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

Minoru Tahara, Robert G. Pergolizzi, Hiroyasu Kobayashi, Anja Krause, Karsta Luettich, Martin L. Lesser, Ronald G. Crystal

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)835-841
Number of pages7
JournalNature Medicine
Volume10
Issue number8
DOIs
Publication statusPublished - 1 Aug 2004

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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