Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions

Abstract

Background Segmental antigen bronchoprovocation has long been used as a model to study allergic pulmonary inflammatory responses. Among the characteristics of the resulting cellular infiltrate is the preferential recruitment of T H 2 lymphocytes. The mechanisms responsible for their selective recruitment remain unknown, but T H 2 cells preferentially express the chemokine receptors CCR4 and CCR8. Objectives We tested the hypothesis that the chemokines thymus- and activation-regulated chemokine (TARC) (CCL17) and macrophage-derived chemokine (MDC) (CCL22), whose receptor is CCR4, and I-309 (CCL1), whose receptor is CCR8, would be released at sites of segmental allergen challenge. Methods Segmental allergen challenge with saline or allergen was performed in 10 adult allergic subjects with asthma, who were off medications. Bronchoalveolar lavage (BAL) was performed at both the saline- and allergen-challenged sites 20 hours after challenge. BAL fluids were analyzed for total cell counts and differentials, and supernatants were assayed by ELISA for levels of TARC, MDC, and I-309. As a control, the BAL fluids were also analyzed for levels of interferon-inducible protein 10 (IP-10) (CXCL10), an IFN-γ—induced chemokine active on CXCR3, a chemokine receptor that is preferentially expressed on T H1 lymphocytes. Results Allergen challenge led to an approximately 6-fold increase in total leukocytes, including lymphocytes, compared with those seen at saline-challenged sites. At antigen-challenged sites, eosinophils predominated. Chemokine levels at control, saline-challenged sites were either below the detectable limit or low, with the predominant chemokine detected being IP-10. At antigen-challenged sites, levels of MDC, TARC, and IP-10 were all significantly increased compared with saline sites, each with a median of 486 to 1130 pg/mL detected. On the basis of a comparison with serum values, BAL chemokine levels at most antigen-challenged sites could not be accounted for by transudation from plasma. In contrast, levels of I-309 were extremely low or undetectable in all BAL and serum samples tested. Finally, BAL levels of MDC significantly correlated with those for TARC, but no significant correlations were found between levels of chemokine and any cell type. Conclusions These data suggest that among the chemokines measured in this study, IP-10 is the predominant chemokine detected 20 hours after saline challenge, likely representing baseline production of a chemokine that favors T H 1 cell recruitment. At antigen-challenged sites, levels of both CCR4 and CXCR3 active chemokines, but not CCR8 active chemokines, are markedly increased and are produced at levels that are likely to have biologic significance. Given the preferential accumulation of T H 2 cells at these antigen-challenged sites, the increased production of CCR4-active chemokines might contribute to this response.