Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice

Michael P. Brown, David J. Topham, Mark Y. Sangster, Jingfeng Zhao, Kirsten J. Flynn, Sherri L. Surman, David L. Woodland, Peter C. Doherty, Andrew G. Farr, Paul K. Pattengale, Malcolm K. Brenner

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Inherited deficiency of the CD40 ligand (X-linked hyper-IgM syndrome) is characterized by failure of immunoglobulin isotype switching and severe defects of cell-mediated immunity. To test the potential for gene transfer therapy to correct this disorder, we transduced murine bone marrow or thymic cells with a retroviral vector containing the cDNA for the murine CD40 ligand (CD40L) and injected them into CD40L(-/-) mice. Even low-level, constitutive expression of the transgene stimulated humoral and cellular immune functions in these mice. With extended follow-up, however, 12 of 19 treated mice developed T-lymphoproliferative disorders, ranging from polyclonal increases of lymphoblasts to overt monoclonal T-lymphoblastic lymphomas that involved multiple organs. Our findings show that constitutive (rather than tightly regulated), low-level expression of CD40L can produce abnormal proliferative responses in developing T lymphocytes, apparently through aberrant interaction between CD40L+ and TCRαβ+CD40+ thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.

Original languageEnglish (US)
Pages (from-to)1253-1260
Number of pages8
JournalNature Medicine
Volume4
Issue number11
DOIs
StatePublished - Nov 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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