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Prediction of the role of granulocyte-macrophage colony-stimulating factor in animals and man from in vitro results

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Abstract

The possibility of predicting the clinical effects of cytokines from in vitro data is discussed, using GM-CSF as an example. GM-CSF incubated with bone marrow cells has been shown to induce proliferation and colony formation, predominantly of the colony-forming unit granulocyte and granulocyte-macrophage types. Daily treatment of normal monkeys with GM-CSF resulted in transient neutropenia followed by neutrophilia. After withdrawal of GM-CSF the neutrophil levels returned to baseline. Predictably, GM-CSF administration results in accelerated neutrophil recovery in patients with chemotherapy-induced neutropenia. GM-CSF has also been shown to induce microbial killing by neutrophils and monocytes in vitro. This activity translated into a dose-related protection of GM-CSF-pretreated mice infected with lethal doses of micro-organisms. Interleukin-3 (IL-3) increases the cellularity of the bone marrow and GM-CSF can induce mobilization of bone marrow cells into the peripheral blood. Therefore, it was predicted and subsequently proved that a combination of these cytokines is synergistic, increasing the yields of peripheral blood progenitor cells which could be collected and then retransplanted into patients undergoing myeloablative chemotherapy. Monkeys injected with recombinant human IL-3 and GM-CSF had increased antibody titres to human IL-3 compared with monkeys given IL-3 alone, suggesting a potential use of GM-CSF which was not predicted from its in vitro results, that of vaccine adjuvancy. Thus, for any new mediator a broad range of tests of its activity in vitro may enable prediction of its activity in vivo, but it is also important to document any unexpected effects in in vivo studies which may give indications of new uses.

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References

  1. Broxmeyer HE, Vadhan-Raj S Preclinical and clinical studies with the hematopoietic colony-stimulating factors and related interleukins. Immunology Research 1989, 8: 185–201.

    Google Scholar 

  2. Green AR Peptide regulatory factors: multifunctional mediators of cellular growth and differentiation. Lancet 1989, i: 705–707.

    Article  Google Scholar 

  3. Metcalf D Haemopoietic growth factors I. Lancet 1989, i: 825–827.

    Article  Google Scholar 

  4. Metcalf D Haemopoietic growth factors II: Clinical applications. Lancet 1989, i: 885–886.

    Article  Google Scholar 

  5. Ruef C, Coleman DL Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Reviews of Infectious Diseases 1990, 12: 41–62.

    PubMed  Google Scholar 

  6. Donahue RE, Wang EA, Stone DK, Kamen R, Wong GG, Sehgal PK, Nathan DG, Clark SC Stimulation of haematopoiesis in primates by continuous infusion of recombinant human GM-CSF. Nature 1986, 321: 872–875.

    Article  PubMed  Google Scholar 

  7. Mayer P, Lam C, Obenaus H, Liehl E, Besemer J Recombinant human GM-CSF induces leukocytosis and activates peripheral blood polymorphonuclear neutrophils in nonhuman primates. Blood 1987, 70: 206–213.

    PubMed  Google Scholar 

  8. Mayer P, Lam C, Obenaus H, Liehl E, Besemer J Efficacy of recombinant human granulocyte-macrophage colony-stimulating factor in rhesus monkeys. Annals of the New York Academy of Sciences 1987, 511: 17–29.

    PubMed  Google Scholar 

  9. Geissler K, Valent P, Mayer P, Hinterberger W, Lechner K, Bettelheim P Recombinant human interleukin-3 expands the pool of circulating hematopoietic progenitor cells in primates: synergism with recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990, 75: 2305–2310.

    PubMed  Google Scholar 

  10. Monroy RL, Skelly RR, MacVittie TJ, Davis TA, Sulbek JJ, Clark SC, Donahue RE The effect of recombinant GM-CSF on the recovery of monkeys transplanted with autologous bone marrow. Blood 1987, 70: 1696–1699.

    PubMed  Google Scholar 

  11. Nienhuis AW, Donahue RE, Karisson S, Clark SC, Agricula B, Antinoff N, Pierce JE, Turner P, Anderson WF, Nathan DG Recombinant human granulocytemacrophage colony-stimulating factor shortens the period of neutropenia after autologous bone marrow transplantation in a primate model. Journal of Clinical Investigation 1987, 80: 573–577.

    PubMed  Google Scholar 

  12. Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, Oette D, Whitley M, Frei E, Schnipper LE Effect of recombinant human granulocytemacrophage colony-stimulating factor on chemotherapy-induced myelosuppression. New England Journal of Medicine 1988, 319: 593–598.

    PubMed  Google Scholar 

  13. Brandt SJ, Peters WP, Atwater SK, Kutzberger J, Borowitz MJ, Jones RB, Shpall EJ, Bast RC, Gilbert CJ, Oette DH Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. New England Journal of Medicine 1988, 318: 869–876.

    PubMed  Google Scholar 

  14. Socinski MA, Cannistra SA, Elias A, Antman KH, Schnipper L, Griffin JD Granulocyte-macrophage colony-stimulating factor expands the circulating haemopoietic progenitor cell compartment in man. Lancet 1988, i: 1194–1198.

    Article  Google Scholar 

  15. Gianni AM, Siena S, Bregni M, Tarella C, Stern AC, Pileri A, Bonadonna G Granulocyte-macrophage colony-stimulating factor to harvest circulating haemopoietic stem cells for autotransplantation. Lancet 1989, ii: 580–585.

    Article  Google Scholar 

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

    PubMed  Google Scholar 

  17. Weisbart RH, Golde DW, Clark SC, Wong GG, Gasson JC Human granulocyte-macrophage colonystimulating factor is a neutrophil activator. Nature 1985, 314: 361–364.

    Article  PubMed  Google Scholar 

  18. Mayer P, Schütze E, Lam C, Krieck F, Liehl E Recombinant murine granulocyte-macrophage colony-stimulating factor augments neutrophil recovery and enhances resistance to infections in myelosuppressed mice. Journal of Infectious Diseases 1991, 163: 584–590.

    PubMed  Google Scholar 

  19. Donahue RE, Seehra J, Metzger M, Lefebvre D, Rock B, Carbone S, Nathan DG, Garnick M, Sehgal PK, Laston D, Lavallie E, McCoy J, Schendel PF, Norton C, Turner K, Yang Y, Clark SC Human IL-3 and GM-CSF act synergistically in stimulating hematopoiesis in primates. Science 1988, 241: 1820–1823.

    PubMed  Google Scholar 

  20. Mayer P, Valent P, Schmidt G, Liehl E, Bettelheim P The in vivo effects of recombinant human interleukin-3: demonstration of basophil differentiation factor, histamine producing activity, and priming of GM-CSF — responsive progenitors in non human primates. Blood 1989, 74: 613–621.

    PubMed  Google Scholar 

  21. Mayer P, Geissler K, Valent P, Ceska H, Bettelheim P, Liehl E Recombinant human interleukin-6 is a potent inducer of the acute phase response and elevates the blood platelets in nonhuman primates. Experimental Hematology 1991, 19: 688–696.

    PubMed  Google Scholar 

  22. Mayer P, Geissler K, Ward M, Metcalf D Recombinant human leukemia inhibitory factor induces acute phase proteins and raises the blood platelet counts in nonhuman primates; Blood 1993, 81: 3226–3233.

    PubMed  Google Scholar 

  23. Fischer HG, Frosch S, Konrad R, Reske K, Reske Kunz AB Granulocyte-macrophage colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function. Journal of Immunology 1988, 141: 3882–3888.

    Google Scholar 

  24. Morrissey PJ, Bressler L, Park LS, Alpert A, Gillis S Granulocyte-macrophage stimulating factor augments the primary antibody response by enhancing the function of antigen presenting cells. Journal of Immunology 1987, 139: 1113–1119.

    Google Scholar 

  25. Inaba K, Steinman RM, Witmer Pack M, Hikeki A, Inaba M, Sudo T, Wolpe S, Schuler G Identification of proliferating dendritic cell precursors in mouse blood. Journal of Experimental Medicine 1992, 175: 1157–1167.

    Article  PubMed  Google Scholar 

  26. Jones T, Stern A, Lin R Potential role of granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant. European Journal of Clinical Microbiology and Infectious Diseases 1994, 13, Supplement 2: 47–53.

    Google Scholar 

  27. Socinski MA, Cannistra SA, Sulivan R, Elias A, Antman K, Schnipper L, Griffin JD Granulocyte-macrophage colony stimulating factor induces the expression of the CD 11b surface adhesion molecule on human granulocytes in vivo. Blood 1988, 72: 691–697.

    PubMed  Google Scholar 

  28. Sisson SD, Dinarello CA Production of interleukin-1α, interleukin-1β and tumour necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood 1988, 72: 1368–1374.

    PubMed  Google Scholar 

  29. Kaplan G, Walsh G, Laarni SG, Meyn P, Barkhardt RA, Abalos RM, Barker J, Frindt PA, Fajardo TT, Colona R, Cohn ZA Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth and enhanced wound healing. Journal of Experimental Medicine 1992, 175: 1717–1728.

    Article  PubMed  Google Scholar 

  30. Bussolino F, Wang JM, De Filippi P, Turrini F, Sanavio F, Edgell CJS, Aglietta M, Arare P, Mantovani A Granulocyte and granulocyte-macrophage colony-stimulating factors induce human endothelial cells to migrate and proliferate. Nature 1989, 337: 471–473.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunopharmacology, Sandoz Forschungsinstitut GmbH, Brunnerstrasse 59, 1235, Vienna, Austria

    E. Liehl, J. Hildebrandt, C. Lam & P. Mayer

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  1. E. Liehl
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  2. J. Hildebrandt
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  3. C. Lam
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  4. P. Mayer
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Liehl, E., Hildebrandt, J., Lam, C. et al. Prediction of the role of granulocyte-macrophage colony-stimulating factor in animals and man from in vitro results. Eur. J. Clin. Microbiol. Infect. Dis. 13 (Suppl 2), S9–S17 (1994). https://doi.org/10.1007/BF01973596

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