McDyer J F, Hackley M N, Walsh T E, Cook J L, Seder R A
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
J Immunol. 1997 Jan 1;158(1):492-500.
Multidrug-resistant tuberculosis (MDRTB) has emerged as a challenging clinical problem in both HIV-infected and -uninfected individuals. In this study, immune responses from HIV-negative patients with MDRTB were compared with those of healthy purified protein derivative (PPD)-positive and PPD-negative individuals. These responses were characterized by measuring the proliferation and cytokine production from PBMCs stimulated in vitro with Mycobacterium tuberculosis, PPD, or mitogens. MDRTB patients with CD4 counts >500/microl stimulated in vitro with M. tuberculosis had similar immune responses (proliferation, IFN-gamma, and IL-2 production) as the PPD-positive and -negative controls. By contrast, MDRTB patients with CD4 counts <500/microl had markedly deficient immune responses to similar stimuli. In these patients, IFN-gamma production could be restored by adding IL-12 to the in vitro cultures. IL-12 also caused a striking increase in the amount of IFN-gamma produced from PBMCs of both PPD-positive and -negative controls. The role of endogenous IL-12 production was also studied. Addition of anti-IL-12 to cultures resulted in a two- to eightfold decrease in IFN-gamma production in response to PHA stimulation. Inhibition of IFN-gamma was also observed when cells were stimulated by M. tuberculosis and PPD. Using Staphylococcus aureus Cowan strain as a mitogenic stimulus, IL-12 p70 was produced in similar amounts in all groups tested. TNF-alpha production was also assessed from cells stimulated by M. tuberculosis. Addition of IL-12 to the cultures did not cause a significant enhancement of TNF-alpha production. Last, production of IL-10 and IL-4 in response to M. tuberculosis and PHA, respectively, was not significantly different among all groups tested. These results suggest that patients with MDRTB tuberculosis with CD4 T cell counts <500/microl have impaired IFN-gamma and IL-2 responses and might benefit by adjunctive IL-12 therapy.
耐多药结核病（MDRTB）已成为HIV感染和未感染个体中一个具有挑战性的临床问题。在本研究中，将耐多药结核病HIV阴性患者的免疫反应与健康的纯化蛋白衍生物（PPD）阳性和PPD阴性个体的免疫反应进行了比较。通过测量体外受结核分枝杆菌、PPD或丝裂原刺激的外周血单核细胞（PBMC）的增殖和细胞因子产生来表征这些反应。CD4计数>500/微升的耐多药结核病患者在体外受结核分枝杆菌刺激时，其免疫反应（增殖、IFN-γ和IL-2产生）与PPD阳性和阴性对照相似。相比之下，CD4计数<500/微升的耐多药结核病患者对类似刺激的免疫反应明显不足。在这些患者中，通过在体外培养物中添加IL-12可恢复IFN-γ的产生。IL-12还使PPD阳性和阴性对照的PBMC产生的IFN-γ量显著增加。还研究了内源性IL-12产生的作用。向培养物中添加抗IL-12导致对PHA刺激的IFN-γ产生减少2至8倍。当细胞受结核分枝杆菌和PPD刺激时，也观察到IFN-γ的抑制。使用金黄色葡萄球菌考恩菌株作为促有丝分裂刺激物，在所有测试组中产生的IL-12 p70量相似。还评估了受结核分枝杆菌刺激的细胞产生的TNF-α。向培养物中添加IL-12并未导致TNF-α产生的显著增强。最后，在所有测试组中，分别对结核分枝杆菌和PHA反应产生的IL-10和IL-4没有显著差异。这些结果表明，CD4 T细胞计数<500/微升的耐多药结核病患者的IFN-γ和IL-2反应受损，辅助IL-12治疗可能有益。
