title: SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease.
abstract: X-linked lymphoproliferative disease (XLP1) arises from mutations in the gene encoding SLAM-associated protein (SAP) and leads to abnormalities of NKT-cell development, NK-cell cytotoxicity, and T-dependent humoral function. Curative treatment is limited to allogeneic hematopoietic stem cell (HSC) transplantation. We tested whether HSC gene therapy could correct the multilineage defects seen in SAP(-/-) mice. SAP(-/-) murine HSCs were transduced with lentiviral vectors containing either SAP or reporter gene before transplantation into irradiated recipients. NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice. Baseline immunoglobulin levels were significantly increased and T-dependent humoral responses to NP-CGG, including germinal center formation, were restored in SAP-transduced mice.We demonstrate for the first time that HSC gene transfer corrects the cellular and humoral defects in SAP(-/-) mice providing proof of concept for gene therapy in XLP1.
authors.affiliation: Centre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Rivat
authors.forename: Claire
authors.initials: C
authors.lastname: Booth
authors.forename: Maria
authors.initials: M
authors.lastname: Alonso-Ferrero
authors.forename: Michael
authors.initials: M
authors.lastname: Blundell
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
mesh_terms: D000818:Animals; D019070:Cell Lineage; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins