Tumor necrosis factor-directed therapy of autoimmune encephalomyelitis by the phosphodiesterase IV inhibitor rolipram

Experimental immunotherapies for multiple sclerosis

“…Pentoxifylline was effective in EAE [88,114]. The PDE type IV inhibitor rolipram could block TNF-and IFN-~, secretion in human MBP-specific T cells in a stereospecific manner and also inhibited EAE in the Lewis rats [129], in SJL mice (Sommer et al, in preparation) and also in the marmoset EAE model [41]. Since the substance has few side effects and can be administered orally it provides an attractive alternative to the treatments with monoclonal antibodies or soluble TNF receptors.…”

“…Since the administration of monoclonal antibodies is costly and causes a number of problems during long-term treatment, there has been considerable interest in iden-tifying other approaches to interfere with the production of TNF/LT and IFN-'7. It has been shown that phosphodiesterase (PDE) inhibitors are able to block lymphocyte activation and the secretion of TNF-c~ and IFN-',/ via the increase of intracellular cAMP levels [122,129]. This group of agents can be separated into phosphodiesterase inhibitors with relatively nonspecific action such as pentoxifylline and those that specifically block certain PDE types.…”

“…In contrast to the unspecific PDE inhibitors, the PDE type IV is almost exclusively expressed in the CNS and in lymphoid cells and thus has significantly less side effects. The drug was originally developed and tested as an antidepressant but also has a potent suppressive effect on TNF and, to a lesser extent, on IFN-7 secretion [41, 129,130]. Pentoxifylline was effective in EAE [88,114].…”