title: Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice.
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 TCRalphabeta+CD40+ thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.
authors.affiliation: Cell and Gene Therapy Program, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Brown
authors.forename: D J
authors.initials: DJ
authors.lastname: Topham
authors.forename: M Y
authors.initials: MY
authors.lastname: Sangster
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: K J
authors.initials: KJ
authors.lastname: Flynn
authors.forename: S L
authors.initials: SL
authors.lastname: Surman
authors.forename: D L
authors.initials: DL
authors.lastname: Woodland
authors.forename: P C
authors.initials: PC
authors.lastname: Doherty
authors.forename: A G
authors.initials: AG
authors.lastname: Farr
authors.forename: P K
authors.initials: PK
authors.lastname: Pattengale
authors.forename: M K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D023201:CD40 Ligand; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007111:Immunity, Cellular / Q000235:genetics; D008223:Lymphoma / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D013953:Thymus Neoplasms / Q000276:immunology; D014161:Transduction, Genetic; D014779:Virus Replication; D014960:X Chromosome
chemical_list: D008562:Membrane Glycoproteins; D023201:CD40 Ligand