Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Christine Rivat1,*,
  2. Claire Booth1,*,
  3. Maria Alonso-Ferrero1,
  4. Michael Blundell1,
  5. Neil J. Sebire2,
  6. Adrian J. Thrasher1, and
  7. H. Bobby Gaspar1
  1. 1Centre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, London, United Kingdom; and
  2. 2Department of Histopathology, Great Ormond Street Hospital National Health Service Foundation Trust, London, United Kingdom

Key Points

  • This study provides proof of concept that SAP gene transfer into HSCs can correct the multiple immune defects seen in XLP1.


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.

  • Submitted July 26, 2012.
  • Accepted November 11, 2012.
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