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Communications to the Editor |

Interleukin-8 Neutralization for COPD FREE TO VIEW

Ken-ichiro Inoue, MD; Hirohisa Takano, MD; Rie Yanagisawa, PhD; Toshikazu Yoshikawa, MD
Author and Funding Information

Affiliations: National Institute for Environmental Studies, Tsukuba, Japan,  Lebanon, NH

Correspondence to: Ken-ichiro Inoue, MD, Inhalation Toxicology Research Team, and Pathophysiology Research Team, National Institute for Environmental Studies, 16–2 Onogawa, Tsukuba, 305-8506 Japan; e-mail: inoue.kenichirou@nies.go.jp



Chest. 2005;128(1):464-465. doi:10.1378/chest.128.1.464
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To the Editor:

When we read the article in CHEST (September 2004)1 by Mahler et al, we may think that placebo-controlled trials are difficult to perform. The overall results by Mahler et al cannot support the use of anti-interleukin (IL)-8 therapy as an alternative therapeutic option for COPD patients. However, we would like to add some other points to this preliminary report.

First of all, as Mahler et al1described in the introduction to the article, the pathogenesis of COPD consists of several mediators other than IL-8. Target molecules in COPD involve tumor necrosis factor, interferon-γ, and IL-6 as cytokines, CCL2, CCL3, and CCL13 as chemokines, and several proteinases such as matrix metalloproteinase and neutrophil elastase.23 Thus, only IL-8 blockade itself may not have a great influence on disease activity. We are also concerned about the relatively low circulatory levels of the cytokine (ie, < 50 pg/mL) in the subjects examined. Alternatively, these data may indicate that IL-8 does not contribute to the symptoms of COPD in stable stages of the disease. Instead, we want to be informed of any previous studies in the literature in which the possible correlations between IL-8 and an exacerbated phase of COPD have been demonstrated.

In the “Results” section, the differences in the transition dyspnea index total score between the fully human monodonal IgG2 antibody directed against interleukin-8 (ABX-IL-8)-treated group and the placebo group showed significance only at week 2 in their follow-up period. The results suggest that an IL-8 neutralizing strategy may be effective only for the short-term use of a chemoattractant of effector cells (neutrophils) in patients with COPD. Since COPD is one of the representative chronic disorders, the results by Mahler and coworkers cannot satisfy the patients and physicians.

Finally, we think the administration of ABX-IL-8 by inhalation should lead to better, more optimistic outcomes for subjects. The majority of reports45 have shown elevated IL-8 levels in the sputum samples of patients with COPD. However, as we have confirmed in murine models, the elevated levels of the local expression of proinflammatory cytokines, such as IL-1β, and chemokines, such as keratinocyte chemoattractant, macrophage inflammatory protein-1α, and macrophage chemoattractant protein-1, during lung inflammation are not always paralleled by systemic circulatory levels of the molecules (unpublished observation). Future clinical studies using an inhaled type of IL-8 antagonistic agent may provide comfort for patients with this troublesome disease.

Mahler, DA, Huang, S, Tabrizi, M, et al (2004) Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study.Chest126,926-934. [CrossRef] [PubMed]
 
De, Boer WI Cytokines and therapy in COPD: a promising combination?Chest2002;121,209S-218S. [CrossRef] [PubMed]
 
Barnes, PJ, Hansel, TT Prospects for new drugs for chronic obstructive pulmonary disease.Lancet2004;364,985-996. [CrossRef] [PubMed]
 
Tsoumakidou, M, Tzanakis, N, Siafakas, NM Induced sputum in the investigation of airway inflammation of COPD.Respir Med2003;97,863-871. [CrossRef] [PubMed]
 
Beeh, KM, Kornmann, O, Buhl, R, et al Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4.Chest2003;123,1240-1247. [CrossRef] [PubMed]
 
To the Editor:

We appreciate the interest expressed by Dr. Inoue and colleagues in our study evaluating monoclonal therapy recognizing interleukin (IL)-8 in patients with COPD. We agree that recruitment of subjects and performance of placebo-controlled trials in patients with symptomatic COPD are both difficult and challenging. However, such randomized controlled trials are critical for providing the scientific evidence to assess new therapies for patients with COPD.

As noted in the subtitle and in the “Discussion,” this was a pilot study to investigate monoclonal antibody therapy directed against IL-8 to treat the inflammatory component of the disease. As suggested by Dr. Inoue and colleagues, there are many unanswered questions about the role and the importance of the numerous mediators of inflammation in COPD. This study was performed to explore treatment of a new target (IL-8) that modulates inflammation in this condition. The results of this study showed that three infusions of monoclonal antibody recognizing IL-8 (ABX-IL8) were safe and well tolerated compared with placebo. These safety data are quite reassuring. Moreover, these data provide preliminary information so that additional studies can be designed and performed to assess the appropriate dose of ABX-IL8, to consider whether inhaled administration of ABX-IL8 may be beneficial (as suggested by Dr Inoue and associates), and to examine which outcome measures are appropriate to evaluate biological agents in COPD.


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References

Mahler, DA, Huang, S, Tabrizi, M, et al (2004) Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study.Chest126,926-934. [CrossRef] [PubMed]
 
De, Boer WI Cytokines and therapy in COPD: a promising combination?Chest2002;121,209S-218S. [CrossRef] [PubMed]
 
Barnes, PJ, Hansel, TT Prospects for new drugs for chronic obstructive pulmonary disease.Lancet2004;364,985-996. [CrossRef] [PubMed]
 
Tsoumakidou, M, Tzanakis, N, Siafakas, NM Induced sputum in the investigation of airway inflammation of COPD.Respir Med2003;97,863-871. [CrossRef] [PubMed]
 
Beeh, KM, Kornmann, O, Buhl, R, et al Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4.Chest2003;123,1240-1247. [CrossRef] [PubMed]
 
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