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(Chest. 2005;128:4030-4035.)
© 2005 American College of Chest Physicians

T-Helper Type 1/T-Helper Type 2 Balance in Malignant Pleural Effusions Compared to Tuberculous Pleural Effusions*

Masakazu Okamoto, MD; Yoshinori Hasegawa, MD, FCCP; Toru Hara, MD; Naozumi Hashimoto, MD; Kazuyoshi Imaizumi, MD; Kaoru Shimokata, MD, FCCP and Tsutomu Kawabe, MD

* From the Division of Respiratory Medicine (Drs. Okamoto, Hasegawa, Hara, Hashimoto, Imaizumi, and Shimokata), Department of Medicine, Nagoya University Graduate School of Medicine; and the Department of Medical Technology (Dr. Kawabe), Nagoya University Graduate School of Health Science, Nagoya, Japan.

Correspondence to: Tsutomu Kawabe, MD, Department of Medical Technology, Nagoya University Graduate School of Health Science, 1-1-20 Daikou-minami, Higashi-ku, Nagoya 461-8673, Japan; e-mail: kawabet{at}med.nagoya-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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)-{gamma} 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-{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.

Results: 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.

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-{gamma} activity through combination of IL-12 and IL-18, and that it will lead to new therapies for malignant effusion.

Key Words: malignant pleural effusion • T-cell immunoglobulin domain, mucin domain • T-helper type 1 • T-helper type 2 • tuberculous pleural effusion


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
When exudative pleural effusions accumulate in the pleural space, various cells produce many kinds of cytokines or chemokines that contribute to the progress of pleuritis.1234 On encountering an antigen, naïve CD4+ T-helper precursor cells enact a specific process that results in differentiation toward the T-helper type 1(Th1) or T-helper type 2 (Th2) lineage. Th1 cells produce interleukin (IL)-2 and interferon (IFN)-{gamma}, whereas Th2 cells produce IL-4, IL-5, and IL-10.5 Both malignant and tuberculous pleural effusions are typical lymphocytic pleural effusions.6 Several studies reported that tuberculous pleuritis is a Th1-dominant disease2 and malignant pleuritis a Th2-dominant disease.7

Tuberculosis is a granulomatous disorder, and the cellular immune response plays an important role in the defense mechanism. CD4+ T-cells in tuberculous pleural effusions are Th1 dominant and are activated enough to produce Th1 cytokines.8 We have recently reported that the concentrations of IFN-{gamma}-inducing cytokines (ie, IL-12 and IL-18), IFN-{gamma}, and IFN-{gamma}-inducible chemokines (ie, interferon-{gamma}-inducible protein of 10 kd, monokine induced by IFN-{gamma}, and IFN-inducible T-cell {alpha} chemoattractant) are all higher in tuberculous pleural effusions than in malignant pleural effusions.9 IL-12 is known to induce a Th1 response in undifferentiated CD4+ cells, and this supports Th1 dominance at the morbid site of tuberculosis.10 In Mycobacterium tuberculosis infections, IL-18 is also produced by activated macrophages and induces IFN-{gamma} in synergy with IL-12.

The Th1/Th2 cytokine balance, however, in malignant pleural effusions may influence pathophysiologic process of pleural disease. Local immune reactions in malignant pleural effusions have been reported to favor the Th2 pathway, which suppresses antitumor immunity by cytokines such as IL-10. The development of pleural effusions is associated with the presence of an increased number of immune cells in the pleural space.1112 CD4+ T-cells present in malignant pleural effusions are reported as Th2 dominant.13

It is important to analyze the regulation of cytokine production from the pleural cells and the subsequent recruitment of immune cells to the pleural space. Whether or not T-cells isolated from pleural effusion are clearly polarized toward Th1 or Th2 is not clear in malignant pleural effusions.

To evaluate the Th1/Th2 balance in malignant pleural effusion, we examined the concentration of cytokines in the pleural effusion associated with lung cancer and compared them with those in tuberculous pleurisy. We further investigated the function of isolated T-cells from pleural effusions and studied whether there were soluble factors that inhibit the production of IFN-{gamma} in malignant pleural effusions. Finally, we studied the expression of T-cell immunoglobulin domain, mucin domain (Tim-3) messenger RNA that recently has been identified as one of the Th1-specific surface molecules using reverse transcriptase-polymerase chain reaction (RT-PCR).14


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Subjects with lymphocytic exudative pleural effusions were enrolled from December 2001 to May 2003. Pleural effusions were defined as exudative using Light’s criteria.15 We collected effusion samples from 7 patients with tuberculous pleurisy and 19 patients with malignant pleurisy caused by lung cancer.

The diagnosis of tuberculous pleural effusion was made on the basis of the presence of any of the following criteria: isolation of M tuberculosis from the pleural fluid or tissue, detection of caseating granulomas in the pleural tissue, a smear positive for acid-fast bacilli (AFB) from the pleural fluid or tissue, and detection of mycobacterial-specific DNA by polymerase chain reaction (PCR) from the pleural samples. Malignant pleurisy caused by lung cancer was diagnosed on the basis of the finding of malignant cells during cytologic examination of the pleural fluid. We conducted the study in accordance with the guidelines of the Declaration of Helsinki and with the approval of our local ethics committee. Informed consent for cytokine measurements and cellular analysis was obtained from all patients.

Enzyme-Linked Immunosorbent Assay
Pleural effusions were obtained by sterile thoracentesis and heparinized. After centrifugation at 378g for 5 min at 4°C, cell-free supernatant was aliquoted and preserved at – 80°C until the measurement of cytokine concentrations. To avoid repeated freeze/thaw cycles, we thawed the aliquoted samples from each group just once and then tested them. IFN-{gamma}, IL-12, and IL-4 were measured with the use of enzyme-linked immunosorbent assays (Human Interferon-{gamma} Set and Human IL-12 [p40] Set; BD Pharmingen; San Diego, CA; and Human IL-4 ELISA Ready-SET-Go!; eBioscience; San Diego, CA, respectively), in accordance with the instructions of the manufacturer.

Pleural Cells and Cell Line
Pleural cells were maintained in RPMI 1640 medium supplemented with 2 mmol/L L-glutamine, 100 U/mL penicillin, 100 µg/mL streptomycin, 0.25 µg/mL amphotericin B, and 10% fetal calf serum, designated as complete RPMI (CRPMI) medium, at 37°C in a humidified atmosphere containing 5% CO2. T-cells were enriched using a nylon wool column (Wako; Osaka, Japan) from pleural effusion as described previously.16 The suspension after adherence to a nylon wool column contained > 85% T-cells in malignant and tuberculous pleural effusions confirmed by FACSCalibur flow cytometer with CellQuest software (Becton Dickinson; Mountain View, CA). The human myelomonocytic KG-1 cells were purchased from American Type Culture Collection (Manassas, VA) and were cultured in CRPMI medium.

IFN-{gamma} Production from KG-1
KG-1 (3 x 105/well) were resuspended in triplicate into 96-well plates in CRPMI medium, and added with the same volume of cell-free fluid separated from malignant pleural effusion, containing various concentrations of recombinant human IL-18 (0 to 80 ng/mL) for 24 h in a humidified atmosphere containing 5% carbon dioxide. Culture supernatants were collected and stored at – 80°C until measurement of IFN-{gamma} concentrations.

Stimulation of T-Cells with IL-12 and/or IL-18
The enriched T-cells (5 x 105/well) were incubated in triplicate in CRPMI medium alone, stimulated with recombinant human IL-12 (40 ng/mL), recombinant human IL-18 (20 ng/mL), or both recombinant human IL-12 (40 ng/mL) and IL-18 (20 ng/mL) in 96-well plates for 24 h in a humidified atmosphere containing 5% carbon dioxide. Supernatants were collected and stored at – 80°C until measurement of IFN-{gamma} concentrations.

RT-PCR
Total RNA was extracted using ISOGEN (Nippon Gene; Toyama, Japan) from enriched T-cells of malignant and tuberculous pleurisy. Five micrograms of total RNA were amplified by RT-PCR under the following conditions: 94°C, 30 s; 62°C, 30 s; and 72°C, 45 s, for 35 cycles. The primer set specific for Tim-3 (sense; 5'-ACAGAGCGGAGGTCGGTCAGAATG-3', antisense; 5'- AGCCAGAGCCAGCCCAGCACAGAT-3') was used to amplify human Tim-3 messenger RNA. The ß-actin messenger RNA expression was analyzed using the following primers: sense; 5'-CAAGAGATGGCCACGGCTGCT-3', antisense; 5'-TCCTTCTGCATCCTGTCGGCA-3'. The PCR reaction contained PCR buffer, 5 mmol/L MgCl2, 1 mmol/L deoxynucleoside triphosphate, 0.8 U/L of ribonuclease inhibitor, 0.1 U/µL AMV-RTase XL, 0.1 U/µL AMV-Optimized Taq, and 0.4 µmol/L of each primer (TaKaRa Biochemicals; Tokyo, Japan). The PCR products of Tim-3 and ß-actin are fragments 571 base-pair and 275 base-pair in length, respectively. Amplified products were electrophoresed in a 2% agarose gel and visualized by ethidium bromide staining.

Statistical Analysis
The results were analyzed by Mann-Whitney U test for comparison between the two groups and by nonparametric equivalents of analysis of variance for multiple comparisons. The Fisher exact test was used to compare categorical variables as appropriate. Data are expressed as median and range or mean ± SD and were considered statistically significant at p < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
Characteristics of patients and pleural effusions studied are summarized in Table 1 . Pleural fluid protein and adenosine deaminase concentrations and the ratio of pleural lymphocytes to neutrophils were lower in malignant pleural effusions than those in tuberculous pleural effusions. However, we could not find significant differences with regard to pleural fluid lactate dehydrogenase (LDH), serum protein, and serum LDH concentrations between the two groups.


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  		Table 1.. Characteristics of Patients and Pleural Effusions*

 
Caseating granulomas or AFB were detected in pleural biopsy specimens from seven patients with tuberculous pleurisy. Pleural fluid culture results for AFB were positive in one patient. Among the patients with malignancies, 14 had adenocarcinoma and 5 had squamous cell carcinoma.

Cytokine Concentrations in Pleural Fluid
Concentrations of IFN-{gamma} and IL-12 in pleural fluids were significantly lower in the malignant group (IFN-{gamma}: median, 45.8 pg/mL [0 to 715.4 pg/mL]; IL-12: median, 415.3 pg/mL [0 to 1,758.2 pg/mL]) than those in the tuberculous group (IFN-{gamma}: median, 1,064.7 pg/mL [72.8 to 5,823.0 pg/mL]; IL-12: median, 1,455.4 pg/mL [421.2 to 2,167.7 pg/mL]). The IL-4 concentration was not different between the two groups (malignant, 4.3 pg/mL [0 to 146.5 pg/mL]; vs tuberculosis, 2.4 pg/mL [0 to 175.8 pg/mL]). The ratios of IFN-{gamma} or IL-12 to Th2 cytokine have been used as an indicator of the type of T-helper pathway.17 The Th1 pathway was favored when the ratio was relatively high, while the Th2 pathway was favored when it was relatively low. The ratios of IFN-{gamma} and IL-12 to IL-4 were significantly lower in malignant pleural effusions (IFN-{gamma}/IL-4: median, 1.4 [0 to 190.6]; IL-12/IL-4: median, 27.4 [0 to 346.0]) than in tuberculous pleural effusions (IFN-{gamma}/IL-4: median, 53.6 [2.2 to 445.1]; IL-12/IL-4: median, 93.5 [8.3 to 637.9]; p = 0.037 and p = 0.044, respectively) [Fig 1 ]. These results showed that malignant pleural effusions were not Th1-dominant but Th2-dominant disease, and tuberculous pleural effusions clearly favor the Th1 pathway.



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  		Figure 1.. Box plot for the ratios of IFN-{gamma} to IL-4 and those of IL-12 to IL-4 in malignant and tuberculous pleural effusions on the basis of measurement by enzyme-linked immunosorbent assay. Bold lines indicate medians; box plots indicate 25th to 75th percentiles. A bar indicates from the lower quartile to the minimum point, and another bar indicates from the upper quartile to the maximum point.

 
IFN-{gamma} Production by Isolated T-Cells Incubated with IL-12 and/or IL-18
We cultured T-cells enriched from malignant pleural effusions with IL-12 and/or IL-18 to examine the polarity of T-cells toward Th1 or Th2. Neither IL-12 alone nor IL-18 alone were found to have remarkable effects on T-cells in terms of IFN-{gamma} production. However, T-cells produced a significant amount of IFN-{gamma} when cultured with a combination of IL-12 (p < 0.05) and IL-18 (p < 0.05) [Fig 2 ]. These results showed that T-cells in malignant pleural effusions had enough reactivity against Th1-inducing cytokine, and these T-cells seemed to be naïve or polarized to Th1 cells.



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  		Figure 2.. IFN-{gamma} production by T-lymphocytes isolated from malignant pleural effusions. T-lymphocytes were isolated from pleural effusions and cultured with IL-12 alone, IL-18 alone, IL-12 and IL-18, or CRPMI medium alone for 24 h.

 
Evaluation of Inhibitory Activity of Malignant Pleural Effusions in IFN-{gamma} Production
The levels of IFN-{gamma} concentration within malignant pleural effusions were generally low, although T-cells from malignant pleural effusions could produce IFN-{gamma} in vitro. To examine the poor production mechanisms of IFN-{gamma} in malignant pleural effusions, we checked the inhibitory activity against IFN-{gamma} production, especially induced by IL-18 stimulation. For this purpose, we used KG-1 cells, a human myelomonocytic cell line that has been reported to produce IFN-{gamma} in response to IL-18 stimulation.18 As shown in Figure 3 , IFN-{gamma} production was not different under each recombinant human IL-18 concentration between the addition of malignant pleural effusions and medium alone. These results showed that the mechanism of lower IFN-{gamma} production in malignant pleuritis was not due to soluble factors that inhibit production of IL-18-inducing IFN-{gamma} by KG-1 cells within malignant pleural effusions.



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  		Figure 3.. IFN-{gamma} production by KG-1 cells mediated by various concentrations of IL-18 with or without malignant pleural effusions.

 
Analysis of Tim-3 Expression by RT-PCR
As shown in Figure 4 , T-cells isolated from tuberculous pleural effusions (samples 1 to 4) expressed detectable levels of Tim-3 messenger RNA. However, it was not detected in samples 5 to 8, which were extracted from malignant pleural effusions. These results showed that T-cells from malignant pleural effusions were not characteristic of Th1.



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  		Figure 4.. Expression of Tim-3 messenger RNA in T-cells of tuberculous and malignant pleural effusions. Lanes 1 to 4: tuberculosis; lanes 5 to 8: malignant.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we confirmed that cytokine status and T-cell reactivity within the tuberculous pleural effusions were polarized strongly toward a Th1 response. Although Tim-3 expression was not detected in T-cells in the malignant pleural effusions, they could produce a significant amount of IFN-{gamma} with a combination of IL-12 and IL-18 in vitro. Furthermore, we could not detect the inhibitory effects of malignant pleural effusions against IL-18-inducing IFN-{gamma} production. Based on these observations, we thought that T-cells in the malignant pleural effusions are mainly naïve or not definitely polarized to Th1, and that a malignant tumor does not actively distort the cytokine condition through production of soluble inhibitors within effusions.

Among host defense mechanisms within tuberculous pleural effusions, the major responsive cells are CD4+ T-cells19 capable of producing high concentrations of IFN-{gamma} after in vitro stimulation with a purified protein derivative.2021 In the case of malignancy, pleural effusions caused by lung cancer occur secondary to direct pleural involvement and/or metastases with an accumulation of lymphocytes,1112 especially helper T-cells. Many in vitro and in vivo studies have reported that the production of IFN-{gamma} induced by Th1 cells plays an important role in host antitumor immunity.22 However, an earlier study23 pointed out that malignant pleuritis is a Th2-dominant disease and that cellular immunity has been lacking in malignant pleural effusions. IFN-{gamma} and other Th1 cytokines are typically lower in advanced cancer patients, while IL-4 can be higher or unchanged.24 Nodules of non-small cell lung cancer freshly removed from patients expressed a marked imbalance toward Th2.25 With both IL-4 and IL-10, which have been proven as inhibitors of Th1 and promoters of Th2 activity, the recognized capability of cancerous tissue to suppress immunity is readily rationalized.25 In the present investigation, we studied several cytokines; however, the concentrations of IL-4 in each disease were not different, although the IFN-{gamma} and IL-12 levels in tuberculous pleural effusions were significantly higher than those of malignant pleural effusions, which were consistent with previous data.13810 T-cells within the malignant pleural effusions were not found to develop a polarized Th2 immune response.

Although we could not show the cytokine milieu of malignant pleural effusions as Th2 dominant, Th1 cytokines were also few or undetectable. Our results, however, suggest that T-cells in malignant pleural effusions had sufficient ability to shift to the Th1 type, as shown by increase of IFN-{gamma} production in stimulation with IL-12 and IL-18. Moreover, T-cells in malignant pleural effusions are not terminally differentiated cells as reported previously.7 IL-12 has been reported not only to induce up-regulation of the IL-18 receptor on T-cells but also to heighten their responsiveness to IL-18 and to enhance IFN-{gamma} production in a Th1 response.26 To examine whether or not inhibitory activity of malignant pleural effusions on IFN-{gamma} production is present, we tried to detect soluble factors such as IL-18 binding protein. IL-18 binding protein2728 is a circulating high-affinity decoy receptor for IL-182930 and works as a naturally occurring specific and secreted inhibitor of IL-18 bioactivity. For purpose of analyzing the inhibitor of IL-18, we used KG-1 cells and examined IFN-{gamma} production by IL-18 stimulation.18 Addition of malignant pleural effusions did not inhibit IL-18-inducing IFN-{gamma} production by KG-1 cells, thus indicating that the mechanism of lower IFN-{gamma} production in malignant pleuritis was not due to soluble inhibitors within effusions. Furthermore, Chen et al7 have reported that the cytolytic activity of lymphocytes in malignant effusions and peripheral blood lymphocytes was different in an ex vivo experiment after 6-day culture with cytokine treatment. In the present study, our results indicated no soluble factors for IL-18-inducing IFN-{gamma} production by KG-1 cells, and these results support the same authors’ conclusions that lymphocytes in malignant effusions themselves were different from peripheral blood lymphocytes in their ability to kill tumor cells, even though lymphocytes in malignant effusions have enough property to polarize to Th1.

A Th1-specific cell surface molecule called Tim-3 has recently been identified.14 Although Th1 and Th2 cells are characterized originally by their cytokine profiles, the cell surface protein Tim-3 is useful for the differentiation between Th1 and Th2 cells. Tim-3 is a type I membrane protein of 281 amino acids whose extracellular domain consists of an IgV-like domain followed by a mucin-like region. Although all tuberculous pleural fluid T-cells expressed detectable levels of Tim-3 messenger RNA, those cells in malignant pleural effusions did not express Tim-3.

In summary, we conclude that pleural fluid T-cells in tuberculous pleurisy are strongly polarized toward Th1. However, T-cells in the malignant pleural effusions are naïve or not definitely polarized to Th1 and a malignant tumor does not actively distort the cytokine condition through production of soluble inhibitors within effusions. This study will lead to new therapeutic strategies for promoting antitumor immunotherapy using Th1 cells induced from T-cells primed by autologous tumor cells in malignant pleural effusions by combination of IL-12 and IL-18 in an ex vivo stimulation.


   Acknowledgements
 
We thank those who provided pleural effusions, as well as Ms. Keiko Shimamoto and Ms. Ayako Asai for technical assistance.


   Footnotes
 
Abbreviations: AFB = acid-fast bacilli; CRPMI = complete RPMI; IFN = interferon; IL = interleukin; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase-polymerase chain reaction; Th1 = T-helper type 1; Th2 = T-helper type 2; Tim-3 = T-cell immunoglobulin mucin, mucin domain

Received for publication March 25, 2005. Accepted for publication September 26, 2005.


   References
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 Abstract
 Introduction
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 References
 

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