granulocyte-macrophage colony-stimulating factor

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May 3, 2012 - in patients receiving GM-CSF with leukopenia. Together with Dr. William Peters of Duke University Medical Center (Durham, NC), we have also ...
From bloodjournal.hematologylibrary.org by guest on May 3, 2012. For personal use only.

1990 75: 1895-1896

Serum levels of tumor necrosis factor alpha in patients treated with granulocyte-macrophage colony-stimulating factor [letter; comment] B Stehle, C Weiss, AD Ho and W Hunstein

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From bloodjournal.hematologylibrary.org by guest on May 3, 2012. For personal use only.

CORRESPONDENCE

SERUM LEVELS OF TUMOR NECROSIS FACTOR a IN PATIENTS TREATED WITH GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

To the Editor: Recently Sisson and Dinarello' showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates human peripheral blood mononuclear cells in vitro to produce tumor necrosis factor (TNF) as well as interleukin-la (IL-la) and IL-16. We have analyzed the serum levels of TNF a in vivo in three patients with non-Hodgkin's lymphomas receiving GM-CSF (250 pg/m2) for hematologic reconstitution after chemotherapy (ARAC, mitoxantrone) for 10 days, and five patients receiving GM-CSF

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for the enhancement of pluripotent hematopoetic progenitors before harvesting for peripheral progenitor cell transplantation. The concentration of TNF was determined by an immunoradiometric assay (IRMA) obtained from IRE-Medgenix, Fleurus, Belgium. The IRMA does not crossreact with IL-1, IL-2, interferon a,interferon 6, or interferon y. In all three patients receiving GM-CSF for hematologic reconstitution after chemotherapy, there was a sharp increase in TNF levels with a maximum after 3 to 4 days of GM-CSF administration (Fig 1A). In two control patients receiving chemotherapy without administration of GM-CSF there was no increase in TNF levels. Thus, the in vivo results confirm the in vitro data of Sisson and Dinarello that GM-CSF can stimulate the production of TNF. Sisson and Dinarello discussed that GM-CSF-induced TNF may exhibit a negative effect on hematopoesis.'.2 Our findings demonstrate that administration of GM-CSF results in an increase of TNF levels during aplasia, whereas on onset of hematologic reconstitution a suppression of TNF release was observed (Fig 1, A and B). Thus, in our patients the negative effect of TNF on hematopoesis was suppressed at onset of hematologic reconstitution. As GM-CSF enhances hematologic reconstitution, this inhibition of TNF production could also be a GM-CSF-controlled process. It should be discussed that a TNF peak controlled by GM-CSF might function as a trigger signal preceding hematologic reconstitution. However, in patients with normal peripheral leukocyte counts who were receiving GM-CSF for the enhancement of pluripotent hematopoetic progenitors, we did not observe a TNF peak. Thus, in vivo the effects of GM-CSF are complex and depend on the hematologic conditions. BERND STEHLE Medizinische KIinik Fakultat f i r Klinische Medizin Mannheim der Universitat Heidelberg CLAUS WEISS ANTHONY D. HO WERNER HUNSTEIN Abteilung Innere Medizin V der Medizinischen Universitatsklinik und Poliklinik der Universitat Heidelberg Hospitalstr.3 FRG

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Fig 1. TNF serum levels (A) and leukocyte counts (B) in patients with non-Hodgkin's lymphomas receiving GMCSF for hematologic reconstitution after chemotherapy (day -2, end of chemotherapy; days 0 to 10, GM-CSF treatment).

Blood, Vol75, No 9 (May 1). 1990: pp 1895-1899

1. Sisson DS, Dinarello CA: Production of interleukin-la, interleukin-10 and tumor necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood72:1368,1988 2. Murase T, Hotta T, Saito H, Ohno R: Effect of recombinant human tumor necrosis factor on the colony growth of human leukemia progenitor cells and normal hematopoietic progenitor cells. Blood 69:467,1987

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From bloodjournal.hematologylibrary.org by guest on May 3, 2012. For personal use only. 1896

CORRESPONDENCE

RESPONSE Dr Stehle et al have demonstrated elevated circulating T N F levels in patients receiving GM-CSF with leukopenia. Together with Dr William Peters of Duke University Medical Center (Durham, NC), we have also measured similar elevations of T N F in patients receiving GM-CSF during bone marrow reconstitution, and agree with Dr Stehle that these findings confirm our published in vitro observations. The mechanism by which GM-cSF induces T N F production in leukopenic patients may be due to a priming effect of GM-CSF on the fixed macrophagic cell population. We believe that in patients with severe leukopenia, there is likely an endotoxin leak or local infection, particularly from the gastrointestinal or respiratory tracts, which triggers the synthesis of TNF. With the return of the peripheral leukocyte count, normal host defense barriers are reestablished and the CM-CSF primed macrophage is no longer triggered to synthesize TNF, although it remains in a primed state.

This hypothesis would also explain why elevated T N F levels are not observed in patients receiving GM-CSF without leukopenia or infection. Recent data from our laboratory (Sirko and Dinarello, manuscript in Preparation) support the concept that GM-CSF Primes hn" mononuclear cells to synthesize significantly more TNF, IL-1, and IL-6 when exposed to very low concentrations of endotoxin a m pared with mononuclear cells exposed to endotoxin only. Interestingly, the increased IL-1 and IL-6 production may be beneficial in terms of stem cell responses to GM-CSF, whereas the T N F would provide a suppressive effect. CHARLES A. DINARELLO Division of Geographic Medicine and Infectious Diseases Tufts University School of Medicine Boston. MA