Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency Academic Article uri icon


MeSH Major

  • CD40 Ligand
  • Gene Expression Regulation
  • Genetic Diseases, X-Linked
  • Genetic Engineering
  • Hypergammaglobulinemia
  • Immunoglobulin M
  • RNA, Messenger


  • X-linked immunodeficiency with hyper-IgM (HIGM1), characterized by failure of immunoglobulin isotype switching, is caused by mutations of the CD40 ligand (CD40L), which is normally expressed on activated CD4(+) T cells. As constitutive expression of CD40L induces lymphomas, we corrected the mutation while preserving the natural regulation of CD40L using pre-mRNA trans-splicing. Bone marrow from mice lacking CD40L was modified with a lentivirus trans-splicer encoding the normal CD40L exons 2-5 and was administered to syngenic CD40L-knockout mice. Recipient mice had corrected CD40L mRNA, antigen-specific IgG1 responses to keyhole limpet hemocyanin immunization, regulated CD4(+) T-cell CD40L expression after CD3 stimulation in primary and secondary transplanted mice, attenuation of Pneumocystis carinii pneumonia, and no evidence of lymphoproliferative disease over 1 year. Thus, HIGM1 can be corrected by CD40L trans-splicing, leading to functional correction of the genetic defect without the adverse consequences of unregulated expression of the CD40L gene.

publication date

  • August 2004



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1038/nm1086

PubMed ID

  • 15273748

Additional Document Info

start page

  • 835

end page

  • 41


  • 10


  • 8