Prevention and suppression of autoimmune encephalomyelitis by EUK-8, a synthetic catalytic scavenger of oxygen-reactive metabolites.
Breakdown of T cell tolerance to self-myelin basic protein induces an autoimmune process that leads to demyelination of the central nervous system (CNS) in multiple sclerosis (MS) patients. While the autoimmune disease is initiated by antigen-specific autoreactive T cells, there is accumulating evidence that CNS injury is essentially mediated by CNS-infiltrating inflammatory cells. In addition, it is established that activated macrophages and polymorphonuclear cells contribute to tissue damage in several inflammatory diseases by releasing highly reactive oxygen metabolites. It was therefore possible that demyelination associated with MS results from oxidative injury caused by a cascade of oxygen reactive metabolites produced by CNS-infiltrating activated macrophages and other inflammatory cells. To address this question, we tested the effect of a synthetic catalytic scavenger of oxygen radicals, EUK-8, on experimental allergic encephalomyelitis (EAE) in mice, the animal model for MS in humans. We observed that repeated injection of EUK-8 starting at the time of EAE induction delayed the onset and markedly reduced the severity of the disease. Strikingly, all EUK-8-treated mice completely recovered after 40 days. In addition, we showed that posttreatment with EUK-8 4 days after EAE induction also resulted in a significant amelioration of EAE disease. These results indicate that oxygen metabolites secreted by inflammatory cells at the site of tissue destruction play a major role in the induction and presumably the perpetuation of the autoimmune disease. This study also suggests that treatment with oxygen metabolites scavengers may represent a novel and promising strategy to prevent the onset and to block the course of ongoing autoimmune encephalomyelitis and other inflammatory autoimmune diseases.
Malfroy
B
B
Eukarion, Incorporated, Bedford, Massachusetts 01730, USA.
Doctrow
S R
SR
Orr
P L
PL
Tocco
G
G
Fedoseyeva
E V
EV
Benichou
G
G
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005029:Ethylenediamines / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006168:Guinea Pigs; D051379:Mice; D004676:Myelin Basic Protein / Q000276:immunology; D009942:Organometallic Compounds / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D005029:Ethylenediamines; D016166:Free Radical Scavengers; D004676:Myelin Basic Protein; D009942:Organometallic Compounds; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II)