Skip to main content
SpringerLink
Log in

Granulocyte-macrophage colony-stimulating factor in the sera of patients with aplastic anemia

  • Original Article
  • Published:
The clinical investigator Aims and scope Submit manuscript

Summary

To clarify the role of growth factors in the pathophysiology of aplastic anemia we measured serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels in 33 aplastic anemia patients by a specific and sensitive enzyme-linked immunosorbent assay. GM-CSF serum levels of patients with aplastic anemia were significantly higher than in healthy volunteers. GM-CSF levels were correlated with the severity of aplastic anemia but not with the absolute neutrophil count. Since T lymphocytes are one of the main sources of GM-CSF, our data provide further evidence for in vivo T lymphocyte activation in aplastic anemia. GM-CSF serum levels are higher in patients responding to immunosuppressive treatment than in nonresponders. Elevated serum GM-CSF might be predictive of a good response to immuno-suppressive therapy. GM-CSF serum levels are lower immediately after treatment with antilymphocyte globulin/antithymocyte globulin (ALG/ATG) than corresponding pretreatment values. Thus we cannot confirm the hypothesis that ALG/ATG effects in vivo are mediated by stimulating the release of growth factors. We conclude that in aplastic anemia the primary defect is a failure in GM-CSF response rather than in GM-CSF supply.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AA:

aplastic anemia

ALG:

antilymphocyte globulin

ATG:

antithymocyte globulin

CyA:

cyclosporine A

ELISA:

enzyme-linked immunosorbent assay

Epo:

erythropoietin

G-CSF:

granulocyte colony-stimulating factor

GM-CSF:

granulocyte-macrophage colony-stimulating factor

IFN-γ:

interferon-γ

IL:

interleukin

MP:

methylprednisolone

nSAA:

nonsevere aplastic anemia

rh:

recombinant human

SAA:

severe aplastic anemia

TNF-α:

tumor necrosis factor-α

References

  1. Adams JA, Barrett AJ (1982) Haematopoietic stimulators in the serum of patients with severe aplastic anaemia. Br J Haematol 52:327–335

    Google Scholar 

  2. Antin JH, Smith BR, Holmes W, Rosenthal DS (1988) Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome. Blood 72:705–713

    Google Scholar 

  3. Barbano GC, Schenone A, Roncella S, Ghio R, Corcione A, Mori PG, Ferrarini M, Pistoia V (1988) Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the Clonal Level. Blood 72:956–963

    Google Scholar 

  4. Bickel M, Wahl SM, Mergenhagen SE, Pluznik DH (1988) Granulocyte-macrophage colony stimulating factor regulation in murine T cells and its relation to cyclosporin A. Exp Hematol 16:691–695

    Google Scholar 

  5. Broudy VC, Kaushansky K, Segal GM, Harlan JM, Adamson JW (1986) Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony stimulating factor. Proc Natl Acad Sci USA 83:7467–7471

    Google Scholar 

  6. Camitta BM, Thomas ED, Nathan DG, Gale RP, Kopecky KJ, Rappaport JM, Santos G, Gordon-Smith EC, Storb R (1979) A prospective study of androgens and bone marrow transplantation for aplastic anemia. Blood 53:504–514

    Google Scholar 

  7. Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann F, Freund M, Meusers P, Salama A, Heimpel H (1991) A prospective trial of antilymphocyte globulin and methylprednisolone with or without cyclosporine for treatment of aplastic anemia. N Engl J Med 324:1297–1304

    CAS  PubMed  Google Scholar 

  8. Gascon P, Zoumbos NC, Scala G, Djeu JY, Moore JG, Young NS (1985) Lymphokine abnormalities in aplastic anemia: implications for the mechanism of action of antihymocyte globulin. Blood 65:407–413

    Google Scholar 

  9. Herrmann F, Mertelsmann R (1989) Polypeptides controlling hematopoietic cell development and activation. I. In vitro results. Blut 58:117–128

    Google Scholar 

  10. Herrmann F, Oster W, Meuer SC, Lindemann A, Mertelsmann R (1988) Interleukin-1 induces T cell production of granulocyte-macrophage colony stimulating factor. J Clin Invest 81:1415–1418

    Google Scholar 

  11. Hinterberger W, Adolf G, Aichinger G, Dudczak R, Geißler K, Höcker P, Huber C, Kalhs P, Knapp W, Köller U, Lechner K, Volc-Platzer B (1988) Further evidence for lymphokine overproduction in severe aplastic anemia. Blood 72:266–272

    Google Scholar 

  12. Kawano Y, Nissen C, Gratwohl A, Speck B (1988) Immunostimulatory effects of different antilymphocyte globulin preparations: a possible clue to their clinical effect. Br J Haematol 68:115–119

    Google Scholar 

  13. Kojima S, Matsuyama T, Kodera Y (1992) Hematopoietic growth factors released by marrow stromal cells from patients with aplastic anemia. Blood 79:2256–2261

    Google Scholar 

  14. Metcalf D, Begley CG, Johnson GR, Nicola NA, Vadas MA, Lopez AF, Williamson DJ, Wong GC, Clark SC, Wang EA (1986) Biologic properties in vitro of a recombinant human granulocyte-macrophage colony-stimulating factor. Blood 67:37–45

    Google Scholar 

  15. Munker R, Gasson J, Ogawa M, Koeffler HP (1986) Recombinant human TNF induces production of granulocytemonocyte colony-stimulating factor. Nature 323:79–82

    Google Scholar 

  16. Nakao S, Matsushina K, Young N (1988) Decreased interleukin 1 production in aplastic anaemia. Br J Haematol 71:431–436

    Google Scholar 

  17. Nimer SD, Golde DW, Kwan L, Lee K, Clark S, Champlin R (1991) In vitro production of granulocyte-macrophage colony stimulating factor in aplastic anemia: possible mechanisms of action of antithymocyte globulin. Blood 78:163–168

    Google Scholar 

  18. Nissen-Druey C (1989) Pathophysiology of aplastic anemia. Bailliéres Clin Haematol 2:37–49

    Google Scholar 

  19. Nissen C, Moser Y, Speck B, Bendy J (1983) Haemopoietic stimulators and inhibitors in aplastic anaemia serum. Br J Haematol 54:519–530

    Google Scholar 

  20. Nissen C, Moser Y, Speck B, Gratwohl A, Weis J (1985) Stimulatory serum factors in aplastic anaemia. Br J Haematol 61:499–512

    Google Scholar 

  21. Piacibello W, Lu L, Wachter M, Rubin B, Broxmeyer HE (1985) Release of granulocyte-macrophage colony stimulating factors from major histocombatibility complex class II antigen positive monocytes is enhanced by human gamma interferon. Blood 66:1343–1351

    Google Scholar 

  22. Raghavachar A, Frickhofen N, Digel W, Porzsolt F, Heimpel H (1988) Lymphokines as inhibitors of hematopoietic cell proliferation. Blood Cells 14:471–484

    Google Scholar 

  23. Raghavachar A, Hinterberger W, Kaltwasser JP, Höffken K, Herrmann F, Freund M, Platzer E, Frisch J, Heimpel H, Frickhofen N (1992) Phase I/II trial of recombinant human GM-CSF in aplastic anemia with emphasis on very severe neutropenia and active infection. In: Freund M, Link H, Schmidt R, Welte K (eds) Cytokines in hematopoiesis, oncology and AIDS II. Springer, Berlin Heidelberg New York, pp 555–563

    Google Scholar 

  24. Sillaber C, Valent P, Gorischek C, Muhm M, Kier P, Ziwerzina M, Herold M, Thaler J, Geissler K, Hinterberger W, Kundi M, Huber C, Lechner K, Bettelheim P (1990) Detection of circulating endogenous granulocyte macrophage colony-stimulating factor in hematologic malignancies. Blut 61:74 (abstract)

    Google Scholar 

  25. Taniguchi Y, Frickhofen N, Raghavachar A, Digel W, Heimpel H (1990) Antilymphocyte immunoglobulins stimulate peripheral blood lymphocytes to proliferate and release lymphokines. Eur J Haematol 44:244–251

    Google Scholar 

  26. Torok-Storb B, Johnson GG, Bowden R, Storb R (1987) Gamma-interferon in aplastic anemia: inability to detect significant levels in sera or demonstrate hematopoietic suppressing activity. Blood 69:629–633

    Google Scholar 

  27. Vadhan-Raj S, Buescher S, Broxmeyer HE, Le Maistre A, Lepe-Zuniga V, Ventura G, Jeha S, Horwitz LJ, Trujillo J, Gillis S, Hittelman WN, Gutterman JU (1988) Stimulation of myelopoiesis in patients with aplastic anemia by recombinant human granulocyte-macrophage colony-stimulating factor. N Engl J Med 319:1628–1634

    Google Scholar 

  28. Watari K, Asano S, Shirafuji, Kodo H, Ozawa K, Takaku F, Kamachi S (1989) Serum granulocyte colony-stimulating factor levels in healthy volunteers and patients with various disorders as estimated by enzyme immunoassay. Blood 73:117–122

    Google Scholar 

  29. Yen YP, Zabala P, Doney K, Clemons G, Gillis S, Powell JS, Adamson JW (1985) Hematopoietic growth factors in human serum. Erythroid burst-promoting activity in normal subjects and in patients with severe aplastic anemia. J Lab Clin Med 106:384–392

    Google Scholar 

  30. Zoumbos NC, Gascon P, Djen JY, Young NS (1985) Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo. Proc Natl Acad Sci USA 82:188–192

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abteilung Innere Medizin III, Universität Ulm, Robert-Koch-Strasse 8, W-7900, Ulm, FRG

    H. Schrezenmeier,  A. Raghavachar & H. Heimpel

Authors
  1. H. Schrezenmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Raghavachar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Heimpel
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schrezenmeier, H., Raghavachar, A. & Heimpel, H. Granulocyte-macrophage colony-stimulating factor in the sera of patients with aplastic anemia. Clin Investig 71, 102–108 (1993). https://doi.org/10.1007/BF00179989

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00179989

Key words

Search

Navigation