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Therapeutic evaluation of interleukin-1 for stimulation of hematopoiesis in primates after autologous bone marrow transplantation

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Biotherapy

Abstract

A multiple dose IL-1 therapy was evaluated for its capability to stimulate hematopoiesis in normal primates and to restore hematopoiesis after autologous bone marrow transplantation. The administration of IL-1 to normal animals over a dose range of 0.5 to 10 ug/kg/d led to a 7-12 fold increase in peripheral blood neutrophil and monocyte counts after 24 hours. This increase in the mature peripheral blood myeloid cells was followed by changes in the myeloid composition of the bone marrow, where the percentage of myeloid elements increased along with a transient increase in myeloid progenitor cell activity. IL-1 treatment also led to an initial decrease in platelet counts of 10-30% during the first 3 days of treatment. However, a striking finding was a significant and long lasting stimulation of increased platelet production with platelet counts increasing to 77% of baseline 3 days after cessation of treatment and remaining elevated for the next 10 days. The therapeutic potential of the IL-1 regimen to restore hematopoiesis was further evaluated in an established autologous bone marrow transplantation model. In monkeys receiving IL-1 doses, 1.0 and 5.0 ug/kg/d, neutrophil counts recovered to >0.5 x 10e9/1 on day 16, one day earlier than control, but the recovery to baseline neutrophil counts occurred 5 days sooner than control. IL-1 therapy had its greatest effect on the restoration of platelet counts after transplantation, reaching >100 x 10e9/l by day 21, two weeks earlier than control. This work demonstrates that IL-1 therapy stimulates myelopoiesis but its most promising clinical application is the stimulation of platelet production.

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References

  1. Bartelmez SH, Stanley ER. Synergism between hemopoietic growth (HGFs) detected by their effects on cells bearing receptors for a lineage specific HGF: assay of hemopoietin-1. J Cell Physiol 1985; 122: 370–8.

    PubMed  Google Scholar 

  2. Stanley ER, Bartocci A, Patinkin D, Rosendaal M, Bradley TR. Regulation of very primitive, multipotent, hemopoietic cells by hemopoietin-1. Cell 1986; 45: 667–74.

    PubMed  Google Scholar 

  3. 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 1987; 84: 5267–71.

    PubMed  Google Scholar 

  4. Zsebo KM, Wypych J, Yuschenkoff VN, Lu H, Hunt P, Dukes PP, Langley KE. Effects of hematopoietin-1 and interleukin-1 activities on early hematopoietic cells of the bone marrow. Blood 1988; 71: 962–68.

    PubMed  Google Scholar 

  5. Moore MAS, Warren DJ. Synergy of interleukin-1 and granulocyte colony-stimulating factor:in vivo stimulation of stem cell recovery and hematopoietic regeneration following 5-flurouracil treatment of mice. Proc Natl Acad Sci 1987; 84: 7134–8.

    PubMed  Google Scholar 

  6. Warren DJ, Moore MAS. Synergism among interleukin1, interleukin-3, and interleukin-5 in the production of eosinophils from primitive hemopoietic stem cells. J Immunol 1988; 140: 94–9.

    PubMed  Google Scholar 

  7. Ulich TR, del Castillo J, Keys M, Granger GA, Ni R-X. Kinetics and mechanisms of recombinant human interleukin-1 and tumor necrosis factor-induced changes in circulating number of neutrophils and lymphocytes. J Immunol 1987; 139: 3406–15.

    PubMed  Google Scholar 

  8. Stork LC, Peterson VM, Rundus CH, Robinson WA. Interleukin-1 enhances murine granulopoiesisin vivo. Exp Hematol 1988; 16: 163–7.

    PubMed  Google Scholar 

  9. Vogel SN, Douches SD, Kaufman EN, Neta R. Induction of colony-stimulating factorin vivo by recombinant interleukin-1 and recombinant tumor necrosis factor. J Immunol 1987; 138: 2143–8.

    PubMed  Google Scholar 

  10. Morrissey P, Charrier K, Bressler L, Alpert A. The influence of IL-1 treatment on the reconstitution of the hemopoietic and immune systems after sublethal radiation. J Immunol 1988; 140: 4204–10.

    PubMed  Google Scholar 

  11. Benjamin WR, Tare NS, Hayes TJ, Becker JM, Anderson TD. Regulation of hemopoiesis in myelosuppressed mice by human recombinant IL-1. J Immunol 1989; 142; 792–9.

    PubMed  Google Scholar 

  12. Johnson CS, Keckler DJ, Topper MI, Braunschweiger, Furmanski P.In vivo effects of recombinant interleukin-1 in mice: stimulation of granulocytic, monocytic, megakaryocytic and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin. Blood 1989; 73: 678–83.

    PubMed  Google Scholar 

  13. Castelli MP, Black PL, Schneider M, Pennington R, Abe F, Talmadge JE.Protective, restorative, and therapeutic properties of recombinant human IL-1 in rodent models. J Immunol 1988; 140: 3830–7.

    PubMed  Google Scholar 

  14. Broudy VC, Kaushansky K, Harlan JM, Adamson JW. Interleukin-1 stimulates human endothelial cells to produce granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor. J Immunol 1987; 139: 464–8.

    PubMed  Google Scholar 

  15. Kaushansky K, Lin N, Adamson JW. Interleukin 1 stimulates fibroblasts to synthesize granulocyte macrophage colony-stimulating factors. J Clin Invest 1988; 81: 92–7.

    PubMed  Google Scholar 

  16. Fibbe WE, van Damme J, Billiau A, Voogt PJ, Duinkerken N, Kluck PMC, Falkenburg JHF. Interleukin-1 induces release of granulocyte macrophage colony stimulating activity from human mononuclear phagocytes. Blood 1986; 68: 1316–21.

    PubMed  Google Scholar 

  17. Bagby GC. Interleukin-1, stromal cells, granulopoiesis, and the inflammatory response. Biotherapy 1989; 1: 255–62.

    PubMed  Google Scholar 

  18. Dinarello CA. Interleukin-1. Revs Infect Dis 1984; 6: 51–95.

    Google Scholar 

  19. Neta R, Sztein MB, Oppenheim JJ, Gillis S, Douches SD. Thein vivo effects of interleukin-1. I. Bone marrow cells are induced to cycle after administration of interleukin-1. J Immunol 1987; 139: 1861–6.

    PubMed  Google Scholar 

  20. Schwartz GN, MacVittie TJ, Vigneulle RM, Patchen ML, Douches SD, Oppenheim JJ, Neta R. Enhanced hematopoietic recovery in irradiated mice pretreated with interleukin-1 (IL-1). Immunopharm Immunotoxicol 1987; 9: 371–9.

    Google Scholar 

  21. Stork L, Barczuk L, Kissinger M, Robinson W. Interleukin-1 accelerates murine granulocyte recovery following treatment with cyclophosphamide. Blood 1989; 73: 938–44.

    PubMed  Google Scholar 

  22. Gasparetto C, Laver J, Abboud M, Gillio A, Smith C, O'Reilly RJ, Moore MAS. Effects of interleukin-1 on hematopoietic progenitors: evidence of stimulatory and inhibitory activities in a primate model. Blood 1989; 74: 547–50.

    PubMed  Google Scholar 

  23. Crown J, Kemeny N, Jakubowski A, Sheridan C, Gasparetto C, Toner G, Meisenberg B, Abboud M, Sinha S, Gordon M, Houston C, Oettgen H, Buhles WC, Cheney T, Moore MAS, Kelsen D, Gabrilove J. Phase I-II trial of recombinant human interleukin-1B in patients with metastatic colorectal cancer receiving 5-flurouracil. Blood 1989; 74 (suppl 1): 15a.

    Google Scholar 

  24. Monroy RL, Skelly RR, MacVittie TJ, Sauber JJ, Clark SC, Donahue RE. The effect of recombinant GM-CSF on the recovery of monkeys transplanted with autologous bone marrow. Blood 1987; 70: 1696–9.

    PubMed  Google Scholar 

  25. Gubler U, Chua AO, Stern AS, Hellman CP, Vitek MP, Dechiara TM, Benjamin WR, Collier KG, Dukovich M, Familletti PC, Fielder-Nagy C, Jenson J, Kaffka K, Kilian P, Stremlo D, Weittreich BH, Woehle D, Mizel SB, Lomedico PT. Recombinant human interleukin-1: purification and biological characterization. J Immunol 1986; 136: 2492–5.

    PubMed  Google Scholar 

  26. Monroy RL, MacVittie TJ, Darden JH, Schwartz GN, Patchen ML. The rhesus monkey: a model for hematopoietic stem cell studies. Exp Hematol 1986; 14: 904–11.

    PubMed  Google Scholar 

  27. Brandt SJ, Peters WP, Atwater SK, Kurtzberg 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 chemotherapy and autologous bone marrow transplantation. N Engl J Med 1988; 318: 869–75.

    PubMed  Google Scholar 

  28. Nienhuis AW, Donahue RE, Karlsson S, Clark SC, Agricola B, Antinoff N, Pierce JE, Turner P, Anderson WF, Nathan DG. Recombinant human GM-CSF shortens the period of neutropenia after autologous bone marrow transplantation in a primate model. J Clin Invest 1987; 80: 573–7.

    PubMed  Google Scholar 

  29. Williams DE, Morrissey PJ. Alterations in Megakaryocyte and Platelet compartments following IL-1 administration to normal mice. J Immunol 1989; 142: 4361–5.

    PubMed  Google Scholar 

  30. Warren MK, Conroy LB, Rose JS. The role of interleukin-6 and interleukin-1 in megakaryocyte development. Exp Hematol 1989; 17: 1095–9.

    PubMed  Google Scholar 

  31. Long MW, Hutchinson RJ, Gragowski LL, Heffner CH, Emerson SG. Synergistic regulation of human megakaryocyte development. J Clin Invest 1988; 82: 1779–86.

    PubMed  Google Scholar 

  32. Bruno E, Miller ME, Hoffman R. Interacting cytokines regulate in vitro human megakaryocytopoiesis. Blood 1989; 73: 671–7.

    PubMed  Google Scholar 

  33. Broudy VC, Zuckerman KS, Jetmalani S, Fitchen JH, Bagby GC. Monocytes stimulate fibroblastoid bone marrow stromal cells to produce multilineage hematopoietic growth factors. Blood 1986; 68: 530–4.

    PubMed  Google Scholar 

  34. Tosato G, Jones KD. Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. Blood 1990; 75: 1305–10.

    PubMed  Google Scholar 

  35. Sironi M, Breviario F, Proserpio P, Biondi A, Vecchi A, Van Damme J, Dejana E, Mantovani A. IL-1 stimulates IL-6 production in endothelial cells. J Immunol 1989; 142: 549–56.

    PubMed  Google Scholar 

  36. Zeidler C, Souza L, Welte K.In vivo effects of interleukin-6 on hematopoietis in primates. Blood 1989; 74 (suppl 1): 154a.

    Google Scholar 

  37. Asano S, Okano A, Ozawa K, Nakahata T, Ishibashi T, Koike K, Kimura H, Tanioka Y, Shibuya A, Harano T, Kishimoto T, Takaku F, Akiyama Y. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood 1990; 75: 1602–5.

    PubMed  Google Scholar 

  38. Ishibashi T, Kimura H, Shikama Y, Uchida T, Kariyone S, Hirano T, Kishimoto T, Takatsuki F, Akiyama Y. Interleukin-6 is a potent thrombopoietic factor in mice. Blood 1989; 74: 1241–4.

    PubMed  Google Scholar 

  39. Kimura H, Ishibashi T, Shikama Y, Okano A, Akiyama Y, Uchida T, Mauyama Y. Interleukin-1B (IL-1B) induces thrombocytosis in mice: possible implication of IL-6. Blood 1990; 76: 2493–500.

    PubMed  Google Scholar 

  40. Williams N, Eger RR, Jackson HM, Nelson DJ. Two factor requirement for murine megakaryocyte colony formation. J Cell Physiol 1982; 110: 101–10.

    PubMed  Google Scholar 

  41. Hoffman R. Regulation of megakaryocytopoiesis. Blood 1989; 74: 1196–212.

    PubMed  Google Scholar 

  42. Monroy RL, Skelly RR, Davis TA, Donahue RE, Mac-Vittie TJ. Primate studies with combined growth factor therapies. In: Dicke KA, Spitzer G, eds. Autologous Bone Marrow Transplantation, the Fourth International Symposium, 1989: 645-50.

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Views presented in this paper are those of the authors: no endorsement by the Department of the Navy or the Defense Nuclear Agency has been given or should be inferred. This work was supported by the Naval Medical Research and Development Command, Research Task No. 63706N MM095.003.1007 and the Defense Nuclear Agency Work Unit No. 132082.

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Monroy, R.L., Skelly, R.R., Davis, T.A. et al. Therapeutic evaluation of interleukin-1 for stimulation of hematopoiesis in primates after autologous bone marrow transplantation. Biotherapy 4, 97–108 (1992). https://doi.org/10.1007/BF02171754

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  • DOI: https://doi.org/10.1007/BF02171754

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