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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0247.
Submitted January 28, 2002
Accepted March 22, 2002
Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into lineage-negative bone marrow cells
Naomi Taylor*, Nelly Noraz, Peggy Merida, Cosette Rebouissou, Marcos Steinberg, Makoto Otsu, Fabio Candotti, Christophe Ferrand, and Pierre Tiberghien
Institut de Genetique Moleculaire de Montpellier, Montepellier Cedex 05, France
Genetics and Molecular Biology Branch, NHGRI/NIH, MD, USA
EFS Bourgogne Franche-Comte, Besancon, France
* Corresponding author; email: taylor{at}igm.cnrs-mop.fr.
Mutations in the ZAP-70 protein tyrosine kinase gene result in a severe combined immunodeficiency (SCID) characterized by a selective inability to produce CD8 single positive 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 transplanted with BM 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 ß chain hypervariable region (TCRBV) subfamily. The presence of ZAP-70 in B cells did not affect either lipopolysaccharide (LPS)- or LPS/IL-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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