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Published ahead of print on September 28, 2005, doi:10.1164/rccm.200505-783OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 1, January 2006, 42-55

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Submitted on May 17, 2005
Accepted on September 27, 2005

Importance of Myeloid Dendritic Cells in Persistent Airway Disease After Repeated Allergen Exposure

Toshiyuki Koya1, Taku Kodama1, Katsuyuki Takeda1, Nobuaki Miyahara1, Eun-Seok Yang1, Christian Taube1, Anthony Joetham1, Jung-Won Park1, Azzeddine Dakhama1, and Erwin W Gelfand1*

1 Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, United States

* To whom correspondence should be addressed. E-mail: gelfande{at}njc.org.

Rationale: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) following repeated airway exposure to allergen in sensitized mice. Methods: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7 or 11 occasions. Airway function in response to inhaled methacholine (MCh) was monitored, BAL inflammatory cells counted and goblet cell metaplasia, peribronchial fibrosis and smooth muscle hypertrophy quantitated on tissue sections. Bone marrow-derived dendritic cells (BMDCs) were generated following differentiation of bone marrow cells in the presence of growth factors. Results: Sensitization to OVA in alum, followed by 3 airway exposures to OVA induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis and peribronchial smooth muscle hypertrophy, increased levels of interleukin (IL)-4, IL-5, IL-13, GM-CSF, TGF-{beta}1, eotaxin-1, RANTES, OVA specific IgG1 and IgE, and AHR. Following 7 airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5 and IL-13. Levels of IL-10 in both strains and IL-12 in BALB/c mice increased. Following 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profile continued to change. At this time point, the number of myeloid dendritic cells (mDCs) and expression of CD80 and CD86 in lungs were decreased compared to 3 challenges. Following 11 challenges, intratracheal instillation of BMDCs restored AHR and airway eosinophilia were restored. Conclusions: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in mDC numbers.
Key words: chronic asthma, eosinophil, airway hyperresponsiveness, cytokine, dendritic cells




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