Okamoto Masakazu, Hasegawa Yoshinori, Hara Toru, Hashimoto Naozumi, Imaizumi Kazuyoshi, Shimokata Kaoru, Kawabe Tsutomu
Division of Respiratory Medicine, Nagoya University Graduate School of Health Science, 1-1-20 Daikou-minami, Higashi-ku, Nagoya 461-8673, Japan.
Chest. 2005 Dec;128(6):4030-5. doi: 10.1378/chest.128.6.4030.
Malignant and tuberculous pleurisies are two major causes of lymphocyte-dominant pleurisy. Several studies have already reported that tuberculous pleurisy is a T-helper type 1(Th1)-dominant disease. In this study, we sought to examine the Th1/T-helper type 2 (Th2) balance, especially focusing on the polarizing status of T-cells to Th1/Th2 in malignant pleural effusions by measuring cytokines in pleural effusions and by evaluating the polarizing status of T-cells on the point of stimulation with interleukin (IL)-12 and/or IL-18. Furthermore, we evaluated inhibitors of interferon (IFN)-gamma production in effusions to rule out the possibility of direct inhibition of T-cell polarization.
Effusion samples were collected from 19 patients with malignant pleurisy caused by lung cancer and from 7 patients with tuberculous pleurisy.
Concentrations of pleural fluid IFN-gamma, IL-12, and IL-4 were measured. IFN-gamma production of T-cells enriched from malignant pleural effusions in the presence of IL-12 and/or IL-18 was also examined. We further compared the inhibitory activity of malignant pleural effusions against IFN-gamma production and analyzed the expression of T-cell immunoglobulin mucin, mucin domain (Tim-3), a Th1-specific molecule in pleural fluid T-cells.
Although malignant pleural effusions showed low levels of Th1 and Th2 cytokines and ratios of IFN-gamma and IL-12 to IL-4 were low, isolated T-cells produced a significant level of IFN-gamma in the presence of IL-12 and IL-18. Soluble factors were not found to inhibit IFN-gamma production in malignant pleural effusions. In tuberculous pleural effusion, ratios of IFN-gamma and IL-12 to IL-4 were significantly higher, and T-cells showed the expression of Tim-3 messenger RNA.
We confirmed that T-cells in the malignant pleural effusions are mainly naïve or not definitely polarized to Th1. Moreover, malignant tumor does not actively distort the cytokine condition through production of soluble inhibitors within effusions. The present study indicates that antitumor immunity may be enhanced by restored IFN-gamma activity through combination of IL-12 and IL-18, and that it will lead to new therapies for malignant effusion.
恶性胸膜炎和结核性胸膜炎是淋巴细胞为主型胸膜炎的两个主要病因。已有多项研究报道结核性胸膜炎是以1型辅助性T细胞（Th1）为主导的疾病。在本研究中，我们试图通过检测胸腔积液中的细胞因子，并评估T细胞在白细胞介素（IL）-12和/或IL-18刺激下向Th1/Th2的极化状态，来研究Th1/2型辅助性T细胞（Th2）平衡，尤其关注恶性胸腔积液中T细胞向Th1/Th2的极化状态。此外，我们评估了胸腔积液中干扰素（IFN）-γ产生的抑制剂，以排除直接抑制T细胞极化的可能性。
收集了19例肺癌所致恶性胸膜炎患者和7例结核性胸膜炎患者的胸腔积液样本。
检测胸腔积液中IFN-γ、IL-12和IL-4的浓度。还检测了在IL-12和/或IL-18存在下，从恶性胸腔积液中富集的T细胞产生IFN-γ的情况。我们进一步比较了恶性胸腔积液对IFN-γ产生的抑制活性，并分析了胸腔积液T细胞中Th1特异性分子T细胞免疫球蛋白粘蛋白、粘蛋白结构域（Tim-3）的表达。
尽管恶性胸腔积液中Th1和Th2细胞因子水平较低，IFN-γ和IL-12与IL-4的比值也较低，但分离出的T细胞在IL-12和IL-18存在下产生了显著水平的IFN-γ。未发现可溶性因子抑制恶性胸腔积液中IFN-γ的产生。在结核性胸腔积液中，IFN-γ和IL-12与IL-4的比值显著更高，且T细胞显示出Tim-3信使核糖核酸的表达。
我们证实恶性胸腔积液中的T细胞主要是未成熟的，或者没有明确向Th1极化。此外，恶性肿瘤不会通过在胸腔积液中产生可溶性抑制剂来积极改变细胞因子状态。本研究表明，通过IL-12和IL-18联合恢复IFN-γ活性可能增强抗肿瘤免疫力，并将带来针对恶性胸腔积液的新疗法。
