title: Retroviral-mediated gene transfer restores IL-12 and IL-23 signaling pathways in T cells from IL-12 receptor beta1-deficient patients.
abstract: Genetic deficiency of human IL-12 receptor beta1 chain (IL-12Rbeta1) results in increased vulnerability to weakly pathogenic strains of Mycobacteria and Salmonella. This phenotype results from the combined lack of IL-12 and IL-23 signaling as both cytokine receptors share IL-12Rbeta1. Such infections can be treated by administration of antibiotics and IFN-gamma; however, patients can succumb to infections despite these treatments. Reversion of patients' susceptibility by corrective gene transfer could prevent the infectious episodes, thus providing a beneficial alternative. We therefore evaluated the feasibility of retroviral-mediated gene correction of T cells obtained from patients carrying "null" mutations of IL-12Rbeta1. Transduction of the IL-12Rbeta1 cDNA restored the expression of IL-12Rbeta1 and resulted in the reconstitution of a functional IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-gamma production. IFN-gamma production in response to IL-23 was also corrected after gene transfer. These results indicate that the biological defects of T cells from patients carrying IL-12Rbeta1 deficiency can be corrected by gene transfer and form the basis for further development of gene therapy for this disease.
authors.affiliation: Disorders of Immunity Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Building 49, Room 3A20, MSC 4442, Bethesda, MD 20892-4442, USA.
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Iren
authors.initials: I
authors.lastname: Witte
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
mesh_terms: D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D053707:Receptors, Interleukin-12; D012190:Retroviridae / Q000235:genetics*; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C508438:IL12RB1 protein, human; C508840:IL23A protein, human; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma