Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into bone marrow cells.
Blood
; 100(4): 1248-56, 2002 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-12149205
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 beta 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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Células da Medula Óssea
/
Células-Tronco Hematopoéticas
/
Linfócitos
/
Transfecção
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Estados Unidos