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), ε-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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kies, M. W. in Biology of Brain Dysfunction Vol. 2 (ed. Gaull, G. E.) 185–217 (Plenum, New York, 1973).
Paterson, P. Y. in Textbook of Immunopathology 2nd edn (eds Meischer, P. A. & Müller-Eberhard, H. J.) 179–213 (Grune & Stratton, New York, 1976); J. exp. Med. 111, 119–136 (1960).
Gonatas, N. K. & Howard, J. C. Science 186, 839–841 (1974).
Ortiz-Ortiz, L. & Weigle, W. O. J. exp. Med. 144, 606–616 (1976).
Raine, C. S. Prog. Neuropath. 3, 225–251 (1976).
Appel, S. H. & Bornstein, M. B. J. exp. Med. 119, 303–312 (1964).
Morariu, M. A. & Dalmasso, A. P. Ann. Neurol. 4, 427–430 (1978).
Hirsch, H. E. & Parks, M. E. J. Neurochem. 24, 835–838 (1975).
Smith, M. E., Sedgewick, L. M. & Tagg, J. S. J. Neurochem. 23, 965–971 (1974).
Buletza, G. F. & Smith, M. Biochem. J. 156, 627–629 (1976).
Smith, M. E. J. Neurochem. 27, 1077–1082 (1976); Neurochem. Res. 2, 233–246 (1977).
Rauch, H. C., Einstein, E. R. & Csejtey, J. Neurobiology 3, 195–205 (1973).
Govindavajan, K. R., Rauch, H. C., Clausen, J. & Einstein, E. R. J. neurol. Sci. 23, 295–306 (1974).
Marks, N., Grynbaum, A. & Levine, S. Brain Res. 123, 147–157 (1977).
Cammer, W., Bloom, B. R., Norton, W. T. & Gordon, S. Proc. natn. Acad. Sci. U.S.A. 75, 1554–1558 (1978); in Myelination and Demyelination (ed. Palo, J.) 365–381 (Plenum, NewYork, 1978).
Stoner, G. L., Brosnan, C. F., Wisniewski, H. M. & Bloom, B. R. J. Immun. 118, 2094–2102 (1977).
Umezawa, H. & Aoyagi, T. in Proteinases in Mammalian Cells and Tissues (ed. Barrett, A. J.) 637–662 (North-Holland, New York, 1977).
Wingender, W. in Bayer Symp. V (eds Fritz, H., Tschesche, H., Greene, L. J. & Truscheit, E.) 548–559 (Springer, New York, 1974).
Ambrus, C. M., Ambrus, J. L., Lassman, H. B. & Mink, I. B. Ann. N. Y. Acad. Sci. 146, 430–437 (1968).
Shaw, E. in Bayer Symp. V (eds Fritz, H., Tschesche, H., Greene, L.J. & Truscheit, E.) 531–540 (Springer, New York, 1974).
Schnyder, J. & Baggiolini, J. J. exp. Med. 148, 435–450 (1978).
Ambrus, J.L. et al. in Chemical Control of Fibrinolysis-Thrombolysis (ed. Schor, J. M.) 153–200 (Wiley-Interscience, New York, 1970).
Thompson, R. A. & Felix-Davies, D. D. Br. med. J. ii, 608 (1978).
Tant, D. Br. med. J. i, 266 (1979).
Maurice-Williams, R. S. Br. med. J. i, 945–947 (1978).
Tovi, D. Acta neurol. scand. 49, 163–175 (1973).
Tovi, D., Nilsson, I. M. & Thulin, C.-A. Acta neurol. scand. 48, 393–402 (1972).
Spragg, J. J. Immun. 120, 592–596 (1978).
Agostoni, A. et al. Allergy 33, 216–221 (1978).
Wüthrich, R., Rieder, H. P. & Ritzel, G. Experientia 19, 421–422 (1978).
Sibley, W. A., Kiernat, J. & Laguna, J. F. Neurology 28, 102–105 (1978).
Boehme, D. H., Umezawa, H., Hashim, G. & Marks, N. Neurochem. Res. 3, 185–194 (1978).
Smith, M. E. in The Suppression of Multiple Sclerosis & Experimental Allergic Encephatomyelitis (eds Davison, A. N. & Cuzner, M. L.) (Academic, New York, in the press).
Dano, K. & Reich, E. Cold Spring Harbor Conf. on Cell Proliferation 2, 357–66 (1975).
McFarlin, D. E., Blank, S. E. & Kibler, R. F. J. Immun. 113, 712–15 (1974).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brosnan, C., Cammer, W., Norton, W. et al. Proteinase inhibitors suppress the development of experimental allergic encephalomyelitis. Nature 285, 235–237 (1980). https://doi.org/10.1038/285235a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/285235a0
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.