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Mast cell growth factor (C-Kit Ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3:in vivo hemopoietic effects in irradiated mice compared toin vitro effects

  • Published:
Biotherapy

Abstract

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulatorin vitro. In these studies, we examined thein vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100Μg/kg/day), rmGM-CSF (100Μg/kg/day), rmIL-3 (100Μg/kg/day), or combinations of these cytokines on days 1–17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results ofin vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effectsin vivo andin vitro and emphasize that caution should be taken in attempting to predict cytokine interactionsin vivo in hemopoietically injured animals based onin vitro cytokine effects.

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Abbreviations

GM-CSF:

Granulocyte-Macrophage Colonly-Stimulating Factor

IL-3:

Interleukin-3

MGF:

Mast Cell Growth Factor

SCF:

Stem Cell Factor

rm:

Recombinant Murine

CFU-s:

Colony Forming Unit-Spleen

GM-CFC:

Granulocyte Macrophage Colony-Forming Cell

WBC:

White Blood Cells

RBC:

Red Blood Cells

PLT:

Platelets

SLF:

Steel Factor

G-CSF:

Granulocyte Colonly-Stimulating Factor

IL-1:

Interleukin-1

IL-6:

Interleukin-6

Epo:

Erythropoietin

CFC:

Colony-Forming Cell

Sl:

Steel

BFU-e:

Erythroid Burst Forming Units

s.c:

Subcutaneous

PEG:

Polyethyleneglycol

PIXY321:

GM-CSF/IL-3 Fusion Protein

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Authors and Affiliations

  1. Department of Experimental Hematology, Armed Forces Radiobiology, Research Institute Bethesda, MD, USA

    M. L. Patchen, R. Fischer & T. J. MacVittie

  2. Research Laboratories of Behringwerke, AG, Marburg, Germany

    F. R. Seiler

  3. Immunex Corporation, Seattle, WA, USA

    D. E. Williams

Authors
  1. M. L. Patchen
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  2. R. Fischer
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  3. T. J. MacVittie
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  4. F. R. Seiler
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  5. D. E. Williams
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Patchen, M.L., Fischer, R., MacVittie, T.J. et al. Mast cell growth factor (C-Kit Ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3:in vivo hemopoietic effects in irradiated mice compared toin vitro effects. Biotherapy 7, 13–26 (1993). https://doi.org/10.1007/BF01878150

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