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
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
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DOI：
10.1046/j.1365-2613.2000.00152.x
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发表时间：
2000-06-01
影响因子：
3
通讯作者：
Rook, G
中科院分区：
文献类型：
--
作者：
Hernandez-Pando, R;Orozco, H;Rook, G
BB-94（巴马司他）是一种广谱的基于异羟肟酸的锌金属蛋白酶抑制剂，其抑制基质金属蛋白酶（MMP）和酶的ADAM家族的成员，例如肿瘤坏死因子-α裂解酶（TACE）。这些酶参与结核病炎症过程的调节。Balb/c小鼠感染M.从感染当天开始，用BB-94治疗通过肠内途径感染的结核病患者1个月。细胞因子的免疫组织化学、半定量RT-PCR和ELISA测定显示，在BB-94处理的动物中，IL-1和IL-2表达的缺陷和对IL-4表达的过早偏向，伴随着肉芽肿形成的延迟和疾病进展的更快。这种情况在28天停药后自行纠正。相反，当BB-94仅在1个月后给药时，除了淀粉样蛋白的存在和IL-1 α表达的矛盾增加外，没有显著变化。这些结果揭示了结核病的免疫机制，也表明在用类似的广谱MMP抑制剂治疗的患者中，可能存在某些免疫应答向2型细胞因子谱不适当偏离的风险。
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 This situation corrected itself after the drug was withdrawn at 28 days.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-1 alpha. 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.