SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease

Blood. 2013 Feb 14;121(7):1073-6. doi: 10.1182/blood-2012-07-445858. Epub 2012 Dec 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Disease Models, Animal
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hematopoietic Stem Cell Transplantation
  • Immunity, Cellular
  • Immunity, Humoral
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Killer Cells, Natural / immunology
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology*
  • Lymphoproliferative Disorders / pathology
  • Lymphoproliferative Disorders / therapy*
  • Mice
  • Mice, Knockout
  • Natural Killer T-Cells / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signaling Lymphocytic Activation Molecule Associated Protein

Substances

  • Intracellular Signaling Peptides and Proteins
  • Recombinant Fusion Proteins
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins