Treatment with BB-94, a broad spectrum inhibitor of zinc-dependent metalloproteinases, causes deviation of the cytokine profile towards type-2 in experimental pulmonary tuberculosis in Balb/c mice.
BB-94 (batimastat) is a broad- spectrum hydroxamic acid-based zinc metalloproteinase inhibitor that inhibits both the matrix metalloproteinases (MMP) and members of the ADAM family of enzymes such as Tumour Necrosis Factor-alpha Cleaving Enzyme (TACE). These enzymes are involved in the regulation of inflammatory processes in tuberculosis. Balb/c mice infected with M. tuberculosis via the intratracheal route were treated with BB-94 for 1 month, starting on the day of infection. Immunohistochemistry, semiquantitative RT-PCR and ELISA assays for cytokines revealed a deficit in IL-1 and IL-2 expression and a premature bias towards IL-4 expression, accompanied by a delay in granuloma formation and more rapid progression of disease in BB-94-treated animals. This situation corrected itself after the drug was withdrawn at 28 days. In contrast, when BB-94 was administered only after 1 month there were no significant changes apart from the presence of amyloid, and a paradoxically increased expression of IL-1alpha. These results cast light on mechanisms of immunity in tuberculosis and also indicate that in patients treated with similar broad-spectrum MMP inhibitors there may be a risk of inappropriate deviation of some immune responses towards a Type-2 cytokine profile.
Hernandez-Pando
R
R
Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutricion 'Salvador Zubiran', Mexico City, Mexico.
Orozco
H
H
Arriaga
K
K
Pavön
L
L
Rook
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004334:Drug Administration Schedule; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007378:Interleukins / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D015996:Survival Rate; D013876:Thiophenes / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology; D015032:Zinc / Q000502:physiology
D000970:Antineoplastic Agents; D016207:Cytokines; D007378:Interleukins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D015032:Zinc