Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need fortight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

Mutations in the CD40 ligand (CD40L) are responsible for human hyper immuno globulin M (IgM) syndrome. The absence of the interaction between CD40L, ex pressed 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 immunodefic iency 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 transge nic mice in which CD40L expression was deregulated. Widespread ectopic expr ession 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 h yper IgM syndrome, these results suggest that when we modify very tightly r egulated genes such as cytokines or other growth factors, particular care h as to be taken to avoid excessive stimulation of the target cells.