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.
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP- animals that received transplants of mixtures of wild type (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 virus which was normalized in animals that received transplants of 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 with 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 virus was also improved in gene-corrected animals.
Strom
Ted S
TS
Division of Experimental Hematology, Department of Hematology/Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA.
Turner
Stephen J
SJ
Andreansky
Samita
S
Liu
Haiyan
H
Doherty
Peter C
PC
Srivastava
Deo Kumar
DK
Cunningham
John M
JM
Nienhuis
Arthur W
AW
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology; D011506:Proteins / Q000008:administration & dosage* / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic / Q000379:methods; D016896:Treatment Outcome; D014923:Wiskott-Aldrich Syndrome / Q000150:complications / Q000276:immunology / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein
D011506:Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein