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

Christine Rivat, Claire Booth, Maria Alonso-Ferrero, Michael Blundell, Neil J. Sebire, Adrian J. Thrasher and H. Bobby Gaspar

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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