR, Ortaldo JR, Reynolds C, Riccardi C, Santoni A, et al. Augmentation of natural killer (NK) cell activity by interferon and interferon inducers. In: Hersh EM, et al., editors. Augmentating agents in cancer therapy. New York: Raven; 1981. pp. 253–265. [Google Scholar]
  • 10.Hersh EM, Chirigos MA, Mastrangelo MJ, et al. Progress in cancer research and therapy. In: Hersh EM, et al., editors. Augmenting agents in cancer therapy. New York: Raven; 1981. pp. 1–574. [Google Scholar]
  • 11.Hibbs JB, Lambert LH, Remington JS. Macrophage-mediated nonspecific cytotoxicity. Possible role in tumor resistance. Nature New Biol. 1982;235:48. doi: 10.1038/newbio235048a0. [DOI] [PubMed] [Google Scholar]
  • 12.Julius HE, Simpson E, Herzenberg LA. A rapid method for the isolation of functional thymus derived murine lymphocytes. Eur J Immunol. 1975;3:645. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  • 13.Kiessling R, Klein E, Wigzell H. Natural killer cells in the mouse: I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunopharmacol. 1975;5:112. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  • 14.Kumagai K, Itoh K, Suzuki R, Hinuma S, Saitoh F. Studies of murine large granular lymphocytes: I. Identification as effector cells in NK and K cytotoxicities. J Immunol. 1982;129:388. [PubMed] [Google Scholar]
  • 15.Kuribayashi K, Gillis S, Kern DE, Henney CB. Murine NK cell cultures: Effect of interleukin 2 and interferon on cell growth and cytotoxic reactivity. J Immunol. 1982;126:2321. [PubMed] [Google Scholar]
  • 16.Leung KH, Karen HS. Regulation of cytotoxic reactivity of NK cells by interferon and PGE2. In: Herberman RB, editor. NK cells and other natural effector cells. New York: Academic; 1982. pp. 615–620. [Google Scholar]
  • 17.Lotzova E, Savary CA, Quesada JR, Gutterman JJ, Hersh EM. Analysis of natural killer cell cytotoxicity of cancer patients trated eith recombinant interferon. INCI. 1983;71:903. [PubMed] [Google Scholar]
  • 18.Luini W, Boraschi D, Albert S, Aleotti A, Tagliabue A. Morphological characterization of a cell population responsible for natural killer activity. Immunology. 1981;43:663. [PMC free article] [PubMed] [Google Scholar]
  • 19.Maluish AE, Conlon J, Ortaldo JR, Sherwin SA, Seavitt R, Fein S, Weirnik P, Oldham RK, Herberman RB. Modulation of NK and monocyte activity in advanced cancer patients receiving interferon. In: Merigan TC, Friedeman RM, editors. Interferons. New York: Academic; 1982. pp. 377–386. [Google Scholar]
  • 20.Maluish AE, Ortaldo JR, Conlon JC, Sherwin SA, Leavitt R, Strong DM, Weirnik P, Oldham RK, Herberman RB. Depression of natural killer cytotoxicity after in vivo administration of recombinant leukocyte interferon. J Immunol. 1983;131:503. [PubMed] [Google Scholar]
  • 21.Pace JL, Russell SW. Activation of mouse macrophages for tumor cell killing: I. Quantitative analysis of interactions between lymphokine and lipopolysaccharide. J Immunol. 1981;126:1863. [PubMed] [Google Scholar]
  • 22.Piccoli M, Saito T, Chirigos MA. Biomodal effects of MVE-2 on cytotoxic activity of natural killer cell and macrophage tumoricidal activities. Int J Immunopharmacol. 1984;6:569. doi: 10.1016/0192-0561(84)90067-5. [DOI] [PubMed] [Google Scholar]
  • 23.Reynolds CW, Timonen T, Ortaldo JR, Herberman RB. Natural killer activity in the rat: I. Isolation and characterization of the effector cells. J Immunol. 1981;127:282. [PubMed] [Google Scholar]
  • 24.Santoni A, Riccardi C, Barlozzari T, Herberman RB. Suppression of activity of mouse natural killer (NK) cells by activated macrophages from mice treated with pyran copolymer. Int J Cancer. 1980;26:837. doi: 10.1002/ijc.2910260619. [DOI] [PubMed] [Google Scholar]
  • 25.Santoni A, Riccardi C, Barlozzari T, Herberman RB. C. parvum-induced suppressor cells for mouse NK activity. In: Herberman RB, editor. NK cells and other natural effector cells. New York: Academic; 1982. pp. 519–526. [Google Scholar]
  • 26.Schultz RM, Papametheakis JD, Chirigos MA. Interferon, an inducer of macrophage activation by polyanions. Science. 1977;197:674. doi: 10.1126/science.877584. [DOI] [PubMed] [Google Scholar]
  • 27.Schultz RM, Papametheakis JD, Leutzeller J, Ruiz P, Chirigos MA. Macrophage involvement in the protective effect of pyran copolymer against the Madison lung carcinoma M109. Cancer Res. 1977;37:358. [PubMed] [Google Scholar]
  • 28.Taramelli D, Holden HT, Varesio L. Endotoxin requirement for macrophage activation by lymphokines in a rapid microcytotoxicity assay. J Immunol Methods. 1980;37:225. doi: 10.1016/0022-1759(80)90309-9. [DOI] [PubMed] [Google Scholar]
  • 29.Taramelli D, Holden HT, Varesio L. In vitro induction of tumoricidal and suppressor macrophages by lymphokines: Possible feedback regulation. J Immunol. 1981;126:2123. [PubMed] [Google Scholar]
  • 30.Timonen T, Saksela E, Ranki A, Haryry P. Fractionation, morphological and functional characterization of effector cells responsible for human natural killer activity against cell line targets. Cell Immunol. 1979;48:133. doi: 10.1016/0008-8749(79)90106-0. [DOI] [PubMed] [Google Scholar]
  • 31.Timonen T, Ortaldo J, Herberman R. Characteristics of human large granular lymphocytes and relationship to NK and K cells. J Exp Med. 1981;153:569. doi: 10.1084/jem.153.3.569. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES