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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2024-2031
Treatment of Non-Obese Diabetic (NOD)/Severe-Combined Immunodeficient
Mice (SCID) With flt3 Ligand and Interleukin-7 Impairs the B-Lineage
Commitment of Repopulating Cells After Transplantation of Human
Hematopoietic Cells
Ursula Kapp,
Mickie Bhatia,
Dominique Bonnet,
Barbara Murdoch, and
John E. Dick
From the Department of Genetics, Research Institute, Hospital for
Sick Children, Toronto, Ontario, Canada; and Department of
Molecular and Medical Genetics, University of Toronto, Toronto,
Ontario, Canada.
Until recently, the identification of cellular factors that govern
the developmental program of human stem cells has been difficult due to
the absence of repopulation assays that detect human stem cells. The
transplantation of human bone marrow (BM) or cord blood (CB) into
non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) mice
has enabled identification of primitive human cells capable of
multilineage repopulation of NOD/SCID mice (termed the
SCID-repopulating cell [SRC]). Here, we examined the effect of
long-term in vivo treatment with various combinations of human
cytokines on the developmental program of SRC. Detailed flow cytometric
analysis of engrafted mice indicated that the vast majority of the
human graft of untreated mice was comprised of B lymphocytes at various
stages of development as well as myeloid and primitive cells; T cells
were not reproducibly detected. Many studies, including murine in vitro
and in vivo data and human in vitro experiments, have suggested that
flt3 ligand (FL) and/or Interleukin-7 (IL-7) promotes T- and
B-cell development. Unexpectedly, we found that treatment of engrafted
mice with the FL/IL-7 combination did not induce human T- or B-cell
development, but instead markedly reduced B-cell development with a
concomitant shift in the lineage distribution towards the myeloid
lineage. Effects on lineage distribution were similar in engrafted mice
transplanted with highly purified cells indicating that the action of
the cytokines was not via cotransplanted mature cells from CB or BM
cells. These data show that the lineage development of the human
graft in NOD/SCID mice can be modulated by administration of
human cytokines providing a valuable tool to evaluate the in vivo
action of human cytokines on human repopulating cells.
© 1998 by The American Society of Hematology.
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