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J Exp Med. 1992 March 1; 175(3): 789–796.
PMCID: PMC2119140

Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients

Abstract

Natural killer cell stimulatory factor (NKSF), or interleukin 12 (IL- 12), is a heterodimeric lymphokine produced by B cells that has multiple effects on T and NK cell functions. NKSF at concentrations as low as 0.4 pM enhances the spontaneous cytotoxic activity of peripheral blood lymphocytes (PBL) against a variety of tumor-derived target cell lines and virus-infected target cells. The combined treatment of PBL with NKSF and IL-2 results in a less than additive enhancement of cytotoxicity. NKSF enhances the cytotoxic activity of spontaneously cytotoxic CD16+CD5- NK cells and does not confer cytotoxic activity to CD16-CD5+ T cells. PBL from patients infected with human immunodeficiency virus (HIV) have significantly lower cytotoxic activity against tumor-derived target cells and virus-infected target cells than PBL from control healthy donors. Treatment of PBL from HIV- infected patients with NKSF and/or IL-2 results in an increase of NK cell cytotoxicity against both types of target cells to levels similar to or higher than those of untreated PBL from healthy donors. PBL from HIV-infected patients produce interferon gamma in response to NKSF and/or IL-2, although at levels 5- or 10-fold lower than those produced by PBL from healthy donors. The multiple biological effects of NKSF, its activity at very low molar concentrations, and its ability to synergize with other physiological stimuli suggest that NKSF/IL-12 is a lymphokine likely to have physiological importance and considerable therapeutic potential.

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Selected References

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  • Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. [PMC free article] [PubMed]
  • Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed]
  • Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. [PubMed]
  • Gubler U, Chua AO, Schoenhaut DS, Dwyer CM, McComas W, Motyka R, Nabavi N, Wolitzky AG, Quinn PM, Familletti PC, et al. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. [PubMed]
  • Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospísil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. [PMC free article] [PubMed]
  • Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizonnite R, Gubler U, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed]
  • Fontana L, Sirianni MC, de Sanctis G, Carbonari M, Ensoli B, Aiuti F. Deficiency of natural killer activity, but not of natural killer binding, in patients with lymphoadenopathy syndrome positive for antibodies to HTLV-III. Immunobiology. 1986 Jul;171(4-5):425–435. [PubMed]
  • Bonavida B, Katz J, Gottlieb M. Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. I. Defective trigger on NK cells for NKCF production by target cells, and partial restoration by IL 2. J Immunol. 1986 Aug 15;137(4):1157–1163. [PubMed]
  • Katzman M, Lederman MM. Defective postbinding lysis underlies the impaired natural killer activity in factor VIII-treated, human T lymphotropic virus type III seropositive hemophiliacs. J Clin Invest. 1986 Apr;77(4):1057–1062. [PMC free article] [PubMed]
  • Sirianni MC, Soddu S, Malorni W, Arancia G, Aiuti F, Soddus S. Mechanism of defective natural killer cell activity in patients with AIDS is associated with defective distribution of tubulin. J Immunol. 1988 Apr 15;140(8):2565–2568. [PubMed]
  • Murray HW, Rubin BY, Masur H, Roberts RB. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med. 1984 Apr 5;310(14):883–889. [PubMed]
  • Cauda R, Tyring SK, Tamburrini E, Ventura G, Tambarello M, Ortona L. Diminished interferon gamma production may be the earliest indicator of infection with the human immunodeficiency virus. Viral Immunol. 1987;1(4):247–258. [PubMed]
  • Rudy T, Opelz G, Gerlach R, Daniel V, Schimpf K. Correlation of in vitro immune defects with impaired gamma interferon response in human-immunodeficiency-virus-infected individuals. Vox Sang. 1988;54(2):92–95. [PubMed]
  • Vuillier F, Bianco NE, Montagnier L, Dighiero G. Selective depletion of low-density CD8+, CD16+ lymphocytes during HIV infection. AIDS Res Hum Retroviruses. 1988 Apr;4(2):121–129. [PubMed]
  • Nokta MA, Pollard RB. Patterns of interferon-gamma production by peripheral blood mononuclear cells from patients with human immunodeficiency virus infection. J Interferon Res. 1990 Apr;10(2):173–181. [PubMed]
  • Sirianni MC, Tagliaferri F, Aiuti F. Pathogenesis of the natural killer cell deficiency in AIDS. Immunol Today. 1990 Mar;11(3):81–82. [PubMed]
  • Perussia B, Starr S, Abraham S, Fanning V, Trinchieri G. 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. 1983 May;130(5):2133–2141. [PubMed]
  • Murphy M, Loudon R, Kobayashi M, Trinchieri G. Gamma interferon and lymphotoxin, released by activated T cells, synergize to inhibit granulocyte/monocyte colony formation. J Exp Med. 1986 Jul 1;164(1):263–279. [PMC free article] [PubMed]
  • Chehimi J, Bandyopadhyay S, Prakash K, Perussia B, Hassan NF, Kawashima H, Campbell D, Kornbluth J, Starr SE. In vitro infection of natural killer cells with different human immunodeficiency virus type 1 isolates. J Virol. 1991 Apr;65(4):1812–1822. [PMC free article] [PubMed]
  • Trinchieri G, Santoli D, Dee RR, Knowles BB. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation. J Exp Med. 1978 May 1;147(5):1299–1313. [PMC free article] [PubMed]
  • Henney CS, Kuribayashi K, Kern DE, Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981 May 28;291(5813):335–338. [PubMed]
  • Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehra J, London L, Perussia B. Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 1984 Oct 1;160(4):1147–1169. [PMC free article] [PubMed]
  • Ostensen ME, Thiele DL, Lipsky PE. Tumor necrosis factor-alpha enhances cytolytic activity of human natural killer cells. J Immunol. 1987 Jun 15;138(12):4185–4191. [PubMed]
  • Rosenberg ZF, Fauci AS. The immunopathogenesis of HIV infection. Adv Immunol. 1989;47:377–431. [PubMed]
  • Rossol S, Voth R, Laubenstein HP, Müller WE, Schröder HC, Meyer zum Büschenfelde KH, Hess G. Interferon production in patients infected with HIV-1. J Infect Dis. 1989 May;159(5):815–821. [PubMed]
  • Lane HC, Siegel JP, Rook AH, Masur H, Gelmann EP, Quinnan GV, Fauci AS. Use of interleukin-2 in patients with acquired immunodeficiency syndrome. J Biol Response Mod. 1984 Oct;3(5):512–516. [PubMed]
  • Mertelsmann R, Welte K, Sternberg C, O'Reilly R, Moore MA, Clarkson BD, Oettgen HF. Treatment of immunodeficiency with interleukin-2: initial exploration. J Biol Response Mod. 1984 Oct;3(5):483–490. [PubMed]
  • Volberding P, Moody DJ, Beardslee D, Bradley EC, Wofsy CB. Therapy of acquired immune deficiency syndrome with recombinant interleukin-2. AIDS Res Hum Retroviruses. 1987 Summer;3(2):115–124. [PubMed]
  • Schwartz DH, Skowron G, Merigan TC. Safety and effects of interleukin-2 plus zidovudine in asymptomatic individuals infected with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1991;4(1):11–23. [PubMed]
  • Murphy PM, Lane HC, Gallin JI, Fauci AS. Marked disparity in incidence of bacterial infections in patients with the acquired immunodeficiency syndrome receiving interleukin-2 or interferon-gamma. Ann Intern Med. 1988 Jan;108(1):36–41. [PubMed]
  • Heagy W, Groopman J, Schindler J, Finberg R. Use of IFN-gamma in patients with AIDS. J Acquir Immune Defic Syndr. 1990;3(6):584–590. [PubMed]
  • Murray HW, Scavuzzo D, Jacobs JL, Kaplan MH, Libby DM, Schindler J, Roberts RB. In vitro and in vivo activation of human mononuclear phagocytes by interferon-gamma. Studies with normal and AIDS monocytes. J Immunol. 1987 Apr 15;138(8):2457–2462. [PubMed]
  • Heagy W, Kelley VE, Strom TB, Mayer K, Shapiro HM, Mandel R, Finberg R. Decreased expression of human class II antigens on monocytes from patients with acquired immune deficiency syndrome. Increased expression with interferon-gamma. J Clin Invest. 1984 Dec;74(6):2089–2096. [PMC free article] [PubMed]
  • Heagy W, Strom TB, Kelley VE, Collela J, Crumpacker C, Williams JM, Shapiro HM, Laubenstein L, Finberg R. Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome. Infect Immun. 1989 Nov;57(11):3619–3628. [PMC free article] [PubMed]

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