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.
Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into bone marrow cells
Otsu, M.; Steinberg, M.; Ferrand, C.; Merida, P.; Rebouissou, C.; Tiberghien, P.; Taylor, N.; Candotti, F.; Noraz, N.
2002-08-15 / vol 100 / pages 1248-1256
in-vivo; antigen receptor; severe combined immunodeficiency; t-cells; therapy; zap-70; green fluorescent protein; negative selection; receptor-gamma chain; tyrosine kinases