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

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.

• Authors: Makoto Otsu, Marcos Steinberg, Christophe Ferrand, Peggy Merida, Cosette Rebouissou, Pierre Tiberghien, Naomi Taylor, Fabio Candotti, Nelly Noraz
• Journal: Blood (Blood) Vol. 100 Issue 4 Pg. 1248-56 (Aug 15 2002) ISSN: 0006-4971 [Print] United States
• PMID: 12149205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Antigen, T-Cell, alpha-beta
• Protein-Tyrosine Kinases
• ZAP-70 Protein-Tyrosine Kinase
• Zap70 protein, mouse

Topics

• Animals
• Bone Marrow Cells (metabolism)
• CD4-Positive T-Lymphocytes (physiology)
• CD8-Positive T-Lymphocytes (physiology)
• Cell Differentiation
• Gene Expression
• Genetic Vectors
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells (metabolism)
• Immunophenotyping
• Lymphocytes (immunology, physiology)
• Mice
• Mice, Knockout
• Polymerase Chain Reaction
• Protein-Tyrosine Kinases (deficiency, genetics)
• Receptors, Antigen, T-Cell, alpha-beta (genetics)
• Retroviridae (genetics)
• Severe Combined Immunodeficiency (genetics, therapy)
• Transfection
• ZAP-70 Protein-Tyrosine Kinase