Résumé :
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Communication n° 449 Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T-cell dependent antibody-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. The anti-AChR response is regulated by Th1-type cytokines including TNF-alpha, interferon-gamma, IL-18 and IL-12. DNA microarray analysis comparing the gene expression of myasthenic and healthy rats revealed increased levels of phosphodiesterase 1 (PDE1) in LNC and of PDE4 and PDE2 in muscles of EAMG rats. Real time quantitative PCR analysis indicated that EAMG is characterized by a significant increase of PDE subtypes 1, 3, 4 and 7 in LNCs, and of PDE subtypes 2, 3, 4 and 7 in muscles. In view of these findings we tested the effect of pentoxifylline (PTX), a general PDE inhibitor, on the course of EAMG in rats. PTX treatment starting at the acute or at the chronic phase of EAMG inhibited the progression of EAMG in a dose-dependent manner. Suppression of EAMG by PTX was accompanied by mRNA down-regulation of PDEs 1, 4, 7 and TNF-alpha in muscles as well as down-regulation of PDE4, TNF-alpha, IL-18, IL-12 and IL-10 in LNC. In contrast, the expression of Foxp3, a transcription factor essential for CD4+CD25+ regulatory T cells (Treg) function, was increased in splenic lymphocytes although the Treg numbers remained unchanged. In addition PTX reduced the expression of the endopeptidase cathepsin-l in EAMG muscles. These results suggest that inhibition of PDE by PTX or by other PDE inhibitors may potentially be considered for immunotherapy of MG and other autoimmune diseases.
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