Wallis Robert S
PPD, Washington, DC, USA.
J Investig Dermatol Symp Proc. 2007 May;12(1):16-21. doi: 10.1038/sj.jidsymp.5650031.
Tumor necrosis factor (TNF) plays a pathogenic role in psoriasis and rheumatoid arthritis but is essential for host defenses against mycobacteria and other granulomatous pathogens. The risk of reactivation of latent Mycobacterium tuberculosis infection is significantly greater with the TNF monoclonal antibody infliximab than with the soluble TNF-receptor etanercept. We have examined the biologic basis of this difference using whole blood culture. Infliximab and adalimumab reduced the proportion of T buciclate-responsive cells by 70 and 50%, respectively, and suppressed antigen-induced IFN-gamma production by 70 and 64%. In contrast, etanercept produced no significant effect. The difference between infliximab and etanercept remained whether one compared equal or peak therapeutic drug concentrations, suggesting a relationship to mechanism of action rather than pharmacokinetics. Adalimumab and etanercept caused divergent, concentration dependent effects on control of intracellular growth of M. tuberculosis. None of the drugs induced significant levels of apoptosis or necrosis in monocytes or T cells, excluding T-cell death as a mechanism for suppression of antigen-induced responses. IL-10 production was equally suppressed by all three drugs, excluding excess IL-10 as a regulatory mechanism. The tuberculosis risk posed by infliximab may reflect its combined effects on TNF and IFNgamma.
肿瘤坏死因子(TNF)在银屑病和类风湿性关节炎中发挥致病作用,但对于宿主抵御分枝杆菌和其他肉芽肿病原体至关重要。与可溶性TNF受体依那西普相比,TNF单克隆抗体英夫利昔单抗使潜伏性结核分枝杆菌感染再激活的风险显著更高。我们使用全血培养研究了这种差异的生物学基础。英夫利昔单抗和阿达木单抗分别使对布西克拉特反应的T细胞比例降低了70%和50%,并使抗原诱导的IFN-γ产生分别抑制了70%和64%。相比之下,依那西普没有产生显著影响。无论比较的是相等还是峰值治疗药物浓度,英夫利昔单抗和依那西普之间的差异仍然存在,这表明与作用机制而非药代动力学有关。阿达木单抗和依那西普对结核分枝杆菌细胞内生长的控制产生了不同的浓度依赖性影响。这些药物均未在单核细胞或T细胞中诱导显著水平的凋亡或坏死,排除了T细胞死亡作为抑制抗原诱导反应的机制。所有三种药物对IL-10产生的抑制作用相同,排除了过量IL-10作为调节机制。英夫利昔单抗带来的结核病风险可能反映了其对TNF和IFNγ的综合作用。