当前位置： SCI文献检索 > BLOOD期刊下所有文献 > Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice.

Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice.

Abstract：

:A recent clinical trial of gene therapy for X-linked severe combined immunodeficiency (XSCID) has shown that retroviral-mediated gene correction of bone marrow stem cells can lead to the development of normal immune function. These exciting results have been preceded by successful immune reconstitution in several XSCID mouse models, all carrying null mutations of the common gamma chain (gamma(c)). One question not formally addressed by these previous studies is that of possible dominant-negative effects of the endogenous mutant gamma(c) protein on the activity of the wild-type transferred gene product. The present work was therefore undertaken to study whether corrective gene transfer was applicable to an XSCID murine model with preserved expression of a truncated gammac molecule (Deltagamma(c+)-XSCID). Gene correction of Deltagamma(c+)-XSCID mice resulted in the reconstitution of lymphoid development, and preferential repopulation of lymphoid organs by gene-corrected cells demonstrated the selective advantage of gamma(c)-expressing cells in vivo. Newly developed B cells showed normalization of lipopolysaccharide-mediated proliferation and interleukin-4 (IL-4)-induced immunoglobulin G1 isotype switching. Splenic T cells and thymocytes of treated animals proliferated normally to mitogens and responded to the addition of IL-2, IL-4, and IL-7, indicating functional reconstitution of gammac-sharing receptors. Repopulated thymi showed a clear increase of CD4-/CD8- and CD8+ fractions, both dramatically reduced in untreated Deltagamma(c+)-XSCID mice. These improvements were associated with the restoration of Bcl-2 expression levels and enhanced cell survival. These data indicate that residual expression of the endogenous truncated gamma(c) did not lead to dominant-negative effects in this murine model and suggest that patient selection may not be strictly necessary for gene therapy of XSCID.

journal_name

Blood

journal_title

Blood

authors

Otsu M,Sugamura K,Candotti F

doi

10.1182/blood.v97.6.1618

subject

Has Abstract

pub_date

2001-03-15 00:00:00

pages

1618-24

issue

eissn

0006-4971

issn

1528-0020

journal_volume

pub_type

杂志文章

在线工具

Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice.