T-helper type 1/T-helper type 2 balance in malignant pleural effusions compared to tuberculous pleural effusions

Study objectives: 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)-γ production in effusions to rule out the possibility of direct inhibition of T-cell polarization. Patients: Effusion samples were collected from 19 patients with malignant pleurisy caused by lung cancer and from 7 patients with tuberculous pleurisy. Measurements: Concentrations of pleural fluid IFN-γ, IL-12, and IL-4 were measured. IFN-γ 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-γ production and analyzed the expression of T-cell immunoglobulin mucin, mucin domain (Tim-3), a Th1-specific molecule in pleural fluid T-cells. Results: Although malignant pleural effusions showed low levels of Th1 and Th2 cytokines and ratios of IFN-γ and IL-12 to IL-4 were low, isolated T-cells produced a significant level of IFN-γ in the presence of IL-12 and IL-18. Soluble factors were not found to inhibit IFN-γ production in malignant pleural effusions. In tuberculous pleural effusion, ratios of IFN-γ and IL-12 to IL-4 were significantly higher, and T-cells showed the expression of Tim-3 messenger RNA. Conclusions: 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-γ activity through combination of IL-12 and IL-18, and that it will lead to new therapies for malignant effusion.