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

Int J Exp Pathol. 2000 Jun;81(3):199-209. doi: 10.1046/j.1365-2613.2000.00152.x.


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 This situation corrected itself after the drug was withdrawn at 28 days.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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cytokines / drug effects*
  • Cytokines / metabolism
  • Drug Administration Schedule
  • Hypersensitivity, Delayed / immunology
  • Hypersensitivity, Delayed / prevention & control
  • Interleukins / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Protease Inhibitors / pharmacology*
  • Survival Rate
  • Thiophenes / pharmacology*
  • Tuberculosis, Pulmonary / immunology*
  • Tuberculosis, Pulmonary / pathology
  • Zinc / physiology


  • Antineoplastic Agents
  • Cytokines
  • Interleukins
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Thiophenes
  • Phenylalanine
  • batimastat
  • Zinc