Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-γ-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell α-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p ≤ 0.018). TSLP and TARC/CCL17 expression correlated with airway obstruction. Although the total numbers of cells expressing CCR4, CCR8, and CXCR3 did not significantly differ in the asthmatics and controls, there was evidence of selective infiltration of CD4+/CCR4+ T cells in the asthmatic biopsies which correlated with TARC and MDC expression and airway obstruction. Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines. Our data implicate TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10 in asthma pathogenesis. These may act partly through selective development and retention, or recruitment of Th2 cells bearing their receptors.

In these studies, IFN gamma-inducing factor (IGIF), unlike IL-12, did not drive Th1 development in BALB/c or C57BL/6 mice, but like IL-1alpha, potentiated IL-12-driven Th1 development in BALB/c mice. IGIF and IL-12 synergized for IFN gamma production from Th1 cells. Unlike IL-1alpha, IGIF had no effect on Th2 cells. IGIF signaled through IRAK, IL-1 receptor-associated kinase, to induce nuclear translocation of p65/p50 NFkappaB in Th1 cells. IL-1alpha had no effect on proliferation, cytokine production, or NFkappaB activation in Th1 cells but activated NFkappaB and proliferation in Th2 cells. Thus, Th1 and Th2 cells may differ in responsiveness and receptor expression for IL-1 family molecules. IGIF and IL-1alpha may differentially amplify Th1 and Th2 effector responses, respectively.

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The role of eosinophils as effector cells in asthma pathogenesis has been questioned since an anti-interleukin (IL)-5 monoclonal antibody (mepolizumab), which depleted blood and sputum eosinophils, failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness. However, the effect of IL-5 blockade on tissue eosinophils was not examined. We sought to determine whether mepolizumab depletes airway tissue eosinophils and their products. Twenty-four patients with mild asthma received three intravenous doses of either 750 mg of mepolizumab or placebo in a randomized, double-blind, parallel-group fashion over 20 weeks. Mepolizumab produced a median decrease from baseline of 55% for airway eosinophils (interquartile range, 29-89%; p = 0.009 versus placebo), 52% for bone marrow eosinophils (45-76%, p = 0.003), and 100% for blood eosinophils (range, 67-100%, p = 0.02). Mepolizumab had no appreciable effect on bronchial mucosal staining of eosinophil major basic protein. There were no significant changes in clinical measures of asthma (airway hyperresponsiveness, FEV1, and peak flow recordings) between the mepolizumab and placebo-treated groups. Anti-IL-5 treatment reduces but does not deplete airway or bone marrow eosinophils. The role of the eosinophil remains uncertain. Further clinical studies in asthma with more effective antieosinophil strategies are required.

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Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide–specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti–IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene–deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell–driven response to allergen in vivo by an IL-10–dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.

Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.

No abstract