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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1237-1248
Quantitative assessment of retroviral transfer of the human
multidrug resistance 1 gene to human mobilized peripheral blood
progenitor cells engrafted in nonobese diabetic/severe combined
immunodeficient mice
B. Schiedlmeier,
K. Kühlcke,
H. G. Eckert,
C. Baum,
W. J. Zeller, and
S. Fruehauf
From the German Cancer Research Center, Department D 0200, Heidelberg, Germany; EUFETS GmbH, Idar-Oberstein, Germany;
Heinrich-Pette-Institut, Hamburg, Germany; and the Department of
Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Mobilized peripheral blood progenitor cells (PBPC) are a potential
target for the retrovirus-mediated transfer of cytostatic drug-resistance genes. We analyzed nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse-repopulating CD34+ PBPC from patients with cancer after retroviral transduction in various cytokine
combinations with the hybrid vector SF-MDR, which is based on the
Friend mink cell focus-forming/murine embryonic stem-cell virus and
carries the human multidrug resistance 1 (MDR1) gene. Five to
13 weeks after transplantation of CD34+ PBPC into NOD/SCID mice
(n = 84), a cell dose-dependent multilineage engraftment of human
leukocytes up to an average of 33% was observed. The SF-MDR provirus
was detected in the bone marrow (BM) and in its granulocyte fractions
in 96% and 72%, respectively, of chimeric NOD/SCID mice. SF-MDR
provirus integration assessed by quantitative real-time polymerase
chain reaction (PCR) was optimal in the presence of Flt-3
ligand/thrombopoietin/stem-cell factor, resulting in a 6-fold (24% ± 5% [mean ± SE]) higher average proportion of gene-marked human
cells in NOD/SCID mice than that achieved with IL-3 alone (P < .01). A population of clearly
rhodamine-123dull human myeloid progeny cells could be
isolated from BM samples from chimeric NOD/SCID mice. On the basis of
PCR and rhodamine-123 efflux data, up to 18% ± 4% of transduced
cells were calculated to express the transgene. Our data suggest that
the NOD/SCID model provides a valid assay for estimating the
gene-transfer efficiency to repopulating human PBPC that may be
achievable in clinical autologous transplantation. P-glycoprotein
expression sufficient to prevent marrow aplasia in vivo may be obtained
with this SF-MDR vector and an optimized transduction protocol.
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