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

Abstract

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‐α 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 This situation corrected itself after the drug was withdrawn at 28 days.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‐1α. 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.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady

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