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Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into bone marrow cells

By M. Otsu, M. Steinberg, C. Ferrand, P. Merida, C. Rebouissou, P. Tiberghien, N. Taylor, F. Candotti and N. Noraz

Abstract

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 0 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. (C) 2002 by The American Society of Hematology

Topics: severe combined immunodeficiency receptor-gamma chain green fluorescent protein t-cells in-vivo negative selection tyrosine kinases antigen receptor zap-70 therapy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Publisher: HAL CCSD
Year: 2002
OAI identifier: oai:HAL:hal-02197537v1
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