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 metalloproteinase s, BE-1101, on a delayed-type hypersensitivity (DTH) response in the C NS. We used a recently described model in which heat-killed bacillus C almette-Guerin (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 ti ssue damage including myelin loss. Treatment with BE-1101, which is no t only a potent inhibitor of matrix metalloproteinases but also strong ly 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 inflamma tory macrophages in DTH lesions than in comparable lesions from untrea ted animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals trea ted with dexamethasone was also reduced, but to a lesser degree. No si gnificant effect was seen after administration of pentoxifylline, a ph osphodiesterase inhibitor with effects: including the inhibition of TN F-alpha production. Our results suggest that inhibitors of matrix meta lloproteinases may be of considerable therapeutic benefit in neuroinfl ammatory diseases.