Basic and clinical immunology
Pulmonary TH2 response in Pseudomonas aeruginosa–infected patients with cystic fibrosis

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Background

Pseudomonas aeruginosa infection determines the course of cystic fibrosis (CF) lung disease. Studies in human peripheral blood indicate that P aeruginosa infection is associated with a predominant TH2 immune response, whereas TH1 responses are accompanied by a better pulmonary outcome.

Objective

Analyses of peripheral blood may not correspond directly with the local pulmonary immune response. Therefore, we asked whether the TH1/TH2 response is altered in bronchoalveolar lavage fluid from P aeruginosa–infected patients with CF.

Methods

Bronchoalveolar lavage fluid was obtained from 12 patients with CF chronically infected with P aeruginosa, 11 noninfected patients with CF, and 8 healthy controls. Pulmonary CXCR3+ (TH1) and CCR4+ (TH2) expressing CD4+ and CD8+ lymphocytes were quantified by flow cytometry. Levels of TH1-associated (IL-2, IFN-γ, IFN-γ inducible T cell-α chemoattractant, Monokine induced by IFN-γ, IFN-γ inducible protein of 10 kd) and TH2-associated (IL-4, IL-5, IL-10, thymus and activation-regulated chemokine [TARC], macrophage-derived chemokine) cytokines and chemokines and a panel of proinflammatory molecules were quantified at the protein level. Chemokines mRNA levels were assessed by real time RT-PCR.

Results

P aeruginosa–infected patients with CF had significantly higher levels of pulmonary CCR4+CD4+ (TH2) cells, IL-4, IL-13, and TARC and lower levels of IFN-γ compared with noninfected patients with CF and healthy controls. Bronchoalveolar lavage fluid levels of IL-4, IL-13, and TARC correlated inversely with FEV1 in P aeruginosa–infected patients with CF.

Conclusion

These results reveal the prevalence of a pulmonary TH2 immune response in P aeruginosa–infected patients with CF. The modulation of the pulmonary TH2 response in P aeruginosa infection may be an option for the treatment of P aeruginosa lung disease in patients with CF.

Section snippets

Patients and healthy controls

Twenty-three clinically stable patients with CF (mean FEV1 70% of predicted), including 17 patients with CF from a previous study,34 were selected for this study. All patients were free from acute pulmonary exacerbation. The diagnosis of CF was confirmed by clinical features consistent with CF and 2 independent positive sweat chloride tests (≥60 mEq/L). Chronic P aeruginosa infection was diagnosed if the organism was isolated in at least 2 consecutive sputum samples with a minimum of a 6-month

Pulmonary CCR4+ (TH2) and CXCR3+ (TH1) cells

Percentages of CCR4+CD4+ T (TH2) cells were significantly higher in BALF of P aeruginosa–infected patients with CF compared with noninfected patients and healthy controls (Fig 1). In contrast, CCR4+CD8+ (Tc2), CXCR3+CD4+ (TH1) and CXCR3+CD8+ T cells (T cytotoxic cell type [Tc] 1) were present at low levels and did not differ among the groups. Patients with CF infected with P aeruginosa had slightly more total cells compared with noninfected patients with CF. Percentages of neutrophils,

Discussion

This study shows that BALF of P aeruginosa–infected patients with CF is characterized by increased percentages of TH2 (CCR4+CD4+) cells. This is accompanied by decreased levels of IFN-γ and increased levels of IL-4, IL-13, and TARC, which correlate positively with CCR4+CD4+ cells. Furthermore, the levels of IL-4, IL-13, and TARC are correlated with disease severity (FEV1) in P aeruginosa–infected patients with CF.

Previous studies investigated the TH1/TH2 immune response in P aeruginosa

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    Supported by grants from the Else-Kröner-Fresenius Stiftung, the Friedrich-Baur-Stiftung, the University and Science Program of the Ludwig-Maximilians-University (HWP), and the Clinical Cooperation Groups Pediatric Immune Regulation and Immune Monitoring.

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