Although a number of genetic defects in the P0, peripheral myelin protein-22, and connexin-32 genes recently were shown to cause the demyelinating forms of Charcot-Marie-Tooth disease, there is yet no effective treatment for these patients. Recent studies showed that replication defective adenoviral vectors can efficiently introduce genes into muscle, brain, lung, and other tissues, suggesting that this vector system may be useful for the treatment of a number of genetic diseases. In this work, we demonstrated that a replication deficient adenovirus expressing the Escherichia coli beta-galactosidase gene (AdCMVLacZ) can introduce genes into Schwann cells, in culture as well as in sciatic nerve. Schwann cells cultured at a multiplicity of infection of 250:1 did not demonstrate cytopathic effects. Following injection of AdCMVLacZ into sciatic nerve of rats, lacZ-expressing, myelinating Schwann cells could be detected for at least 45 days. These data suggest that in the future, these vectors may be useful both in perturbing Schwann cell gene expression and in designing therapies for the treatment of Charcot-Marie-Tooth disease.
CC chemokine ligand 2 (CCL2)/monocyte chemotactic protein-1, a member of the CC chemokine family, is a chemoattractant for monocytes and T cells through interaction with its receptor CCR2. In the present study, we examined a T helper cell type 1 (Th1)-dependent disease, proteolipid protein-induced experimental autoimmune encephalomyelitis, in a transgenic mouse line that constitutively expressed low levels of CCL2 in the central nervous system (CNS) under control of the astrocyte-specific glial fibrillary acidic protein promoter. CCL2 transgenic mice developed significantly milder clinical disease than littermate controls. As determined by flow cytometry, mononuclear cell infiltrates in the CNS tissues of CCL2 transgenic and littermate-control mice contained equal numbers of CD4+ and CD8+ T cells, and the CCL2 transgenic mice showed an enhanced number of CNS-infiltrating monocytes. CNS antigen-specific T cells from CCL2 transgenic mice produced markedly less interferon-gamma. Overexpression of CCL2 in the CNS resulted in decreased interleukin-12 receptor expression by antigen-specific T cells. Collectively, these results indicate that sustained, tissue-specific expression of CCL2 in vivo down-regulates the Th1 autoimmune response, culminating in milder clinical disease.
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