Enhanced allergen-induced airway inflammation in paucity of lymph node T cell (plt) mutant mice

Background

Dendritic cells and lymphocytes play a central role in allergic asthma. Chemokines for these cells include the CCR7 agonists secondary lymphoid chemokine/CCL21 and EBV-induced lymphoid chemokine/CCL19, but their role in allergic asthma is poorly understood.

Objective

We sought to determine the effects of abrogation of lymphoid tissue expression of CCR7 agonists on allergic airway responses.

Methods

Paucity of lymphocyte T cell (plt) mutant mice, deficient in EBV-induced lymphoid chemokine/CCL19 and the lymphoid form of secondary lymphoid chemokine/CCL21, were evaluated in an established ovalbumin (OVA)-induced asthma model (plt-OVA group) and compared with similarly immunized +/+ BALB/c mice (+/+OVA group).

Results

APTI responses to methacholine increased similarly in OVA-challenged plt and +/+ mice. However, airway inflammation was strikingly enhanced in plt-OVA mutants over +/+OVA mice and included increased numbers of eosinophils, CD4 and B cells, neutrophils, and total leukocytes in bronchoalveolar lavage fluid and inflammatory cell cuffing around pulmonary arterioles. Enhanced airway inflammation was accompanied by an increase in lung T_H2 activity, with increased levels of IL-4 and monocyte-derived chemoattractant/CCL22.

Conclusions

Induction of allergic asthma in mutant mice with impaired CCR7 responses results in characteristics that resemble severe asthma in human subjects, including severe bronchial lymphocytosis, eosinophilia, and neutrophilia, but not in enhancement in airway hyperreactivity.

Clinical implications

Disruption of chemokines responsible for trafficking of antigen-processing cells and lymphocytes to the draining lymph nodes might lead to enhanced allergic airway responses.

Key words: Asthma, chemokines, CCR7, dendritic cells, EBV-induced lymphoid chemokine/CCL19, eosinophils, lymphocytes, mice, monocyte-derived chemoattractant/CCL22, secondary lymphoid chemokine/CCL21

Abbreviations used: APTI, Airway pressure time index, BAL, Bronchoalveolar lavage, ELC/CCL19, EBV-induced lymphoid chemokine, HRP, Horseradish peroxidase, I-A, Major histocompatibility complex class II Ia antigen, MCP, Monocyte chemoattractant protein, MDC/CCL22, Monocyte-derived chemoattractant, OVA, Ovalbumin, Penh, Enhanced pause, plt, Paucity of lymph node T cell, SLC/CCL21, Secondary lymphoid chemokine, TLN, Thoracic lymph node, WT, Wild-type