Retrovirus-mediated transduction of primary ZAP-70-deficient human T cells results in the selective growth advantage of gene-corrected cells: implications for gene therapy
| Autor: | Hans Yssel, Louise Swainson, Wilhelm Friedrich, Naomi Taylor, M Boyer, Marcos Steinberg, Klaus Schwarz, Nelly Noraz |
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| Přispěvatelé: | Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2000 |
| Předmět: |
MAP Kinase Signaling System
T-Lymphocytes Genetic enhancement Genetic Vectors Immunoblotting Receptors Antigen T-Cell Biology TCIRG1 Consanguinity 03 medical and health sciences Transduction (genetics) Interleukin 21 0302 clinical medicine Genetics Humans Cytotoxic T cell [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology IL-2 receptor T-Cell/metabolism Retroviridae/*genetics Signal Transduction T-Lymphocytes/*enzymology/metabolism ZAP-70 Protein-Tyrosine Kinase Molecular Biology Cell Division Consanguinity Gene Therapy/*methods Gene Transfer Techniques Genetic Vectors/*administration & dosage Humans Immunoblotting Infant Interleukin-2/secretion MAP Kinase Signaling System Protein-Tyrosine Kinases/*deficiency/*genetics Receptors 030304 developmental biology Interleukin 3 0303 health sciences ZAP-70 Protein-Tyrosine Kinase Gene Transfer Techniques Infant Genetic Therapy Protein-Tyrosine Kinases Molecular biology 3. Good health Cell biology Retroviridae Antigen Interleukin 12 Interleukin-2 Molecular Medicine Cell Division Signal Transduction 030215 immunology |
| Zdroj: | Gene Therapy Gene Therapy, Nature Publishing Group, 2000, 7 (16), pp.1392--400. ⟨10.1038/sj.gt.3301249⟩ Gene Therapy, 2000, 7 (16), pp.1392--400. ⟨10.1038/sj.gt.3301249⟩ |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | Humans lacking the ZAP-70 protein tyrosine kinase present with an absence of CD8+ T cells and defective CD4+ T cells in the periphery. This severe combined immunodeficiency is fatal unless treated by allogeneic bone marrow transplantation. However, in the absence of suitable marrow donors, the development of alternative forms of therapy is desirable. Because lymphocytes are long-lived, it is possible that introduction of the wild-type ZAP-70 gene into CD4+ ZAP-70-deficient T cells will restore their immune function in vivo. Initial investigations evaluating the feasibility of gene therapy for ZAP-70 deficiency were performed using HTL V-I-transformed lymphocytes. Although transformation was useful in circumventing problems associated with the maintenance of ZAP-70-deficient T cells and low gene transfer levels, the presence of HTL V-I precluded any biological studies. Here, we investigated a retrovirus-mediated approach for the correction of primary T cells derived from two ZAP-70-deficient patients. Upon introduction of the wild-type ZAP-70 gene, TCR-induced MAPK activation, IL-2 secretion and proliferation were restored to approximately normal levels. Importantly, this gain-of-function was associated with a selective growth advantage of gene-corrected cells, thereby indicating the feasibility of a gene therapy-based strategy. |
| Databáze: | OpenAIRE |
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