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Thymus- and activation-regulated chemokine (TARC/CCL17) is a lymphocyte-directed CC chemokine, which plays a role in the recruitment of CC chemokine receptor-4 positive T helper 2 (Th2) cells. In this study, we measured concentrations of TARC and Th2 cell-derived cytokines in bronchoalveolar lavage (BAL) fluid, as well as TARC concentrations in serum from patients with eosinophilic pneumonia and other interstitial lung diseases. TARC was significantly elevated in BAL fluids from patients with eosinophilic pneumonia (median, 240 pg/ml), whereas TARC was undetectable (< 7 pg/ml) in most cases of hypersensitivity pneumonitis, sarcoidosis, and idiopathic pulmonary fibrosis, as well as in healthy control subjects. Also, when present, quantities were less than 20 pg/ml. Elevated concentrations of interleukin (IL)-4, IL-5, and IL-13 were also detected in BAL fluid from patients with eosinophilic pneumonia. Interestingly, TARC concentrations in BAL fluids were closely correlated with the concentrations of IL-5 and IL-13. A serial examination showed that elevated TARC in BAL fluid rapidly fell to below detectable limits preceding decreases in IL-5 concentration and eosinophil percentage. Our results, in concordance with previous studies, demonstrate the potential activity of TARC for recruiting Th2 cells to the lungs and suggest a significant role for TARC in the pathogenesis of eosinophilic pneumonia.
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Keywords: thymus- and activation-regulated chemokine; T helper 2 cell; interleukin-5; bronchoalveolar lavage fluid; eosinophilic pneumonia
Eosinophilic pneumonia represents a category of disorders defined by the prominent presence of eosinophils (1-3). Eosinophilic pneumonia can be caused by fungal and helminth infections as well as various drug reactions (1, 4). When these specific causes are excluded, eosinophilic pneumonia is classified as idiopathic. Idiopathic eosinophilic pneumonia is divided into two clinical entities, acute eosinophilic pneumonia (AEP) (2) and chronic eosinophilic pneumonia (CEP) (3). Accumulation of eosinophils in the lung is thought to be a principal component of the pathogenesis of these disorders, and eosinophil-derived proteins are likely involved in producing the lung injury that results from eosinophilic pneumonia (5, 6). To date, attention has been focused on the mechanism of eosinophil recruitment into the lung. In this respect, IL-5 is the most specific cytokine for eosinophils. It plays critical roles in recruiting eosinophils, causing degranulation and prolonging eosinophil survival by inhibiting apoptosis (7-9). Previous investigations have documented increased concentrations of IL-5 in BAL fluid from patients with eosinophilic pneumonia (10-12). Furthermore, one study demonstrated that pulmonary eosinophilia in mice could be abrogated by treatment with IL-5 antibodies (13). Thus, IL-5 may play a pivotal role in the pathogenesis of eosinophilic pneumonia.
Recent studies have also suggested that activated T lymphocytes are responsible for pulmonary eosinophilia (14-16).
These T cells predominantly express CD4 antigen (14, 17, 18).
CD4+ T-helper cells have been demonstrated to fall into two
distinct populations, T helper 1 (Th1) and T helper 2 (Th2),
defined by the spectrum of cytokines that they produce (19).
Th1 cells generate IL-2 and interferon-
, whereas Th2 cells
produce IL-4, IL-5, and IL-13 (20). According to the Th1/Th2
paradigm, inflammation associated with allergic disorders is
regarded as a Th2-dominant immune response (19). An increased number of CD4+ lymphocytes and a high concentration of IL-5 in BAL fluids of patients with eosinophilic pneumonia indicate the accumulation of Th2 cells at sites of
inflammation in the lung. This influx of Th2 cells may be a
critical event in the pathogenesis of eosinophilic pneumonia,
however the distinct mechanism by which Th2 cells are recruited to the lung remains unknown.
It has become apparent that Th1 and Th2 cytokine-producing CD4+ cells preferentially express different chemokine receptors, which enables their selective recruitment to sites of inflammation. Th1 cells express CCR5 and CXCR3, whereas Th2 cells express CCR3, CCR4, and CCR8 (21-23). Thymus- and activation-regulated chemokine (TARC/CCL17) (24, 25) is a high affinity ligand for CCR4 and induces selective migration of CCR4-expressing Th2 cells in vitro (22, 24). Neutralization of TARC in vivo leads to inhibition of the Th2-dominant response in a mouse model of bacterial-induced hepatic failure (26). Moreover, TARC is highly expressed in lesions of atopic dermatitis (27) and bronchial asthma (28-30). These recent investigations suggest a potential role for TARC in the pathophysiology of allergic inflammation.
The purpose of this study was to investigate the contribution of TARC to the pathogenesis of eosinophilic pneumonia. We measured TARC concentrations in BAL fluid of patients with idiopathic eosinophilic pneumonia (AEP and CEP) and drug-induced eosinophilic pneumonia (drug-EP). To characterize the immunologic mechanism of eosinophilic pneumonia, results were compared with healthy volunteers and patients with hypersensitivity pneumonitis (HP), sarcoidosis, and idiopathic pulmonary fibrosis (IPF). This is the first report to demonstrate a critical role for TARC in eosinophilic pneumonia.
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Subjects
We recruited 25 patients with eosinophilic pneumonia consisting of 7 patients with AEP, 11 patients with CEP, and 7 patients with drug-EP (Table 1). Eosinophilic pneumonia was principally diagnosed by the presence of prominent eosinophils in BAL fluid and transbronchial lung biopsy specimens. A diagnosis of AEP was established on the basis of previously described criteria (2). Two patients with AEP had a past history of bronchial asthma. Most patients with AEP showed spontaneous improvement, and only two patients received corticosteroid therapy for a few days. Each patient with CEP met the previously described criteria (3). Six patients with CEP were asthmatics and one patient's course was complicated with symptomatic bronchial asthma. Patients with drug-EP satisfied the following diagnostic criteria: prompt improvement after cessation of the causative drug, the absence of other possible causes, and a positive reaction with lymphocyte stimulation tests or recurrence of the symptoms with the drug challenge. One patient with drug-EP had symptomatic bronchial asthma and two patients had past histories of asthma. The study also included patients with HP, sarcoidosis, and IPF as disease control subjects, as well as healthy volunteers (Table 1). The diagnosis was established in each of these patients on the basis of standard clinical criteria and histopathologic evidence.
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At the time of sample retrieval, one patient with AEP, two patients with CEP, and three patients with drug-EP were receiving corticosteroids. None of the patients with HP, sarcoidosis, or IPF received corticosteroid therapy before undergoing BAL.
BAL Fluid Collection
The bronchoscopic study was approved by the ethics committee of the Oita Medical University Hospital, and all subjects provided written informed consent.
BAL was performed as described previously (31). A fiberoptic bronchoscope was wedged into the right middle lobe bronchus or into the left lingula except for the cases of CEP and drug-EP in which the affected segment of the lung was washed. Saline solution was instilled in three aliquots of 50 ml, and BAL fluids from subjects were collected.
Cell Analysis
The total nucleated cell count was determined in a Bürger hemocytometer. The cells were stained with May-Grünwald-Giemsa solution and a differential count was performed on 300 cells. Lymphocyte subsets were analyzed by direct immunofluorescence with monoclonal antibodies against CD2, CD4, and CD8 using a FACS scan analyzer.
Measurement of TARC, IL-4, IL-5, and IL-13
The prepared supernatants of BAL fluids were re-centrifuged at 15,000 rpm for 1 minute to avoid contamination with cell components. TARC concentration was measured by an enzyme-linked immunosorbent assay (ELISA), using a matched antibody pair according to the manufacturer's protocol (Genzyme, Minneapolis, MN). This ELISA detects TARC with a sensitivity of greater than 7 pg/ml. The concentrations of IL-4, IL-5, and IL-13 in BAL fluid were also measured using a corresponding ELISA kit (Biosource Inc, Camarillo, CA). The minimum detectable doses in the ELISA system of IL-4, IL-5, and IL-13 are 0.27, 4, and 12 pg/ml, respectively.
Statistical Analysis
Results are presented as median values, with minimum and maximum values as the range. The Kruskal-Wallis test was used to compare values of the different groups. In case of a significant difference between groups, intergroup comparisons were assessed by a nonparametric method using the Mann-Whitney U test. Correlation coefficients were determined using the Pearson's linear regression analysis. A p value of p < 0.05 was considered significant.
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Characteristics of BAL Fluid Cells
Cell components of BAL fluid are summarized in Table 2. The cell concentrations in BAL fluid of patients with CEP, drug-EP, and HP were significantly higher than that of healthy subjects. The AEP group had an increased number of cells in BAL fluid as compared with the healthy control group, but the difference did not reach statistical significance (p = 0.064). Patients with AEP, drug-EP, as well as patients with HP and sarcoidosis had a significantly increased percentage of BAL lymphocytes than healthy volunteers. In contrast, there was not a significant difference in percentage of BAL lymphocytes between the CEP group and the control group. The percentage of neutrophils in BAL fluid was significantly increased in the HP group and IPF group when compared with healthy subjects. The percentages of BAL eosinophils were significantly higher in the AEP, CEP, and drug-EP groups than in each of the other groups. There was no difference in eosinophil percentage between the AEP group and the CEP group. The IPF group also had significantly higher percentage of eosinophils than healthy subjects. The CD4/8 ratios of T lymphocyte subsets in the AEP, CEP, and drug-EP groups as well as the sarcoidosis group were elevated as compared with the healthy subject group. When the CD4/8 ratio was compared between all patients with eosinophilic pneumonia and normal volunteers, the difference reached statistically significance (p = 0.030).
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IL-4, IL-5, IL-13, and TARC Concentrations in BAL Fluid from Patients with Various Diffuse Lung Diseases
Concentrations of IL-4, IL-5, IL-13, and TARC were measured by an ELISA. In this study, we used only unconcentrated BAL fluid. The results of IL-4, IL-5, and IL-13 assays are shown in Figure 1. The eosinophilic pneumonia group tended to have higher values of IL-4, however there was no statistically significant difference between groups. Detectable concentrations of IL-5 were found in BAL fluids from 23 of 25 patients with eosinophilic pneumonia, with a median value of 22.0 pg/ml (range, 0-1,088). The eosinophilic pneumonia group had significantly higher concentrations of IL-5 (p < 0.001) compared with the other groups. Although a half of the patients with eosinophilic pneumonia had detectable concentrations of IL-13, significant between-group differences were not detected.
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The results of the TARC assay are shown in Figure 2. TARC was detected in unconcentrated BAL fluids from all patients with eosinophilic pneumonia. The value in the eosinophilic pneumonia group (median, 240 pg/ml; range, 7-17,780 pg/ml) was significantly higher (p < 0.001) compared with those in the other groups. We obtained detectable concentrations of TARC in two patients with sarcoidosis (7 and 10 pg/ml), three patients with IPF (7, 9, and 19 pg/ml), and one healthy subject (7 pg/ml). BAL fluid from the IPF patient with a TARC value of 19 pg/ml consisted of 15% eosinophils. As the eosinophilic pneumonia group included 10 patients with asthma, we examined whether TARC would be elevated in BAL fluids from patients with asthma. When examined in all subjects together, asthmatics had significantly higher TARC concentrations compared with non-asthmatics (p < 0.05, Mann-Whitney U test). However, there were no significant differences in BAL TARC concentrations between asthmatics and nonasthmatics within the eosinophilic pneumonia and the noneosinophilic pneumonia groups when examined separately. Also, TARC concentrations were undetectable in BAL fluid from all seven asymptomatic patients with asthma without eosinophilic pneumonia in our preliminary study (data not shown). Similarly, there were no differences in BAL TARC concentrations between smokers and nonsmokers in this study (Table 3).
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Comparisons of IL-4, IL-5, IL-13, and TARC Concentrations in BAL Fluid between AEP, CEP, and Drug-EP
When we compared IL-4 concentrations in BAL fluid between different types of eosinophilic pneumonia, there was no statistically significant difference in IL-4 concentrations in BAL fluid between groups (Figure 3). Median IL-5 concentrations (pg/ml, range) were 390 (35-1,088) for AEP, 12 (0-193) for CEP, and 13 (0-300) for drug-EP. Patients with AEP had higher concentrations of IL-5 compared with those with CEP (p = 0.029) or drug-EP (p = 0.024). Concentrations of IL-13 in the BAL fluids of patients with AEP were higher than those from patients with CEP (p = 0.011). Median concentrations of TARC (pg/ml, range) were 3,536 (583-17,780) for AEP, 94 (7-782) for CEP, and 91 (13-8,100) for drug-EP. The TARC concentrations in BAL fluid from the AEP group were significantly higher than those of the CEP group (p = 0.014) or drug-EP group (p = 0.012). In the drug-EP group, by far the highest concentration of TARC (8,100 pg/ml) was obtained from a patient with symptomatic bronchial asthma and extensive Stevens-Johnson-type mucocutaneous disease. Similarly, a patient with CEP with symptomatic bronchial asthma provided the highest TARC value in the CEP group.
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Relationship between TARC, IL-4, IL-5, IL-13, and Eosinophilia in BAL Fluid
When we examined BAL samples from all patients, there was no apparent correlation between IL-5 concentrations and the percentages or absolute numbers of eosinophils. However, there were significant positive correlations detected within the AEP and CEP groups when examined separately (r = 0.56 in AEP and r = 0.46 in CEP). There was also a positive correlation between the concentration of TARC and the percentage of eosinophils in BAL fluid within the AEP and the CEP groups (r = 0.48 in the AEP group and r = 0.49 in the CEP group). BAL TARC concentrations did not correlate with the percentages or numbers of total and CD4+ lymphocytes even when examined within each group. A significantly close correlation was found between BAL TARC, and IL-5 determined in patients with eosinophilic pneumonia (Figure 4A) and if extended to all subjects (r = 0.82). TARC concentrations also correlated with IL-13 concentrations in patients with eosinophilic pneumonia (Figure 4B).
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To examine the role of TARC in AEP pathogenesis, a serial examination of BAL fluid for eosinophil counts and the concentrations of TARC and IL-5 were performed for three patients with AEP and spontaneous resolution. Patients underwent the second BAL approximately 2 weeks after the initial examination. Elevated concentrations of TARC in the first BAL dramatically fell to undetectable (< 7 pg/ml) by the second BAL. The concentrations of IL-5 were also decreased; however, IL-5 concentrations obtained by the second BAL were still higher than those from normal subjects and BAL eosinophilia also persisted (Figure 5).
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Serum Concentrations of TARC
Six patients with AEP; nine patients with CEP; six patients with drug-EP; and all patients with HP, sarcoidosis, and IPF, who were examined with BAL fluids, could also be analyzed for the concentration of serum TARC. In addition, 10 healthy individuals were newly recruited for the determination of serum TARC concentrations. As shown in Figure 6, patients with AEP had higher values of serum TARC (median, 17,907 pg/ml; range, 15,533-32,731 pg/ml) compared with the other groups (p < 0.005). TARC values of patients with drug-EP (median, 9,312 pg/ml; range, 1,677-17,176 pg/ml) were also increased compared with those of the CEP group (median, 534 pg/ml; range, 86-1,288 pg/ml) and the noneosinophilic pneumonia groups (p < 0.05). Serum TARC concentrations were also elevated in patients with CEP, sarcoidosis (median, 564 pg/ml; range, 249-18,228 pg/ml), and IPF (median, 475 pg/ml; range, 25-1,122 pg/ml) compared with normal subjects (median, 227 pg/ml; range, 93-410 pg/ml) (p < 0.05). Only concentrations in patients with HP (median, 208 pg/ml; range, 108-964 pg/ml) failed to reach statistical significance when compared with healthy control subjects. There was a positive correlation between concentrations of TARC in serum and BAL fluid (r = 0.57) from patients with eosinophilic pneumonia, whereas no correlation was observed when analysis was extended to all subjects. Also, no correlation was found between TARC concentrations and peripheral eosinophil counts.
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Although eosinophilic pneumonia is characterized by the accumulation of eosinophils and T-lymphocytes in the lungs, the pathophysiology of the disease is not fully understood (1-3, 14-16). Many investigators demonstrated that IL-5 concentrations are elevated in the BAL fluids from patients with several types of eosinophilic pneumonia (10-12, 14, 32). In particular, the observation that the protein and mRNA concentrations of IL-5 were elevated in the BAL fluid from the involved lung segment of CEP, but not in the uninvolved segment, strongly suggests a crucial role of IL-5 in eosinophilic inflammation in this disease (32). In this study, we demonstrated detectable concentrations of IL-4 and IL-13 in many cases of eosinophilic pneumonia, confirming the accumulation and activation of Th2 cells at the sites of inflammation in eosinophilic pneumonia.
Chemokines are a key component of the leukocyte recruitment process (33). A recent paper showed that eotaxin, eosinophil-specific chemoattractant, was detected only in patients
with eosinophilic pneumonia among several interstitial lung
diseases (34). As the corporation between IL-5 and eotaxin to
induce eosinophil accumulation has been reported by several
investigators, eotaxin may play an important role in the recruitment of eosinophils (35). The role of lymphocyte-directed
chemokines in eosinophilic pneumonia have also been measured in BAL fluids. Concentrations of RANTES (regulated
upon activation, normal T-cell expressed and secreted), chemoattractant for T lymphocytes, as well as eosinophils, are significantly elevated in patients with CEP (31), however RANTES concentrations are also elevated in sarcoidosis (34). Concentrations of MIP-1
, which exhibits a chemotactic effect on CD4 T
lymphocytes as well as mononuclear cells, were elevated in
eosinophilic pneumonia when compared with healthy volunteers (34). The known receptor for MIP-1 is CCR5, which is
preferentially expressed on Th1 cells (21, 36). Unlike mentioned chemokines, TARC can selectively recruit CCR4-expressing Th2 lymphocytes in vitro (21, 23). In this study, we
found that TARC is exclusively elevated in eosinophilic pneumonia among various interstitial lung diseases. Our results would suggest that TARC produced in the lung might attract
CCR4-bearing Th2 cells from the peripheral circulation into the
lung, followed by secretion of IL-5 by the recruited Th2 cells,
which would stimulate eosinophilic inflammation. Recently,
Kawasaki and coworkers reported that the specific antibody
against TARC attenuates airway eosinophilia with a concomitant
decrease in Th2 cytokine concentrations (37). Moreover, recent
evidence indicates that IL-4 and IL-13, in combination with tumor necrosis factor-
(TNF-), can upregulate TARC production by alveolar epithelial cells (28, 29), suggesting that there might be an amplification circuit of Th2 responses, based on induction of TARC by IL-4/IL-13 and selective responsiveness to
this chemokine by CCR4-expressing Th2 cells.
It has been indicated that IL-5 is predominantly involved in AEP pathogenesis (12). We found in this study that BAL fluid from patients with AEP had concentrations of TARC that were 30 times higher than that from patients with CEP. The percentage of lymphocytes and the BAL concentrations of IL-13 as well as IL-5 were also significantly higher in AEP than in CEP. Given the differences between AEP and CEP in cytokine concentrations, lymphocyte percentages and clinical features, it is likely that the pathogenesis of these two diseases is distinct. Previous papers indicated that AEP could be, at least in part, due to environmental agents or cigarette smoking (38, 39). Consistent with these findings, there have been recent reports of spontaneous resolution of AEP (15). Indeed, most of our patients with AEP showed spontaneous improvement after several days of hospital admission without receiving corticosteroids. The results of a serial BAL examination for three patients with AEP showed that TARC concentrations dramatically decreased to below the detectable limit within 2 weeks. In contrast, IL-5 was still detectable and BAL eosinophilia persisted. This may suggest that TARC is involved in the early immunologic events of eosinophilic inflammation in AEP, possibly in response to various environmental agents.
Recent investigations have shown that BAL fluid from asthmatic subjects after allergen challenge contains elevated concentrations of TARC, which is likely produced by bronchial epithelium (28-30). In this study, two patients with either CEP or drug-EP had symptomatic asthma at the time of BAL. TARC was significantly elevated in the BAL fluid from both of these patients. Perhaps the asthmatic condition augmented TARC expression in these patients. However, TARC was not elevated in BAL fluid from seven asymptomatic asthmatics without eosinophilic pneumonia in our preliminary study as well as four asthmatics in the noneosinophilic pneumonia group in this study, which was consistent with previously published data (28). These findings suggest that merely having a history of asthma, without the presence of current symptoms, might not significantly influence TARC concentrations in BAL fluids.
We do not have an accurate explanation on why TARC concentration does not correlate with CD4+ T cells in this study. The most likely explanation is that the number of CD4+ cells may not reflect the number of CCR4+ Th2 cells, because the CD4 population consists of both Th1 and Th2 cells. It will be important to conduct a study that specifically measures CCR4+ T cells from BAL fluids of patients with eosinophilic pneumonia.
In this study, high concentrations of serum TARC were obtained from patients with eosinophilic pneumonia and it is likely that lungs are the primary source of TARC. In bronchial asthma, it has been reported that TARC expressed by bronchial epithelial cells (29) and endothelial cells (40), however we could not find any published data regarding the sources of TARC in diffuse lung diseases including eosinophilic pneumonia. As the previous studies demonstrated that TARC is expressed by an alveolar epithelial cell line (28, 29), and also by macrophages in other organs (41), it would be suggested that the likely cell sources of TARC expression in eosinophilic pneumonia are alveolar epithelial cells and alveolar macrophages. Serum TARC concentrations of patients with sarcoidosis and IPF are also higher than that of healthy volunteers despite having undetectable concentrations of TARC in BAL fluid. As the protein in BAL fluid is estimated to be 100 times less concentrated than that of alveolar lining fluid (42), it cannot be excluded that the use of unconcentrated BAL fluids may fail to detect an elevation in alveolar TARC concentration. A possible explanation for serum TARC elevation in sarcoidosis is that granuloma lesions at sites other than the lungs, as well as peripheral monocytes and circulating monocyte-derived dendritic cells are all potential sources of TARC expression.
In conclusion, we have demonstrated exclusively elevated concentrations of TARC in parallel with high concentrations of Th2 cytokines, IL-5, and IL-13 in BAL fluids of patients with eosinophilic pneumonia. Our results suggest that TARC may be crucially involved in the development of eosinophilic pneumonia by trafficking Th2 cells into inflammatory sites. TARC might therefore be a novel target for therapeutic intervention in eosinophilic pneumonia as well as in other allergic disorders.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Eishi Miyazaki, M.D., Ph.D., Third Department of Internal Medicine, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan. E-mail: eishida{at}oita-med.ac.jp
(Received in original form June 21, 2001 and accepted in revised form January 29, 2002).
Acknowledgments: The authors are grateful to Dr. William R. Bishai, Johns Hopkins University, for critically reviewing the manuscript. They also thank Dr. Hiroshi Aono for his kind help in statistical analysis of data.
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References |
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