VI Autologous Bone Marrow Transplantation.pdf - Blog Science ...

THE RECOMBINANT HUMAN LIGAND FOR C-KIT ENHANCES THE IN
VIVO BIOLOGICAL EFFECTS OF RECOMBINANT HUMAN GRANULO­
CYTE COLONY-STIMULATING FACTOR FOR STIMULATING
LEUKOCYTOSIS AND CIRCULATION OF HEMATOPOIETIC
COLONY-FORMING PROGENITOR CELLS IN PRIMATES.
R.G. Andrews, F.R. Appelbaum, G.H. Knitter, W.I. Bensinger, I.D. Bernstein,
I.K. McNiece.
The Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; the
University of Washington Regional Primate Research Center, Seattle,
Washington, USA; Amgen, Inc, Thousand Oaks, California, USA. Supported by
Grants and Contracts NO1-AI-85003, NIHRROOI66, and CA39492 from the
National Institutes of Health, and Amgen, Inc.
The ligand for c-kit, called stem cell factor (SCF), mast cell growth factor
(MGF), kit ligand (KL), and Steel factor or Steel locus factor (SIF) C -4
), is a growth
factor with pleiotropic effects that enhances the proliferation of hematopoietic
colony-forming cells (CFC)in response to specific hematopoietic growth factors(
57
). By itself, SCF stimulates little proliferation of CFC but prolongs the survival
of CFC in vitro. In mice, SCF administration corrects many of the hematopoietic
defects in Sl/SId mice that have mutant SCF genes 0). SCF administered
to normal mice produces a spectrum of biological effects within the hematopoietic
system, including the expansion of cells that reconstitute hematopoiesis after
transplantation into W/Wvmice ( 8
).
We have investigated the biological effects of the recombinant human ligand
for c-kit (rhSCF) on in vivo hematopoiesis in baboons, with particular interest
in the trafficking of hematopoietic progenitor cells. We showed previously
that rhSCF is biologically active on baboon hematopoietic progenitor cells in culture,
as it acts synergistically with G-CSF, GM-CSF, IL-3, Epo, and IL-6 to enhance
the in vitro proliferation of individual CFC as well as increasing the number
of CFC that proliferate in vitro in the presence of these factors (9). Monoclonal
antibodies to the human c-kit molecule, that competitively block rhSCF
binding, also bind to the subpopulation of baboon marrow cells that express
CD34 which includes virtually all progenitor cells as well as transplantable hematopoietic
cells. This suggests that baboons may provide a model for studying
the in vivo biological effects of rhSCF on hematopoiesis.
RhSCF administered to baboons by either continuous intravenous infusion
or subcutaneous injection stimulates a dose dependent leukocytosis, with increases
in white blood cells of multiple types in the circulation, including neutrophils,
monocytes, eosinophils, basophils, and both T and B lymphocytes (9 10
).
RhSCF also stimulates a reticulocytosis and increases the number of circulating
red blood cells and the hematocrit. Platelet counts initially decrease slightly, after
which they return to pretreatment levels, and then increase slightly above
pretreatment values after administration of rhSCF is stopped.
SIXTH INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION 227