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Cytokines in the treatment of fungal infections

  • Published:
Biotherapy

Abstract

The incidence of invasive fungal infections in the immunocompromized host has increased during the past decade. Even the recently developed antifungal drugs are unable to cure these infections in patients with severely impaired host defense mechanisms. Cytokines have great potential to augment host resistance and as adjunctive therapy of invasive mycoses. We discuss the mechanisms of host defense against invasive candidiasis, aspergillosis, and cryptococcosis, and review the use of cytokines and growth factors in this setting. Interleukin-1 has been shown effective in an animal model of disseminated candidiasis, even during severe granulocytopenia. Interferon-γ has been very effective as a modulator of resistance against a variety of fungal infectionsin vitro. The effect of interferon-γ against disseminated candidiasis has been demonstrated in a mouse model. Activation of neutrophils is the main mechanism by which interferon-γ enhances the elimination ofCandida, and consequently the agent is not effective in severly granulocytopenic animals. Data on the role of colony-stimulating factors against fungal pathogens are accumulating, and trials with these agents for hematologic patients with invasive fungal infections are now being performed.

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Abbreviations

CGD:

chronic granulomatous disease

G-CSF:

granulocyte colony-stimulating factor

M-CSF:

monocyte colony-stimulating factor

GM-CSF:

granulocyte-monocyte colony-stimulating factor

IFN-γ :

interferon-gamma

IL:

interleukin

LAK:

lymphokine-activated killer

LPS:

lipopolysaccharide

MDP:

muramyl dipeptide

NK:

natural killer

PMN:

polymorphonuclear leukocytes

rh:

recombinant human

ROI:

reactive oxygen intermediates

TNF:

tumor necrosis factor

References

  1. Bodey GP. Candidiasis in cancer patients. Am J Med 1984; 77: 13–19.

    Google Scholar 

  2. Meunier-Carpentier F, Kiehn TE, Armstrong D. Fungemia in the immunocompromised host. Changing patterns, antigenemia, high mortality. Am J Med 1981; 71: 363–370.

    PubMed  Google Scholar 

  3. Pizzo PA, Robichaud KJ, Gill FA, Witebski FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72: 101–111.

    PubMed  Google Scholar 

  4. Odds FC.Candida and candidosis (2nd ed.). London: Ballière Tindall, 1988.

    Google Scholar 

  5. Bodey G, Bueltmann B, Duguid W,et al. Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis 1992; 11: 99–109.

    PubMed  Google Scholar 

  6. Beck-Sagué CM, Jarvis WR. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980–1990. J Infect Dis 1993; 167: 1247 - 1251.

    PubMed  Google Scholar 

  7. Edwards JE. InvasiveCandida infections — evolution of a fungal pathogen. N Engl J Med 1991; 324: 1060–1062.

    PubMed  Google Scholar 

  8. Pfaller MA. Infection control: opportunistic fungal infections — the increasing importance ofCandida species. Infect Control Hosp Epidemiol 1989; 10: 270–273.

    PubMed  Google Scholar 

  9. Van n't Wout JW, Van der Woude FJ. Fungal infections in solid organ transplant recipients. In: Powderly WB, Van 't Wout JW, ed. Fluconazole. Carnforth (UK): Marius Press, 1992; 82–91.

    Google Scholar 

  10. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2121 published cases. Rev Infect Dis 1990; 12: 1147–1201.

    PubMed  Google Scholar 

  11. Cohen MS, Isturiz RE, Malech HL,et al. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med 1981; 71: 59–66.

    PubMed  Google Scholar 

  12. Denning DW, Follansbee SE, Scolaro M, Norris S, Edelstein H, Stevens DA. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 654–662.

    PubMed  Google Scholar 

  13. Chuck SL, Sande MA. Infections withCryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321: 794–800.

    PubMed  Google Scholar 

  14. Lazzarin A, Umberti Foppa C, Galli M,et al. Impairment of polymorphonuclear leucocyte function in patients with acquired immunodeficiency syndrome and with lymphadenopathy syndrome. Clin Exp Imunol 1986; 65: 105–111.

    Google Scholar 

  15. Umberti Foppa C, Franzetti F, Negri C,et al. Role of PMN's candidacidal activity in the pathogenesis of AIDS-related systemic candidiasis. Boll Ist Sieroter Milan 1987; 66: 471–478.

    PubMed  Google Scholar 

  16. Gutiérrez J, Maroto M, Piédrola G. Granulocyte abnormalities in parenteral drug addicts. The influence of HIV-infection. Allergol Immunopathol 1989; 17: 251–255.

    Google Scholar 

  17. Pos O, Stevenhagen A, Meenhorst PL, Kroon FR, Van Furth R. Impaired phagocytosis ofStaphylococcus aureus by granulocytes and monocytes of AIDS patients. Clin Exp Immunol 1992; 88: 23–28.

    PubMed  Google Scholar 

  18. Brummer E, McEwen JG, Stevens DA. Fungicidal activity of murine inflammatory polymorphonuclear neutrophils: comparison with murine peripheral blood PMN. Clin Exp Immunol 1986; 66: 681–690.

    PubMed  Google Scholar 

  19. Leijh PCJ, Van den Barselaar MT, Van Furth R. Kinetics of phagocytosis and intracellular killing ofCandida albicans by human granulocytes and monocytes. Infect Immun 1977; 17: 313–318.

    PubMed  Google Scholar 

  20. Moser SA, Domer JE. Effects of cyclophosphamide on murine candidiasis. Infect Immun 1980; 27: 376–386.

    PubMed  Google Scholar 

  21. Van 't Wout JW, Linde I, Leijh PCJ, Van Furth R. Contribution of granulocytes and monocytes to resistance against experimental disseminatedCandida albicans infections. Eur J Clin Microbiol Infect Dis 1988; 7: 736–741.

    PubMed  Google Scholar 

  22. Kullberg BJ, Van 't Wout JW, Van Furth R. Role of granulocytes in enhanced host resistance toCandida albicans induced by recombinant interleukin-1. Infect Immun 1990; 58: 3319–3324.

    PubMed  Google Scholar 

  23. Brummer E, Stevens DA. Activation of pulmonary macrophages for fungicidal activity by gamma-interferon or lymphokines. Clin Exp Immunol 1987; 70: 520–528.

    PubMed  Google Scholar 

  24. Brummer E, Morrison CJ, Stevens DA. Recombinant and natural gamma-interferon activation of macrophagesin vitro: different dosage requirements for induction of killing activity against phagocytizable and nonphagocytizable fungi. Infect Immun 1985; 49: 724–730.

    PubMed  Google Scholar 

  25. Sasada M, Johnston RB Jr. Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing ofCandida by macrophages. J Exp Med 1980; 152: 85–98.

    PubMed  Google Scholar 

  26. Sasada M, Kubo A, Nishimura T,et al. Candidacidal activ-ity of monocyte-derived human macrophages: relationship betweenCandida killing and oxygen radical generation by human macrophages. J Leukocyte Biol 1987; 41: 289–294.

    PubMed  Google Scholar 

  27. Van 't Wout JW, Poell R, Van Furth R. The role of BCG-PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol 1992; 36: 713–719.

    PubMed  Google Scholar 

  28. Djeu JY, Blanchard DK, Halkias D, Friedman H. Growth inhibition ofCandida albicans by human polymorphonuclear neutrophils: activation by interferon-γ and tumor necrosis factor. J Immunol 1986; 137: 2980–2984.

    PubMed  Google Scholar 

  29. Wang M, Friedman H, Djeu JY. Enhancement of human monocyte function againstCandida albicans by the colonystimulating factors (CSF): IL-3, granulocyte-macrophage CSF, and macrophage CSF. J Immunol 1989; 143: 671–677.

    PubMed  Google Scholar 

  30. Lehrer RI. The fungicidal mechanisms of human monocytes. I. Evidence for myeloperoxidase-linked and myeloperoxidase-independent candidacidal mechanisms. J Clin Invest 1975; 55: 338–346.

    PubMed  Google Scholar 

  31. Lehrer RI, Szklarek D, Ganz T, Selsted ME. Modulation of thein vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J Clin Invest 1988; 81: 1829–1835.

    PubMed  Google Scholar 

  32. Diamond RD. Immune response to fungal infection. Rev Infect Dis 1989; 11: S1600–S1604.

    PubMed  Google Scholar 

  33. Diamond RD, Krzesicki R, Jao W. Damage to pseudohyphal forms ofCandida albicans by neutrophils in the absence of serumin vitro. J Clin Invest 1978; 61: 349–359.

    PubMed  Google Scholar 

  34. McNamara MP, Wiessner JH, Collins-Lech C, Hahn BL, Sohnle PG. Neutrophil death as a defence mechanism againstCandida albicans infections. Lancet 1988; 2: 1163–1165.

    PubMed  Google Scholar 

  35. Sohnle PG, Collins-Lech C. Comparison of candidacidal and candidastatic activities of human neutrophils. Infect Immun 1990; 58: 2696–2698.

    PubMed  Google Scholar 

  36. Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance toAspergillus. J Clin Invest 1982; 69: 617–631.

    PubMed  Google Scholar 

  37. Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Enhancement of oxidative response and damage caused by human neutrophils toAspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993; 61: 1185–1193.

    PubMed  Google Scholar 

  38. Diamond RD, Krzesicki R, Epstein B, Jao W. Damage to hyphal forms of fungi by human leukocytesin vitro: a possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol 1978; 91: 313–328.

    PubMed  Google Scholar 

  39. Polak-Wyss A. Protective effect of human granulocyte colony-stimulating factor (hG-CSF) onCryptococcus andAspergillus infections in normal and immunosuppressed mice. Mycoses 1991; 34: 205–215.

    PubMed  Google Scholar 

  40. Levitz SM. The ecology ofCryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis 1991; 13: 1163–1169.

    PubMed  Google Scholar 

  41. Huffnagle GB, Yates JL, Lipscomb MF. Immunity to a pulmonaryCryptococcus neoformans infection requires both CD4+ and CD8+ T cells. J Exp Med 1991; 173: 793–800.

    PubMed  Google Scholar 

  42. Lipscomb MF, Alvarellos T, Toews GB,et al. Role of natural killer cells in resistance toCryptococcus neoformans infections in mice. Am J Pathol 1987; 128: 354–361.

    PubMed  Google Scholar 

  43. Salkowski CA, Balish E. Role of natural killer cells in resistance to systemic cryptococcosis. J Leukoc Biol 1991; 50: 151–159.

    PubMed  Google Scholar 

  44. Weinberg PB, Becker S, Granger DL, Koren HS. Growth inhibition ofCryptococcus neoformans by human alveolar macrophages. Am Rev Respir Dis 1987; 136: 1242–1247.

    PubMed  Google Scholar 

  45. Dubos RJ, Schaedler RW. Effects of cellular constituents of mycobacteria on the resistance of mice to heterologous infections. J Exp Med 1957; 106: 703–717.

    PubMed  Google Scholar 

  46. Sher NA, Chaparas SD, Greenberg LE, Bernard S. Effects of BCG,Corynebacterium parvum, and methanol-extraction residu in the reduction of mortality fromStaphylococcus aureus andCandida albicans infections in immunosuppressed mice. Infect Immun 1975; 12: 1325–1330.

    PubMed  Google Scholar 

  47. Van Dissel JT, Stikkelbroeck JJM, Van den Barselaar MT, Sluiter W, Leijh PCJ, Van Furth R. Divergent changes in antimicrobial activity after immunologic activation of mouse peritoneal macrophages. J Immunol 1987; 139: 1665–1672.

    PubMed  Google Scholar 

  48. Langermans JAM, Van der Hulst MB, Nibbering PH, Van Furth R. Activation of mouse peritoneal macrophages during infection withSalmonella typhimurium does not result in enhanced intracellular killing. J Immunol 1990; 144: 4340–4346.

    PubMed  Google Scholar 

  49. Vecchiarelli A, Cenci E, Puliti M,et al. Protective immunity induced by low-virulenceCandida albicans: Cytokine production in the development of the anti-infectious state. Cell Immunol 1989; 124: 334–344.

    PubMed  Google Scholar 

  50. Bistoni F, Vecchiarelli A, Cenci E, Puccetti P, Marconi P, Cassone A. Evidence for macrophage-mediated protection against lethalCandida albicans infection. Infect Immun 1986; 51: 668–674.

    PubMed  Google Scholar 

  51. Cenci E, Romani L, Vecchiarelli A, Puccetti P, Bistoni F. Role of L3T4+ lymphocytes in protective immunity to systemicCandida albicans infection in mice. Infect Immun 1989; 57: 3581–3587.

    PubMed  Google Scholar 

  52. Cluff LE. Effects of endotoxins on susceptibility to infections. J Infect Dis 1970; 122: 205–216.

    PubMed  Google Scholar 

  53. Parant M, Riveau G, Parant F, Dinarello CA, Wolff SM, Chedid L. Effect of indomethacin on increased resistance to bacterial infection and on febrile responses induced by muramyl dipeptide. J Infect Dis 1980; 142: 708–715.

    PubMed  Google Scholar 

  54. Phillips NC, Chedid L. Anti-infectious activity of liposomal muramyl dipeptides in immunodeficient CBA/N mice. Infect Immun 1987; 55: 1426–1430.

    PubMed  Google Scholar 

  55. Oppenheim JJ, Togawa A, Chedid L, Mizel S. Components of mycobacteria and muramyl dipeptide with adjuvant activity induce lymphocyte activating factor. Cell Immunol 1980; 50: 71–81.

    PubMed  Google Scholar 

  56. Mackaness GB. Resistance to intracellular infection. J Infect Dis 1971; 123: 439–445.

    PubMed  Google Scholar 

  57. Hashimoto T.In vitro study of contact-mediated killing ofCandida albicans hyphae by activated murine peritoneal macrophages in a serum-free medium. Infect Immun 1991; 59: 3555–3561.

    PubMed  Google Scholar 

  58. Watanabe K, Kagaya K, Yamada T, Fukazawa Y. Mechanism for candidacidal activity in macrophages activated by recombinant gamma-interferon. Infect Immun 1991; 59: 521–528.

    PubMed  Google Scholar 

  59. Rogers TJ, Balish E. The role of activated macrophages in resistance to experimental renal candidiasis. J Reticuloendothel Soc 1977; 22: 309–318.

    PubMed  Google Scholar 

  60. Baghian A, Lee KW. Role of activated macrophaghes in resistance to systemic candidosis. J Leucocyte Biol 1988; 44: 166–171.

    Google Scholar 

  61. Kampschmidt RF, Pulliam LA. Stimulation of antimicrobial activity in the rat with leukocyte endogenous mediator. J Reticuloendothel Soc 1975; 17: 162–169.

    PubMed  Google Scholar 

  62. Dinarello CA. Interleukin-1. Rev Infect Dis 1984; 6: 51–95.

    PubMed  Google Scholar 

  63. Dinarello CA, Cannon JG, Mier JW, Bernheim HA, LoPreste G. Multiple biological activities of human recombinant interleukin-1. J Clin Invest 1986; 77: 1734–1739.

    PubMed  Google Scholar 

  64. Ellouz F, Adam A, Ciorbaru R, Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun 1974; 59: 1317–1325.

    PubMed  Google Scholar 

  65. Parant M, Chedid L. Stimulation of non-specific resistance to infections by synthetic immunoregulatory agents. Infection 1985; 13: S251–255.

    PubMed  Google Scholar 

  66. Cummings NP, Pabst MJ, Johnston RB Jr. Activation of macrophages for enhanced release of superoxide anion and greater killing ofCandida albicans by injection of muramyl dipeptide. J Exp Med 1980; 152: 1659–1669.

    PubMed  Google Scholar 

  67. Fraser-Smith EB, Matthews TR. Protective effect of muramyl dipeptide analogs against infections ofPseudomonas aeruginosa orCandida albicans in mice. Infect Immun 1981; 34: 676–683.

    PubMed  Google Scholar 

  68. Fraser-Smith EB, Waters RV, Matthews TR. Correlation betweenin vivo anti-Pseudomonas and anti-Candida activities and clearance of carbon by the reticuloendothelial system for various muramyl dipeptide analogs, using normal and immunosuppressed mice. Infect Immun 1982; 35: 105–110.

    PubMed  Google Scholar 

  69. Dinarello CA, Krueger JM. Induction of interleukin-1 by synthetic and naturally occurring muramyl peptides. FASEB J 1986; 45: 2545–2548.

    Google Scholar 

  70. Sanceau J, Falcoff R, Beranger F, Carter DB, Wietzerbin J. Secretion of interleukin-6 (IL-6) by human monocytes stimulated by muramyl dipeptide and tumor necrosis factor alpha. Immunol 1990; 69: 52–56.

    Google Scholar 

  71. Broudy VC, Kaushansky K, Shoemaker SG, Aggarwal BB, Adamson JW. Muramyl dipeptide induces production of hemopoietic growth factorsin vivo by a mechanism independent of tumor necrosis factor. J Immunol 1990; 144: 3789–3794.

    PubMed  Google Scholar 

  72. Vogels MTE, Van der Meer JWM. Use of immune modulators in nonspecific therapy of bacterial infections. Antimicrob Agents Chemother 1992; 36: 1–5.

    PubMed  Google Scholar 

  73. Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991; 77: 1627–1652.

    PubMed  Google Scholar 

  74. Oppenheim JJ, Kovacs EJ, Matsushima K, Durum SK. There is more than one interleukin-1. Immunol Today 1986; 7: 45–56.

    Google Scholar 

  75. Dinarello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis 1988; 10: 168–189.

    PubMed  Google Scholar 

  76. Atkins E. Pathogenesis of fever. Physiol Rev 1960; 40: 580–646.

    PubMed  Google Scholar 

  77. Atkins E. Fever — new perspectives on an old phenomenon. N Engl J Med 1983; 308: 958–959.

    PubMed  Google Scholar 

  78. Kaiser HK, Wood WB Jr. Sudies on the pathogenesis of fever. IX. The production of endogenous pyrogen by polymorphonuclear leukocytes. J Exp Med 1962; 115: 27–36.

    PubMed  Google Scholar 

  79. Platanias LC, Vogelzang NJ. Interleukin-1 — biology, pathophysiology, and clinical prospects. Am J Med 1990; 89: 621–629.

    PubMed  Google Scholar 

  80. Di Giovine Fs, Duff GW. Interleukin 1: the first interleukin. Immunol Today 1990; 11: 13–20.

    PubMed  Google Scholar 

  81. Van der Meer JWM, Vogels MTE, Kullberg BJ. Interleukin-1 and related pro-inflammatory cytokines in the treatment bacterial infections in neutropenic and non-neutropenic animals. Biotherapy 1994; 7: 161–167.

    PubMed  Google Scholar 

  82. Van 't Wout JW, Van der Meer JWM, Barza M, Dinarello CA. Protection of neutropenic mice from lethalCandida albicans infection by recombinant interleukin 1. Eur J Immunol 1988; 18: 1143–1146.

    PubMed  Google Scholar 

  83. Kullberg BJ, Van 't Wout JW, Poell RJM, Van Furth R. Combined effect of fluconazole and recombinant human interleukin-1 on systemic candidiasis in mice. Antimicrob Agents Chemother 1992; 36: 1225–1229.

    PubMed  Google Scholar 

  84. Czuprynski CJ, Brown JF. Purified human and recombinant murine interleukin-1 induced accumulation of inflammatory peritoneal neutrophils and mononuclear phagocytes: possible contributions to antibacterial resistance. Microb Pathogen 1987; 3: 377–386.

    Google Scholar 

  85. Czuprynski CJ, Brown JF, Young KM, Cooley AJ, Kurtz RS. Effects of murine recombinant interleukin 1 alpha on the host response to bacterial infection. J Immunol 1988; 140: 962–968.

    PubMed  Google Scholar 

  86. McIntyre KW, Unowsky J, DeLorenzo W, Benjamin W. Enhancement of antibacterial resistance of neutropenic bone marrow-suppressed mice by interleukin-1α. Infect Immun 1989; 57: 48–54.

    PubMed  Google Scholar 

  87. Stork LC, Peterson VM, Rundus CH, Robinson WA. Interleukin-1 enhances murine granulopoiesisin vivo. Exp Hematol 1988; 16: 163–167.

    PubMed  Google Scholar 

  88. Fibbe WE, Daha MR, Hiemstra PS,et al. Interleukin 1 and poly(rI). poly(rC) induce production of granulocyte CSF, macrophage CSF, and granulocyte-macrophage CSF by human endothelial cells. Exp Hematol 1989; 17: 229–234.

    PubMed  Google Scholar 

  89. Vogel SN, Douches SD, Kaufman EN, Neta R. Induction of colony stimulating factorin vivo by recombinant interleukin 1 alpha and recombinant tumor necrosis factor alpha. J Immunol 1987; 138: 2143–2148.

    PubMed  Google Scholar 

  90. Fibbe WE, Van der Meer JWM, Falkenburg JHF, Hamilton MS, Kluin PM, Dinarello CA. A single low dose of human recombinant interleukin 1 accelerates the recovery of neutrophils in mice with cyclophosphamide-induced neutropenia. Exp Hematol 1989; 17: 805–808.

    PubMed  Google Scholar 

  91. Kullberg BJ, Van 't Wout JW, Van Furth R. No effect of recombinant human interleukin-1 on the numbers of peripheral blood and peritoneal leukocytes during an acute inflammation. Inflammation 1991; 15: 457–470.

    PubMed  Google Scholar 

  92. Blasi E, Farinelli S, Varesio L, Bistoni F. Augmentation of GG2EE macrophage cell line-mediated anti-Candida activity by gamma-interferon, tumor necrosis factor, and interleukin-1. Infect Immun 1990; 58: 1073–1077.

    PubMed  Google Scholar 

  93. Vecchiarelli A, Todisco T, Puliti M, Dottorini M, Bistoni F. Modulation of anti-Candida activity of human alveolar macrophages by interferon-gamma or interleukin-1-alpha. Am J Respir Cell Mol Biol 1989; 1: 49–55.

    PubMed  Google Scholar 

  94. Van der Meer JWM, Barza M, Wolff SM, Dinarello CA. A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal Gram-negative infection. Proc Natl Acad Sci USA 1988; 85: 1620–1623.

    PubMed  Google Scholar 

  95. Langermans JAM, Van der Hulst MEB, Nibbering PH, Hiemstra PS, Fransen L, Van Furth R. IFN-γ-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-α. J Immunol 1992; 148: 568–574.

    PubMed  Google Scholar 

  96. Holtmann H, Wallach D. Down regulation of the receptors for tumor necrosis factor by interleukin-1 and 4β-phorbol-12-myristate-13-acetate. J Immunol 1987; 139: 1161–1167.

    PubMed  Google Scholar 

  97. Kullberg BJ, Vogels MTE, Van der Meer JWM. Immunomodulators in bacterial and fungal infections. A review of their therapeutic potential. Clin Immunother 1994; 1: 43–55.

    Google Scholar 

  98. Beekhuizen H, Corsel-van Tilburg AJ, Blokland I, Van Furth R. Characterization of the adherence of human monocytes to cytokine-stimulated human macrovascular endothelial cells. Immunology 1991; 74: 661–669.

    PubMed  Google Scholar 

  99. Pettipher R, Henderson B. Inflammatory activities of locally or systemically administered interleukin-1. In: Bomford R, Henderson B, ed. Interleukin-1, inflammation and disease. Amsterdam: Elsevier, 1989;218–228.

    Google Scholar 

  100. Roseff SA, Levitz SM. Effect of endothelial cells on phagocyte-mediated anticryptococcal activity. Infect Immun 1993. A. 61: 3818–3824.

    Google Scholar 

  101. Gresser IA and Chekhov MD. Coley's toxins. N Engl J Med 1987; 317: 457.

    PubMed  Google Scholar 

  102. Beutler B, Cerami A. Cachectin/tumor necrosis factor: an endogenous mediator of shock and inflammation. Immunol Res 1986; 5: 281–293.

    PubMed  Google Scholar 

  103. Dinarello CA, Cannon JG, Wolff SM. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 1986; 163: 1433–1450.

    PubMed  Google Scholar 

  104. Cerami A, Beutler B. The role of cachectin/TNF in endotoxic shock and cachexia. Immunol Today 1988; 9: 28–31.

    PubMed  Google Scholar 

  105. Girardin E, Grau GE, Dayer JM, Roux-Lombard P, The J5 study group, Lambert PH. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397–400.

    PubMed  Google Scholar 

  106. Tracey KJ, Beutler B, Lowry SF. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234: 470–474.

    PubMed  Google Scholar 

  107. Waage A, Espevik T, Lamvik J. Detection of tumor necrosis factor-like cytotoxicity in serum from patients with septicaemia, but not from untreated cancer patients. Scand J Immunol 1986; 24: 739–743.

    PubMed  Google Scholar 

  108. Figari IS, Mori NA, Palladino MA Jr. Regulation of neutrophil migration and superoxide production by recombinant tumor necrosis factors-α and -β: comparison to recombinant interferon-γ and interleukin-1α. Blood 1987; 70: 979–984.

    PubMed  Google Scholar 

  109. Seow WK, Thong YH, Ferrante A. Macrophageneutrophil interactions: contrasting effects of the monokines interleukin-1 and tumour necrosis factor (cachectin) on human neutrophil adherence. Immunology 1987; 62: 357–361.

    PubMed  Google Scholar 

  110. Steinbeck MA, Roth JA. Neutrophil activation by recombinant cytokines. Rev Infect Dis 1989; 11: 549–568.

    PubMed  Google Scholar 

  111. Nakane A, Minagawa T, Kohanawa M,et al. Interactions between endogenous gamma interferon and tumor necrosis factor in host resistance and primary and secondaryListeria monocytogenes infections. Infect Immun 1989; 57: 3331–3337.

    PubMed  Google Scholar 

  112. Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA.Leishmania major amastigotes initiate the L-arginine dependent killing mechanism in IFN-γ-stimulated macrophages by induction of TNF-α. J Immunol 1990; 145: 4290–4297.

    PubMed  Google Scholar 

  113. Liew FY, Li Y, Millott S. Tumor necrosis factor-α synergizes with IFN-γ in mediating killing ofLeishmania major through the induction of nitric oxide. J Immunol 1990; 145: 4306–4310.

    Google Scholar 

  114. Alexander HR, Doherty GM, Block MI,et al. Single dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. Infect Immun 1991; 59: 3889–3894.

    PubMed  Google Scholar 

  115. Alexander HR, Sheppard BC, Jensen JC,et al. Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of Gram-negative sepsis. J Clin Invest 1991; 88: 34–39.

    PubMed  Google Scholar 

  116. Van der Meer JWM. The effects of recombinant interleukin1 and recombinant tumor necrosis factor on non-specific resistance to infection. Biotherapy 1988; 1: 19–25.

    PubMed  Google Scholar 

  117. Collins HL, Bancroft GJ. Cytokine enhancement of complement-dependent phagocytosis by macrophages: synergy of tumor necrosis factor-α and granulocytemacrophage colony-stimulating factor for phagocytosis ofCryptococcus neoformans. Eur J Immunol 1992; 22: 1447–1454.

    PubMed  Google Scholar 

  118. Cameron M, Granger D, Kozumbo W, Weinberg B, Koren H, Durack D. Human alveolar macrophage mediated fungistasis occurs independently of L-arginine oxidation. Clin Res 1989; 37: 425A.

    Google Scholar 

  119. Granger DL, Hibbs JB Jr, Perfect JR, Durack DT. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest 1988; 81: 1129–1136.

    PubMed  Google Scholar 

  120. Steinshamn S, Waage A. Tumor necrosis factor and interleukin-6 inCandida albicans infection in normal and granulocytopenic mice. Infect Immun 1992; 60: 4003–4008.

    PubMed  Google Scholar 

  121. Netea MG, Blok WL, Francot G, Buurman WA, Van der Meer JWM. Pentoxifylline-induced decrease in circulating TNF-concentrations is not associated with improved out-come of candidal infection in mice. Eur Cytokine Netw 1992; 3: 223.

    Google Scholar 

  122. Beaman L. Effects of recombinant gamma interferon and tumor necrosis factor onin vitro interactions of human mononuclear phagocytes withCoccidioides immitis. Infect Immun 1991; 59: 4227–4229.

    PubMed  Google Scholar 

  123. Ferrante A. Tumor necrosis factor alpha potentiates neutrophil antimicrobial activity: Increased fungal activity againstTorulopsis glabrata andCandida albicans and associated increases in oxigen radical production and lysosomal enzyme release. Infect Immun 1989; 57: 2115–2122.

    PubMed  Google Scholar 

  124. Diamond RD, Lyman CA, Wysong DR. Disparate effects of interferon-γ and tumor necrosis factor-α on early neutrophil respiratory burst and fungicidal responses toCandida albicans hyphaein vitro. J Clin Invest 1991; 87: 711–720.

    PubMed  Google Scholar 

  125. Wherry J, Wenzel R, Wunderingk R,et al. Monoclonal antibody to human tumor necrosis factor (TNF MAb): multi-center efficacy and safety study in patients with the sepsis syndrome. Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA, 1993: Abstr. 696, p. 246.

  126. Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identification of interferon-γ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983; 158: 670–689.

    PubMed  Google Scholar 

  127. Buchmeier NA, Schreiber RD. Requirement of endogenous interferon-γ production for resolution ofListeria monocytogenes infection. Proc Natl Acad Sci USA 1985; 82: 7404–7408.

    PubMed  Google Scholar 

  128. Ribeiro RA, Cunha FQ, Ferreira SH. Recombinant gamma interferon causes neutrophil migration mediated by the release of a macrophage neutrophil chemotactic factor. Int J Exp Path 1990; 71: 717–725.

    Google Scholar 

  129. Shalaby MR, Aggarwal BB, Rinderknecht E, Svedersky LP, Finkle BS, Palladino MA Jr. Activation of human polymorphonuclear neutrophil functions by interferon-γ and tumor necrosis factors. J Immunol 1985; 135: 2069–2073.

    PubMed  Google Scholar 

  130. Berton G, Zeni L, Cassatella MA, Rossi F. Gamma interferon is able to enhance the oxidative metabolism of human neutrophils. Biochem Biophys Res Commun 1986; 138: 1276–1282.

    PubMed  Google Scholar 

  131. Billiau A. Gamma-interferon: the match that lights the fire? Immunol Today 1988; 9: 37–40.

    PubMed  Google Scholar 

  132. Doherty GM, Lange JR, Langstein HN, Alexander HR, Buresh CM, Norton JA. Evidence for IFN-γ as a mediator for the lethality of endotoxin and tumor necrosis factor-α. J Immunol 1992; 149: 1666–1670.

    PubMed  Google Scholar 

  133. Nacy CA, Fortier AH, Meltzer MS, Buchmeier NA, Schreiber RD. Macrophage activation to killLeishmania major: activation of macrophages for intracellular destruction of amastigotes can be induced by both recombinant interferon-γ and non-interferon lymphokines. J Immunol 1985; 144: 3505–3511.

    Google Scholar 

  134. Nauciel C, Espinasse-Maes F. Role of gamma-interferon and tumor necrosis factor alpha in resistance toSalmonella typhimurium infection. Infect Immun 1992; 60: 450–454.

    PubMed  Google Scholar 

  135. Kurtz RS, Young KM, Czuprynski CJ. Separate and combined effects of recombinant interleukin-1α and gamma interferon on antibacterial resistance. Infect Immun 1989; 57: 553–558.

    PubMed  Google Scholar 

  136. Langermans JAM, Van der Hulst MEB, Nibbering PH, Van der Meide PH, Van Furth R. Intravenous injection of IFN-γ inhibits the proliferation ofListeria monocytogenes in the liver but not in the spleen and peritoneal cavity. Immunol 1992; 77: 354–361.

    PubMed  Google Scholar 

  137. Murray HW. Interferon-γ, the activated macrophage, and host defense against microbial challenge. Ann Intern Med 1988; 108: 595–608.

    PubMed  Google Scholar 

  138. Geertsma MF, Nibbering PH, Pos O, Van Furth R. Interferon-γ-activated human granulocytes kill ingestedMycobacterium fortuitum more efficiently than normal granulocytes. Eur J Immun 1990; 20: 869–873.

    Google Scholar 

  139. Dinauer MC, Ezekowitz RAB. Interferon-γ and chronic granulomatous disease. Curr Opin Immunol 1991; 3: 61–64.

    PubMed  Google Scholar 

  140. Gallin JI, Malech HL, Melnick DA. The international chronic granulomatous disease cooperative study group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 1991; 324: 509–516.

    PubMed  Google Scholar 

  141. Ezekowitz RAB, Sieff CA, Dinauer MC, Nathan DG, Orkin SH, Newburger PE. Restoration of phagocyte function by interferon-γ in X-linked chronic granulomatous disease occurs at the level of a progenitor cell. Blood 1990; 76: 2443–2448.

    PubMed  Google Scholar 

  142. Ezekowitz RAB, Dinauer MC, Jaffe HS, Orkin SH, Newburger PE. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. N Engl J Med 1988; 319: 146–151.

    PubMed  Google Scholar 

  143. Rex JH, Bennett JE, Gallin JI, Malech HL, Decarlo ES, Melnick DA.in vivo interferon-γ therapy augments thein vitro ability of chronic granulomatous disease neutrophils to damageAspergillus hyphae. J Infect Dis 1991; 163: 849–852.

    PubMed  Google Scholar 

  144. Gallin JI. Interferon-gamma in the management of chronic granulomatous disease. Rev Infect Dis 1991; 13: 973–978.

    PubMed  Google Scholar 

  145. Brummer E, Hanson LH, Restrepo A, Stevens DA.in vivo andin vitro activation of pulmonary macrophages by IFN-γ for enhanced killing ofParacoccidioides brasiliensis orBlastomyces dermatitidis. J Immunol 1988; 140: 2786–2789.

    PubMed  Google Scholar 

  146. Beaman L.in vitro response of alveolar macrophages to infection withCoccidioides immitis. Infect Immun 1980; 28: 594–600.

    PubMed  Google Scholar 

  147. Beaman L. Fungicidal activation of murine macrophages by recombinant gamma interferon. Infect Immun 1987; 55: 2951–2955.

    PubMed  Google Scholar 

  148. Brummer E, Hanson LH, Stevens DA. Gamma-interferon activation of macrophages for killing ofParacoccidioides brasiliensis and evidence for nonoxidative mechanisms. Int J Immunopharmacol 1988; 10: 945–952.

    PubMed  Google Scholar 

  149. Fleischmann J, Wu-Hsieh B, Howard DH. The intracellular fate ofHistoplasma capsulatum in human macrophages is unaffected by recombinant interferon-γ. J Infect Dis 1990; 161: 143–145.

    PubMed  Google Scholar 

  150. Wu-Hsieh BA, Howard DH. Intracellular growth inhibition ofHistoplasma capsulatum induced in murine macrophages by recombinant gamma interferon is not due to a limitation of the supply of methionine or cysteine to the fungus. Infect Immun 1992; 60: 698–700.

    PubMed  Google Scholar 

  151. Perfect JR, Granger DL, Durack DT. Effects of antifungal agents and gamma interferon on macrophage cytotoxicity for fungi and tumor cells. J Infect Dis 1987; 156: 316–323.

    PubMed  Google Scholar 

  152. Flesch IEA, Schwamberger G, Kaufmann SHE. Fungicidal activity of IFN-γ-activated macrophages: extracellular killing ofCryptococcus neoformans. J Immunol 1989; 142: 3219–3224.

    PubMed  Google Scholar 

  153. Vecchiarelli A, Dottorini M, Puliti M, Todisco T, Cenci E, Bistoni F. Defective candidacidal activity of alveolar macrophages and peripheral blood monocytes from patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 143: 1049–1054.

    Google Scholar 

  154. Brummer E, Stevens DA. Candidacidal mechanisms of peritoneal macrophages activated with lymphokines or g-interferon. J Med Microbiol 1989; 28: 173–181.

    PubMed  Google Scholar 

  155. Brummer E, Hanson LH, Stevens DA. Kinetics and requirements for activation of macrophages for fungicidal activity — effect of protein synthesis inhibitors and immuno-suppressants on activation and fungicidal mechanism. Cell Immunol 1991; 132: 236–245.

    PubMed  Google Scholar 

  156. Perrusia B, Kobayashi M, Rossi ME, Anegon I, Trinchieri G. Immune interferon enhances functional properties of human granulocytes: role of Fc receptors and effect of lymphotoxin, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor. J Immunol 1987; 138: 765–774.

    PubMed  Google Scholar 

  157. Garner RE, Kuruganti U, Czarniecki CW, Chiu HH, Domer JE.in vivo immune responses toCandida albicans modified by treatment with recombinant murine gamma interferon. Infect Immun 1989; 57: 1800–1808.

    PubMed  Google Scholar 

  158. Garner RE, Kuruganti U, Al-Hussaini LA, Czarniecki CW, Domer JE. Effect ofin vivo administration of recombinant murine gamma interferon onin vitro lymphoproliferative responses following immunization withCandida albicans. Infect Immun 1992; 60: 1927–1935.

    PubMed  Google Scholar 

  159. Kullberg BJ, Van 't Wout JW, Hoogstraten C, Van Furth R. Recombinant interferon-γ enhances resistance to acute disseminatedCandida albicans infection in mice. J Infect Dis 1993; 168: 436–443.

    PubMed  Google Scholar 

  160. Metcalf D. The granulocyte-macrophage colony-stimulating factors. Science 1985; 229: 16–22.

    PubMed  Google Scholar 

  161. Metcalf D, Begley CG, Nicola NA, Johnson GR. Quantitative responsiveness of murine hemopoietic populationin vitro andin vivo to recombinant multi-CSF (IL-3). Exp Hematol 1987; 15: 288–295.

    PubMed  Google Scholar 

  162. Mochizuki DY, Eisenman JR, Conlon PJ, Larsen AD, Tushinski RJ. Interleukin 1 regulates hematopoietic activity, a role previously ascribed to hemopoietin 1. Proc Natl Acad Sci USA 1987; 84: 5267–5271.

    PubMed  Google Scholar 

  163. Fibbe WE, Van Damme J, Billiau A,et al. Interleukin-1 (22-k factor) induces release of granulocyte-macrophage colony-stimulating activity from human mononuclear phagocytes. Blood 1986; 68: 1316–1321.

    PubMed  Google Scholar 

  164. Fibbe WE, Van Damme J, Billiau A,et al. Interleukin 1 induces human marrow stromal cells in long-term culture to produce granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor. Blood 1988; 71: 430–435.

    PubMed  Google Scholar 

  165. Matsumoto M, Matsubara S, Matsuno T,et al. Protective effect of human granulocyte colony-stimulating factor on microbial infection in neutropenic mice. Infect Immun 1987; 55: 2715–2720.

    PubMed  Google Scholar 

  166. Matsumoto M, Tamura M, Matsubara S, Matsuno T, Ono M, Yokota T. Mechanism of protective effect of recombinant human granulocyte colony-stimulating factor (rG-CSF) onPseudomonas infection. Microbiol Immunol 1991; 35: 461–474.

    PubMed  Google Scholar 

  167. Tanaka T, Okamura S, Okada K,et al. Protective effect of recombinant murine granulocyte-macrophage colony-stimulating factor againstPseudomonas aeruginosa infection in leukocytopenic mice. Infect Immun 1989; 57: 1792–1799.

    PubMed  Google Scholar 

  168. Vadas MA, Lopez AF, Gamble JR, Elliot MJ. Role of colony-stimulating factors in leucocyte responses to inflammation and infection. Curr Opin Immunol 1991; 3: 97–104.

    PubMed  Google Scholar 

  169. Nemunaitis J, Rabinowe SN, Singer JW,et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med 1991; 324: 1773–1778.

    PubMed  Google Scholar 

  170. Gorin NC, Coiffier B, Hayat M,et al. Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in Non-Hodgkin's lymphoma: a double-blind placebo-controlled trial. Blood 1992; 80: 1149–1157.

    PubMed  Google Scholar 

  171. Uchida K, Yamamoto Y, Klein TW, Friedman H, Yamaguchi H. Granulocyte-colony stimulating factor facilitates the restoration of resistance to opportunistic fungi in leukopenic mice. J Med Vet Mycol 1992; 30: 293–300.

    PubMed  Google Scholar 

  172. Baldwin GC, Gasson JC, Quan SG,et al. Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci USA 1988; 85: 2763–2766.

    PubMed  Google Scholar 

  173. Weisbart RH, Kwan L, Golde DW, Gasson JC. Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to major physiological chemoattractants. Blood 1987; 69: 18–21.

    PubMed  Google Scholar 

  174. Weisbart RH. Colony-stimulating factors and neutrophils. In: Weisbart RH, ed. Colony-stimulating factors and host defense. 1989: 297–303.

  175. Fleischmann J, Golde DW, Weisbart RH, Gasson JC. Granulocyte-macrophage colony-stimulating factor enhances phagocytosis of bacteria by human neutrophils. Blood 1986; 68: 708–711.

    PubMed  Google Scholar 

  176. Djeu JY. Role of tumor necrosis factor and colony-stimulating factors in phagocyte function againstCandida albicans. Diagn Microbiol Infect Dis 1990; 13: 383–386.

    PubMed  Google Scholar 

  177. Blanchard DK, Michelini-Norris B, Djeu JY. Production of granulocyte-macrophage colony-stimulating factor by large granular lymphocytes stimulated withCandida albicans: Role in activation of human neutrophil function. Blood 1991; 77: 2259–2265.

    PubMed  Google Scholar 

  178. Roilides E, Walsh TJ, Pizzo PA, Rubin M. Granulocyte colony-stimulating factor enhances the phagocytic and bactericidal activity of normal and defective human neutrophils. J Infect Dis 1991; 163: 579–583.

    PubMed  Google Scholar 

  179. Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Neutrophil oxidative burst in response to blastoconidia and pseudohyphae ofCandida albicans: augmentation by granulocyte colony-stimulating factor and interferon-γ. J Infect Dis 1992; 166: 668–673.

    PubMed  Google Scholar 

  180. Sisson SD, Dinarello CA. Production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood 1988; 72: 1368–1374.

    PubMed  Google Scholar 

  181. Smith PD, Lamerson CL, Banks SM,et al. GM-CSF augments human monocyte fungicidal activity forCandida albicans. J Infect Dis 1990; 161: 999–1005.

    PubMed  Google Scholar 

  182. Levitz SM. Activation of human peripheral blood mononuclear cells by interleukin-2 and granulocyte-macrophage colony-stimulating factor to inhibitCryptococcus neoformans. Infect Immun 1991; 59: 3393–3397.

    PubMed  Google Scholar 

  183. Reed SG, Nathan CF, Pihl DL,et al. Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibitTrypanosoma cruzi and release hydrogen peroxide. Comparison with interferon-γ. J Exp Med 1987; 166: 1734–1746.

    PubMed  Google Scholar 

  184. Denis M. Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulentMycobacterium avium and to kill avirulentM. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukocyte Biol 1991; 49: 380–387.

    PubMed  Google Scholar 

  185. Cenci E, Bartocci A, Puccetti P, Mocci S, Stanley ER, Bistoni F. Macrophage colony-stimulating factor in murine candidiasis — serum and tissue levels during infection and protective effect of exogenous administration. Infect Immun 1991; 59: 868–872.

    PubMed  Google Scholar 

  186. Karbassi A, Backer JM, Foster JS, Moore RN. Enhanced killing ofCandida albicans by murine macrophages treated with macrophage colony-stimulating factor: evidence for augmented expression of mannose receptors. J Immunol 1987; 139: 417–421.

    PubMed  Google Scholar 

  187. Hume DA, Denkins Y. The deleterious effect of macrophage colony-stimulating factor (CSF-1) on the pathology of experimental candidiasis in mice. Lymphokine Cytokine Res 1992; 11: 95–98.

    PubMed  Google Scholar 

  188. Khwaja A, Johnson B, Addison IE,et al.In vivo effects on macrophage colony-stimulating factor on human monocyte function. Br J Haematol 1991; 77: 25–31.

    PubMed  Google Scholar 

  189. Nemunaitis J, Meyers JD, Buckner CD,et al. Phase-I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections. Blood 1991; 78: 907–913.

    PubMed  Google Scholar 

  190. Anaissie E, Wong E, Bodey GP, Obrien S, Gutterman J, Vadhan S. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus amphotericin B for disseminated mycoses in neutropenic cancer patients. Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston, TX, 1989: Abstr. 73 p. 113.

  191. Bermudez LEM, Young LS. Tumor necrosis factor, alone or in combination with IL-2, but not IFN-γ, is associated with macrophage killing ofMycobacterium avium complex. J Immunol 1988; 140: 3006–3013.

    PubMed  Google Scholar 

  192. Bermudez LEM, Stevens P, Kolonoski P, Wu M, Young LS. Treatment of experimental disseminatedMycobacterium avium complex infection in mice with recombinant IL-2 and tumor necrosis factor. J Immunol 1989; 143: 2996–3000.

    PubMed  Google Scholar 

  193. Sharma SD, Hofflin JM, Remington JS.In vivo recombinant interleukin 2 administration enhances survival against a lethal challenge withToxoplasma gondii. J Immunol 1985; 135: 4160–4163.

    PubMed  Google Scholar 

  194. Weyand C, Goronzy J, Fathman CG, O'Hanley P. Administrationin vivo of recombinant interleukin-2 protects mice against septic death. J Clin Invest 1987; 79: 1756–1763.

    PubMed  Google Scholar 

  195. Chong KT. Prophylactic administration of interleukin-2 protects mice from lethal challenge with Gram-negative bacteria. Infect Immun 1987; 55: 668–673.

    PubMed  Google Scholar 

  196. 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-γ. Ann Intern Med 1988; 108: 36–41.

    PubMed  Google Scholar 

  197. Snydman DR, Sullivan B, Gill M, Gould JA, Parkinson DR, Atkins MB. Nosocomial sepsis associated with interleukin-2. Ann Intern Med 1990; 112: 102–107.

    PubMed  Google Scholar 

  198. Klempner MS, Noring R, Mier JW, Atkins MB. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med 1990; 322: 959–966.

    PubMed  Google Scholar 

  199. Levitz SM, Dupont MP. Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth ofCryptococcus neoformans in vitro. J Clin Invest 1993; 91: 1490–1498.

    PubMed  Google Scholar 

  200. Beno DWA, Mathews HL. Growth inhibition ofCandida albicans by interleukin-2-activated splenocytes. Infect Immun 1992; 60: 853–863.

    PubMed  Google Scholar 

  201. Djeu JY, Blanchard DK. Regulation of human polymorphonuclear neutrophil (PMN) activity againstCandida albicans by large granular lymphocytes via release of a PMN-activating factor. J Immunol 1987; 139: 2761–2767.

    PubMed  Google Scholar 

  202. Wei S, Serbousek D, Mcmillen S, Blanchard DK, Djeu JY. Suppression of human monocyte function againstCandida albicans by autologous IL-2-induced lymphokine-activated killer cells. J Immunol 1991; 146: 337–342.

    PubMed  Google Scholar 

  203. Wei S, Blanchard DK, McMillen S, Djeu JY. Lymphokine-activated killer cell regulation of T-cell-mediated immunity toCandida albicans. Infect Immun 1992; 60: 3586–3595.

    PubMed  Google Scholar 

  204. Ausiello C, Maleci A, Spagnoli GC, Antonelli G, Cassone A. Cell-mediated cytotoxicity in glioma-bearing patients: differential responses of peripheral blood mononuclear cells to stimulation with interleukin-2 and microbial antigen. J Neuro-Oncol 1988; 6: 329–338.

    Google Scholar 

  205. Chen BDM, Clark CR. Interleukin-3 (IL-3) regulates thein vitro proliferation of blood monocytes and peritoneal exudate macrophages: synergism between a macrophage specific colony-stimulating factor (CSF-1) and IL-3. J Immunol 1986; 137: 563–570.

    PubMed  Google Scholar 

  206. Chen BDM, Mueller M, Olencki T. Interleukin-3 (IL-3) stimulates the clonal growth of pulmonary alveolar macrophage of the mouse: role of IL-3 in the regulation of macrophage production outside the bone marrow. Blood 1988; 72: 685–690.

    PubMed  Google Scholar 

  207. Bleiberg I, Kletter Y, Riklis I, Fabian I. Induction of murine macrophage fungal killing by interleukin 3. Exp Hematol 1989; 17: 895–897.

    PubMed  Google Scholar 

  208. Cohen L, David B, Cavaillon JM. Interleukin-3 enhances cytokine production by LPS-stimulated macrophages. Immunol Lett 1991; 28: 121–126.

    PubMed  Google Scholar 

  209. Marodi L, Forehand JR, Johnston RB Jr. Mechanisms of host defense againstCandida species. 2. Biochemical basis for the killing ofCandida by mononuclear phagocytes. J Immunol 1991; 146: 2790–2794.

    PubMed  Google Scholar 

  210. Walz A, Peveri P, Aschauer H, Baggiolini M. Purification and amino acid sequencing of NAF, a novel neutrophil-activating factor produced by monocytes. Biochem Biophys Res Comm 1987; 149: 755–761.

    PubMed  Google Scholar 

  211. Colditz I, Zwahlen R, Dewald B, Baggiolini M.In vivo inflammatory activity of neutrophil-activating factor, a novel chemotactic peptide derived from human monocytes. Am J Pathol 1989; 134: 755–760.

    PubMed  Google Scholar 

  212. Peveri P, Walz A, Dewald B, Baggiolini M. A novel neutrophil-activating factor produced by human mononuclear phagocytes. J Exp Med 1988; 167: 1547–1559.

    PubMed  Google Scholar 

  213. Lohmann-Matthes ML. Interaction of macrophages and cytokines. Curr Opinion Immunol 1989; 2: 33–38.

    Google Scholar 

  214. Vogels MTE, Lindley IJD, Curfs JAHJ, Eling WMC, Van der Meer JWM. Effects of interleukin-8 on non-specific resistance to infection in neutropenic and normal mice. Antimicrob Agents Chemother 1993; 37: 276–280.

    PubMed  Google Scholar 

  215. Vogels MTE, Lindley I, Van der Meer JWM. Interleukin-8 accelerates death of infected neutropenic mice. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, 1990: 140.

  216. Hack CE, Hart M, Strack van Schijndel RJM,et al. Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect Immun 1992; 60: 2835–2842.

    PubMed  Google Scholar 

  217. Djeu JY, Matsushima K, Oppenheim JJ, Shiotsuki K, Blanchard DK. Functional activation of human neutrophils by recombinant monocyte-derived neutrophil chemotactic factor/IL-8. J Immunol 1990; 144: 2205–2210.

    PubMed  Google Scholar 

  218. Nibbering PH, Pos O, Stevenhagen A, Zomerdijk TPL, Van Furth R. Interleukin-8 enhances the intracellular killing ofMycobacterium fortuitum by human granulocytes. Infect Immun 1993; 61: 3111–3116.

    PubMed  Google Scholar 

  219. Ganz T, Selsted ME, Szklarek D,et al. Defensins: natural peptide antibiotics of human neutrophils. J Clin Invest 1986; 76: 1427–1435.

    Google Scholar 

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    Bart -Jan Kullberg & Jan W. van 't Wout

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    Bart -Jan Kullberg & Jan W. van 't Wout

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Kullberg, B.J., van 't Wout, J.W. Cytokines in the treatment of fungal infections. Biotherapy 7, 195–210 (1994). https://doi.org/10.1007/BF01878486

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