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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0247.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1248-1256
GENE THERAPY
Reconstitution of lymphoid development and function in
ZAP-70-deficient mice following gene transfer into bone
marrow cells
Makoto Otsu,
Marcos Steinberg,
Christophe Ferrand,
Peggy Merida,
Cosette Rebouissou,
Pierre Tiberghien,
Naomi Taylor,
Fabio Candotti, and
Nelly Noraz
From Genetics and Molecular Biology Branch, National
Human Genome Research Institute (NHGRI), National Institutes of Health
(NIH), Bethesda, MD; Institut de Génétique
Moléculaire de Montpellier, UMR 5535/IFR24, Montpellier, France;
and Etablissement Français du Sang Bourgogne/Franche-Comté,
INSERM EPI0119/UPRES EA 2284, Besançon, France.
Mutations in the ZAP-70 protein tyrosine kinase gene result in a
severe combined immunodeficiency (SCID) characterized by a selective
inability to produce CD8+ T cells and a signal transduction
defect in peripheral CD4+ cells. Transplantation of
genetically modified hematopoietic progenitor cells that express the
wild-type ZAP-70 gene may provide significant benefit to some of these
infants. The feasibility of stem cell gene correction for human
ZAP-70 deficiency was assessed using a ZAP-70 knock-out model.
ZAP-70-deficient murine bone marrow progenitor cells were transduced
with a retroviral vector expressing the human ZAP-70 gene. Engraftment
of these cells in irradiated ZAP-70-deficient animals resulted in the
development of mature CD4+ and CD8+ T cells. In
marked contrast, both populations were absent in ZAP-70 / mice undergoing transplantation with bone
marrow progenitor cells transduced with a control vector. Importantly,
ZAP-70-reconstituted T cells proliferated in response to T-cell
receptor stimulation. Moreover, these ZAP-70-expressing T cells
demonstrated a diverse T-cell receptor repertoire as monitored by the
relative usage of each T-cell receptor  chain hypervariable region
subfamily. The presence of ZAP-70 in B cells did not affect either
lipopolysaccharide- or lipopolysaccharide/interleukin-4-mediated
immunoglobulin isotype switching. Altogether, these data indicate that
retroviral-mediated gene transfer of the ZAP-70 gene may prove to have
a therapeutic benefit for patients with ZAP-70-SCID.
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