Proteinase inhibitors suppress the development of experimental allergic encephalomyelitis.

Abstract

Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS) induced in animals by sensitization with white matter or with myelin basic protein (BP)1,2. EAE is dependent on cell-mediated immune (CMI) reactions requiring T-cell sensitization2–4, and demyelination is observed in the vicinity of perivascular infiltrates of mononuclear cells5. However, the mechanisms by which CMI reactions initiate the clinical and pathological expression of EAE have not been well defined. Numerous mechanisms have been proposed for the degradation of myelin, including activated components of the complement system6,7 and the action of enzymes released by inflammatory cells8,9. Among these enzymes, lipases, lysosomal acid proteinases and lymphocyte proteinases have been stressed8–14. Recent reports from this laboratory have suggested that damage to the myelin sheath may be initiated by the release of neutral proteinases, including plasminogen activator, from macrophages activated during an immune response15. If neutral proteinases and, particularly, plasmin, generated from plasminogen by plasminogen activator, have a key role in initiating the clinical signs and pathology of the demyelinating diseases, it might be expected that inhibitors of these enzymes would protect sensitized animals against EAE. Here we have shown that aminomethylcyclohexane carboxylic acid (AMCA), e-amino-caproic acid (EACA) and p-nitrophenylguanidinobenzoate (NPGB), which are inhibitors of plasminogen activator and other neutral proteinases, gave significant protection against the clinical expression of EAE in Lewis rats. Other protease inhibitors gave partial or no protection.