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(Chest. 2003;123:410S-411S.)
© 2003 American College of Chest Physicians

Allergen-Specific Early Neutrophil Infiltration After Allergen Challenge in a Murine Model*

Christian Taube, MD; Azzeddine Dakhama, PhD; Katsuyuki Takeda, MD; Jerry A. Nick, MD and Erwin W. Gelfand, MD

* From the Departments of Pediatrics (Drs. Taube, Dakhama, Takeda, and Gelfand) and Medicine (Dr. Nick), Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Erwin W. Gelfand, MD, 1400 Jackson St, Denver, CO 80206; e-mail: gelfande{at}njc.org

Allergic asthma is characterized by obstruction, hyperresponsiveness, and inflammation of the airways. The inflammatory changes have been described as an accumulation of eosinophils, lymphocytes, and mast cells in the bronchial wall and lumen.1 In the recent past, increased numbers of neutrophils in the airways have been found at different stages of the disease.2 3 4 5 Following allergen challenge in patients with allergic asthma, neutrophils are the first inflammatory cells to accumulate within the airways.6 7 8 In murine models, an increase in the numbers of neutrophils following allergen challenge also has been described.9 In this model, mice sensitized to ovalbumin (OVA) received a single intranasal OVA challenge. Interestingly, the initial inflammatory response within the airways was almost exclusively neutrophilic, and this increased number of neutrophils was transient, and was followed later by an influx of eosinophils and lymphocytes, and by the development of airway hyperresponsiveness.9 To date, the mechanisms underlying this early and transient neutrophil inflammation have not been well-defined. The aim of this study was to determine whether this neutrophil influx is (1) allergen-specific and (2) mediated through an Fc receptor and Ig.

BALB/c mice, mice lacking the high-affinity IgE receptor (Fc{epsilon}RI-/- mice), mice lacking the Fc-common {gamma}-chain (FcR{gamma} chain -/- mice or C57/B6 mice), and B-cell-deficient mice (JH-/- or C57/B6 mice) were sensitized to OVA or ragweed (RW) on days 0 and 14 by intraperitoneal injection. On day 28, mice received a single intranasal challenge (SIN) with either OVA or RW. Following the challenge, BAL fluid was obtained to assess airway inflammation, and levels of neutrophil chemokines (ie, MIP-2 and KC) and tumor necrosis factor (TNF)-{alpha} were assessed in BAL fluid by enzyme-linked immunosorbent assay.

To investigate the kinetics of the neutrophil influx into the airways, BAL fluid was obtained at different time points following SIN. Following the challenge, nonsensitized mice developed a small increase in neutrophil numbers when compared to unchallenged mice. In contrast, sensitized mice showed a significant increase in neutrophil numbers beginning 2 h after the allergen challenge, and peaking at 8 h. At 48 h after the challenge, there was no significant difference in neutrophil numbers between the groups. Similar to this increase in neutrophil numbers, analysis of BAL fluid from sensitized mice showed a rapid increase in neutrophil chemokine levels (ie, MIP-2 and KC) and TNF-{alpha} levels beginning 1 h after challenge and peaking at 8 h. At 24 h, the levels of all three cytokines had returned to baseline values. Nonsensitized mice receiving SIN showed small increases in MIP-2, KC, and TNF-{alpha}, which were significantly lower compared to those in the sensitized mice.

To determine whether this early and transient neutrophil influx was allergen-specific, mice were sensitized to OVA or RW and subsequently were challenged with either OVA or RW. BAL fluid was collected 8 h after challenge, because neutrophil influx into the airways peaked at this time point. Mice sensitized and challenged with the same allergen demonstrated higher numbers of neutrophils in BAL fluid compared to nonsensitized and challenged mice, whereas such increases were not observed in the BAL fluid of mice that had been challenged with the noncorresponding allergen (Table 1 ). Similar levels of MIP-2, TNF-{alpha}, and KC in BAL fluid were significantly increased in sensitized mice that were challenged with the corresponding allergen, compared to sensitized mice that had been challenged with the noncorresponding allergen and to nonsensitized mice.


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  		Table 1.. Neutrophil Inflammation 8 h After the Allergen Challenge Is Allergen Specific

 
Given the antigen specificity, we then determined whether allergen-specific antibodies and Ig receptors are required for this response. JH-/- mice, which are devoid of serum Igs and B cells, and mice lacking the Fc common {gamma}-chain (FcR{gamma}-/-), which fail to express functional Fc{gamma}RI, Fc{gamma}RIII, and Fc{epsilon}RI, were sensitized to OVA and then received SIN. Similar to BALB/c mice, sensitized and challenged C57/B6 wild-type mice showed higher numbers of neutrophils in the BAL fluid 8 h after allergen challenge compared to nonsensitized controls. In contrast, sensitized and challenged B-cell-deficient mice and FcR{gamma}-/- mice showed no increase in neutrophil numbers. Similarly B-cell-deficient and FcR{gamma}-/- mice demonstrated low levels of MIP-2, KC, and TNF-{alpha} compared to the sensitized and challenged wild-type controls.

Because FcR{gamma}-/- mice also fail to express the Fc{epsilon}RI, we investigated the role for Fc{epsilon}RI in mediating this neutrophil response. For this purpose, mice with disruption of the {alpha}-subunit of the Fc{epsilon}RI (ie, Fc{epsilon}RI-/-) were sensitized and challenged. Eight hours after the OVA challenge, sensitized Fc{epsilon}RI-/- mice showed an increase in BAL neutrophil numbers similar to those measured in sensitized wild-type mice.

Taken together, these results demonstrate that neutrophil influx after allergen challenge requires prior sensitization and is allergen-specific. Furthermore, we demonstrated that this transient neutrophil inflammation is mediated through the Fc{gamma} receptor (but not the Fc{epsilon}RI) and is dependent on the presence of the antibody. The contribution of this early and transient neutrophil phase to the development of subsequent eosinophil and lymphocyte accumulation and to altered airway function events remains to be determined.


   Footnotes
 
Abbreviations: OVA = ovalbumin; RW = ragweed; SIN = single intranasal challenge; TNF = tumor necrosis factor


   References
TOP
 References
 

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  3. Martin, RJ, Cicutto, LC, Smith, HR, et al Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143,351-357[ISI][Medline]
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  5. Fahy, JV, Kim, KW, Liu, J, et al Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995;95,843-852[CrossRef][ISI][Medline]
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  7. Kelly, EA, Busse, WW, Jarjour, NN Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med 2000;162,1157-1161[Abstract/Free Full Text]
  8. Nocker, RE, Out, TA, Weller, FR, et al Influx of neutrophils into the airway lumen at 4 h after segmental allergen challenge in asthma. Int Arch Allergy Immunol 1999;119,45-53[CrossRef][ISI][Medline]
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