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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2002-11-3489.
Submitted November 19, 2002
Accepted June 29, 2003
Defects in T-cell-mediated immunity to influenza virus in murine Wiskott-Aldrich Syndrome are corrected by oncoretroviral vector-mediated gene transfer into repopulating hematopoietic cells
Ted S Strom, Stephen J Turner, Samita Andreansky, Haiyan Liu, Peter C Doherty, Deo Kumar Srivastava, John M Cunningham, and Arthur W Nienhuis*
Division of Experimental Hematology, Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Departments of Biochemistry and Pediatrics, University of Tennessee, Memphis, TN, USA
* Corresponding author; email: arthur.nienhuis{at}stjude.org.
The Wiskott-Aldrich Syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia and eczema. We used a murine model created by knock-out of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP- animals transplanted with mixtures of wildtype (WT) and WASP- bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP- mice had a defective secondary T-cell response to influenza which was normalized in animals transplanted with 35% or more WT cells. The WASP gene was inserted into WASP- bone marrow cells with a bicistronic oncoretroviral vector also encoding Green Fluorescent Protein (GFP) followed by transplantation into irradiated male WASP- recipients. There was a selective advantage for gene corrected cells in multiple lineages. Animals having higher proportions of GFP+ T-cells showed normalization of their lymphocyte counts. Gene corrected, blood T-cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell receptor stimulation. The defective secondary T-cell response to influenza was also improved in gene corrected animals.
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