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Enhanced engraftment of hematopoietic progenitor cells in mice treated with
granulocyte colony-stimulating factor before low-dose irradiation:
implications for gene therapy
M Mardiney and HL Malech
Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD 20892- 1886, USA.
Gene therapy for inherited disorders of blood cells will require both
efficient methods for stable gene transfer and nonablative bone marrow
conditioning regimens to allow engraftment of modified hematopoietic
progenitor cells (HPCs). We have used a sensitive murine system for
detecting HPC engraftment using congenic C57BL/6 mice that differ at the
Ly5 locus, which encodes the leukocyte common antigen. The system relies on
the ability of monoclonal antibodies with specificity for Ly5.1 and Ly5.2
(revised nomenclature: CD45.1 and CD45.2, respectively) to distinguish
donor and recipient peripheral blood leukocytes after transplantation of
purified Sca-1+ bone marrow-derived HPCs. No detectable engraftment
occurred in nonirradiated recipient mice, even when as many as 2.0 x 10(6)
SCa-1+HPCs were transplanted. However, in mice receiving total body
irradiation (TBI), engraftment increased as a function of
pretransplantation radiation dose, number of transplanted cells, and time
after transplantation. Moreover, mice receiving either granulocyte
colony-stimulating factor (G-CSF) or G-CSF+ stem cell factor before
low-dose TBI (160 cGy) exhibited a marked increase in engraftment compared
with mice receiving a vehicle control before low- dose TBI (18.9% and 20.6%
v 5.6% at a 1 month, respectively; 29% and 35% v 15.1% at 4 months,
respectively). Use of growth factor pretreatment even allowed TBI doses as
low as 30, 70, or 120 cGy to achieve significant engraftment of donor
progenitors (0.3%, 1.5%, and 6.8% at 1 month, respectively; 1.7%, 5.8%, and
13.9% at 4 months, respectively). All animals remained healthy during the
observation periods. Thus, growth factor preconditioning of the recipient
followed by low-dose TBI may provide an optimal balance between safety and
efficacy in achieving required levels of engraftment for gene therapy of
blood disorders.
Volume 87,
Issue 10,
pp. 4049-4056,
05/15/1996
Copyright © 1996 by The American Society of Hematology
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