Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases.
We have studied the effect of an inhibitor of matrix metalloproleinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guérin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCG (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-alpha release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but to a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-alpha production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.
Matyszak
M K
MK
University Department of Pharmacology, University of Oxford, UK. matyszak@vax.ox.ac.uk
Perry
V H
VH
D000818:Animals; D001593:Benzyl Compounds; D001812:Blood-Brain Barrier; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D006624:Hippocampus / Q000201:enzymology / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000201:enzymology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009163:Mycobacterium bovis / Q000276:immunology; D010431:Pentoxifylline / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D008666:Metalloendopeptidases; D010431:Pentoxifylline