title: Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome.
abstract: Mutations in the CD40 ligand (CD40L) are responsible for human hyper immunoglobulin M (IgM) syndrome. The absence of the interaction between CD40L, expressed by T lymphocytes, and the CD40 receptor present on the surface of B cells is responsible for the inability of B cells to carry out the isotype switch from IgM to the other Ig classes. This leads to a fatal immunodeficiency for which no cure exists. For these reasons, the CD40L gene is a good candidate for gene therapy studies. To investigate the possible effects of the expression of this tightly regulated gene in vivo, we produced transgenic mice in which CD40L expression was deregulated. Widespread ectopic expression appears to be lethal. Overexpression in mature T cells is compatible with life, but in one-third of the cases, mice developed atypical lymphoid proliferations which, occasionally, progressed into frank lymphomas. Even though gene therapy is one of the most promising approaches to cure human hyper IgM syndrome, these results suggest that when we modify very tightly regulated genes such as cytokines or other growth factors, particular care has to be taken to avoid excessive stimulation of the target cells.
authors.affiliation: Department of Human Genome and Multifactorial Diseases, Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Milan, Italy. sacco@itba.mi.cnr.it
authors.forename: M G
authors.initials: MG
authors.lastname: Sacco
authors.forename: M
authors.initials: M
authors.lastname: Ungari
authors.forename: E M
authors.initials: EM
authors.lastname: Catò
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: D
authors.initials: D
authors.lastname: Strina
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: J
authors.initials: J
authors.lastname: Jonkers
authors.forename: L
authors.initials: L
authors.lastname: Zecca
authors.forename: F
authors.initials: F
authors.lastname: Facchetti
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015152:Blotting, Northern; D019013:CD40 Antigens / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D005434:Flow Cytometry; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000628:therapy*; D007124:Immunoenzyme Techniques; D007075:Immunoglobulin M; D008198:Lymph Nodes / Q000648:ultrastructure; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D017931:DNA Primers; D007075:Immunoglobulin M; D023201:CD40 Ligand