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Myelosuppressive conditioning improves autologous engraftment of
genetically marked hematopoietic repopulating cells in dogs
J Barquinero, HP Kiem, C von Kalle, B Darovsky, S Goehle, T Graham, K Seidel, R Storb and FG Schuening
Division of Clinical Research, Fred Hutchinson Cancer Research Center,
Seattle, WA 98104-2092.
We have studied the role of different conditioning regimens for engraftment
of genetically marked hematopoietic repopulating cells in dogs. Peripheral
blood (PB) and/or marrow cells collected after treatment with recombinant
canine stem cell factor (rcSCF) or cyclophosphamide were transduced in a
vector-containing long-term culture system. Three different
vector-producing cell lines with similar viral titers were used. In two of
them, the neo-containing LN vector was packaged either in the PA317 cell
line with an amphotropic murine retrovirus envelope or the PG13 cell line
with the gibbon ape leukemia virus (GALV) envelope. The MFG/GC vector
produced in PA317 cells contained the human glucocerebrosidase gene.
Nineteen dogs received either no conditioning (group A, n = 5), irradiation
to both humeri with 1,000 cGy (group B, n = 5), a sublethal dose of
cyclophosphamide 40 mg/kg (group C, n = 4), a sublethal dose of 200 or 300
cGy total body irradiation (TBI) (group D, n = 3), or an otherwise lethal
dose of 920 cGy TBI (group E, n = 3) before intravenous (groups A, C, D, E)
or intramedullary (group B) infusion of the transduced autologous
hematopoietic cells. Transduction efficiency of hematopoietic cells at the
time of infusion into the animals was similar among the different
conditioning groups. Dogs were observed for at least 6 months. PB
granulocytes were obtained at least every 3 weeks after transplant and
analyzed by polymerase chain reaction for the presence of the transduced
genes. The percentages of positive results in dogs more than 4 weeks after
transplantation were 0% without conditioning, 5% with local irradiation,
18% with sublethal cyclophosphamide, 33% with sublethal TBI, and 17% with
otherwise lethal TBI. Analyzing the influence of conditioning regimens by a
generalized estimating equation (GEE) technique, which considered the use
of different retrovirus vectors and the number of mononuclear cells infused
as potential confounding variables, we found that engraftment of
genetically marked repopulating cells was significantly improved (P <
.001) in dogs receiving systemic conditioning with either otherwise lethal
TBI, sublethal TBI, or sublethal cyclophosphamide compared to dogs with
local irradiation only or no conditioning. Within the limitation of the
experimental design, these data suggest that myeloablative or
myelosuppressive conditioning improves engraftment of genetically marked
hematopoietic repopulating cells.
Volume 85,
Issue 5,
pp. 1195-1201,
03/01/1995
Copyright © 1995 by The American Society of Hematology
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