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 metallop roteinase inhibitor that inhibits both the matrix metalloproteinases (MMP) and members of the ADAM family of enzymes such as Tumour Necrosis Factor-al pha Cleaving Enzyme (TACE). These enzymes are involved in the regulation of inflammatory processes in tuberculosis. Balb/c mice infected with M. tuber culosis via the intratracheal route were treated with BB-94 for 1 month, st arting on the day of infection. Immunohistochemistry, semiquantitative RT-P CR and ELISA assays for cytokines revealed a deficit in IL-1 and IL-2 expre ssion and a premature bias towards IL-4 expression, accompanied by a delay in granuloma formation and more rapid progression of disease in BB-94-treat ed 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 This situation corrected itself after the drug was withdrawn at 28 days.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 para doxically increased expression of IL-1 alpha. These results cast light on m echanisms of immunity in tuberculosis and also indicate that in patients tr eated with similar broad-spectrum MMP inhibitors there may be a risk of ina ppropriate deviation of some immune responses towards a Type-2 cytokine pro file.