This study demonstrates that markers of T cell and eosinophilic inflammation are predictive of disease progression of COPD. Individuals with stable disease have higher plasma levels of IL-2 than those with rapidly progressive COPD and lower plasma eotaxin-1 levels compared to normal controls. In addition, those COPD subjects who experienced a subsequent physiologic deterioration of their disease had markedly higher lung lavage eotaxin-1 levels compared to subjects who demonstrated disease stability over the same time interval. Together, these results suggest that measuring IL-2 and eotaxin-1 levels could enable physicians to identify those COPD patients that require more intensive monitoring and treatment in the future. Moreover, these findings indicate that cell-mediated immune responses have an important effect on the clinical status of this disease.
IL-2 is a Th1 derived cytokine that induces the proliferation and activation of both CD4+ and CD8+ lymphocytes. While several recent studies, have implicated T lymphocytes in the pathogenesis[3
] and functional decline[15
] of COPD, the exact role they play in this disease remains ambiguous. In fact, activation of peripheral CD4+ cells correlates positively with lung function in smokers[17
]. Moreover, smokers with preserved lung function have a prominent up-regulation of T regulatory cells in the lung compared to never smokers and patients with COPD[18
]. In this study we found that the Th1 cytokine IL-2 was significantly elevated in the plasma of COPD patients who demonstrated disease stability over a six-month time period. Together, these data suggest that T cell mediated immune responses can alter the physiologic progression of this disease.
IL-2 may prevent disease progression by promoting virus-specific CD4+ and CD8+ T-cell responses which deter virus replication and thereby limit the damaging effects of chronic viral infection in the lung[19
]. CD8+ cells are increased in the lungs of guinea pigs with latent adenoviral infection[20
] and this increase may act to reduce lung inflammation by suppressing active viral infection[21
]. Respiratory syncytial virus (RSV) diminishes the effector activity of CD8+ cells and the development of CD8+ T cell memory[22
]. This effect, however, can be reversed by IL-2[23
] thus preventing recurrent infection with this common pathogen in patients with COPD[24
]. In addition to viruses, cytotoxic lymphocyte responses, which are coordinated by CD4+ cells, exert an important role in defending against H. influenza infections in the lung[26
]. In fact, studies in mice demonstrate that cigarette smoke alters T cell function which can render the animal more susceptible to infection [27
]. Thus, we postulate that enhanced T cell responses in our stable COPD cohort may have acted to prevent disease progression by limiting the pathogenicity of bacterial and viral infections within the lung.
Another means by which IL-2 may influence disease progression is by regulating the survival of T cells[28
]. In culture, IL-2 promotes T cell survival in part by inducing the expression of Bcl-2, a protein that protects from passive apoptotic cell death (PCD)[29
]. T lymphocyte apoptosis is increased both in the peripheral blood[31
] and lung lavage[32
] of COPD patients. The loss of these T cells can render the lung susceptible to infections[33
] thereby increasing the likelihood of disease exacerbations, an important factor in the progression of the disease[35
]. In addition, the uncleared apoptotic cells can injure the lung by releasing proteases and other harmful intracellular contents[36
]. These damaging effects are accentuated by the fact that pulmonary macrophages from COPD patients have a defect in their ability to phagocytose apoptotic cells in the lung[37
]. Conversely, it is conceivable that IL-2 protects the lung by actually stimulating the apoptosis of auto-reactive T lymphocytes. IL-2 has been shown to program mouse lymphocytes for apoptosis and mice deficient in IL-2Rα are resistant to Fas-mediated activation induced cell death (AICD)[38
]. Activation induced cell death is a critical process for maintaining self-tolerance[39
]. IL-2 by activating AICD can eliminate autoreactive T cells and prevent the development of inflammatory responses to self antigens which are capable of generating emphysematous changes in the lung[40
In contrast to IL-2, increases in eotaxin-1 were associated with disease progression in COPD. We found significant increases in lung lavage eotaxin-1 levels in COPD patients compared to normal controls. More importantly, those patients whose lung function subsequently declined over the ensuing six months had significantly higher lavage eotaxin-1 levels than those subjects with stable lung function over the same time period. In addition, disease stability was associated with decreased plasma eotaxin-1 levels. Eotaxin-1 is a CC chemokine (CCL11) that binds to the CC chemokine receptor 3 (CCR3) on the surface of eosinophils thereby inducing eosinophil activation[41
] and migration[42
]. Lung eosinophilia has been linked with bronchial hyperreactivity in COPD patients[1
]. Moreover, the expression of both eotaxin-1 and CCR3 is up regulated during exacerbations of chronic bronchitis[43
] and eotaxin-1 levels are associated with bronchodilator response and the extent of emphysema on CT scans[44
]. Coupled with these previous findings, our data indicate that eotaxin-1-mediated lung eosinophilia may be a critical factor in the progression of this disease.
It is important to note that all the study participants at baseline were former smokers who were clinically stable and had no signs of exacerbation or recent infection. In fact, the presence of an exacerbation was an exclusion criterion for the trial. Thus, we cannot ascribe the subsequent decline in FEV1 in the rapid decliners to the presence of disease exacerbation or inherent differences with the stable COPD cohort. Indeed, both the rapid decliners and stable COPD subjects selected for these studies had GOLD IIB disease with visual evidence of emphysema occupying ≤ 10% of the lung on CT scan. The subjects did not use steroids for at least two months prior to study entry and did not have excessive airway hyperreactivity during bronchodilator testing. Similarly, our study findings cannot be attributed to the study drug-retinoic acid. Plasma and lavage measurements were taken at baseline prior to initiation of retinoic acid and retinoic acid itself had no impact on any of the physiologic, radiographic or quality of life measures at the six or nine-month time point[9
Given the multiple analyses that were conducted it is conceivable that the changes in IL-2 may have occurred by chance. However, further plasma IL-2 analyses on an additional 6 rapid decliners and 17 stable COPD subjects confirmed the differences between these two groups. However, prospective analyses will be needed to validate these results and determine if these findings can be extrapolated to a more heterogeneous population of COPD subjects. A strength of this study is that it contains both plasma and lung lavage analyses on a well-characterized cohort of previously stable advanced emphysema subjects. The literature regarding the impact of T cell and eosinophil related cytokines in advanced emphysema is limited-particularly for lung lavage. In fact, this is one of the only studies to examine the relationship between a lung lavage biomarker and subsequent rate of decline of lung function in COPD[45
]. Thus, our findings provide important novel evidence that these cell types are involved in the progression of the disease.