Role of plasmacytoid dendritic cell subsets in allergic asthma.

Plasmacytoid dendritic cells (pDCs) are major type-I interferon-producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs, and Fms-like tyrosine kinase-3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9(+) , CD9(+) , and CD2(+) pDCs. Recently, three subsets of pDCs were described, namely CD8α(-) ß(-) , CD8α(+) ß(-) , and CD8α(+) ß(+) subsets. Interestingly, CD8α(+) ß(-) and CD8α(+) ß(+) but not CD8α(-) ß(-) pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3(+) regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease, in particular allergic asthma.

Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy.

Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4-Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4-Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4-Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4-Ig. Co-administration of CTLA-4-Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4-Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4-Ig is independent of IDO expression. We show that CTLA-4-Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4-Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation.

Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy.

BACKGROUND: Allergen-specific immunotherapy (SIT) has been used since 1911, yet its mechanism of action remains to be elucidated. There is evidence indicating that CD4(+)FOXP3(+) regulatory T cells (Treg cells) are induced during SIT in allergic patients. However, the contribution of these cells to SIT has not been evaluated in vivo. OBJECTIVE: To evaluate the in vivo contribution of (i) CD4(+) CD25(+) T cells during SIT and of (ii) SIT-generated inducible FOXP3(+) Treg cells during allergen exposure to SIT-mediated suppression of asthmatic manifestations. METHODS: We used a mouse model of SIT based on the classical OVA-driven experimental asthma. Treg cells were quantified by flow cytometry 24 and 96 h post SIT treatment. We depleted CD4(+) CD25(+) T cells prior to SIT, and CD4(+)FOXP3(+) T cells prior to allergen challenges to study their contribution to the suppression of allergic manifestations by SIT treatment. RESULTS: Our data show that depletion of CD4(+)CD25(+) T cells at the time of SIT treatment reverses the suppression of airway hyperresponsiveness (AHR), but not of airway eosinophilia and specific IgE levels in serum. Interestingly, the number of CD4(+)CD25(+)FOXP3(+) T cells is transiently increased after SIT in the spleen and blood, suggesting the generation of inducible and presumably allergen-specific Treg cells during treatment. Depletion of CD4(+)FOXP3(+) Treg cells after SIT treatment partially reverses the SIT-induced suppression of airway eosinophilia, but not of AHR and serum levels of specific IgE. CONCLUSION AND CLINICAL RELEVANCE: We conclude that SIT-mediated tolerance induction towards AHR requires CD4(+)CD25(+) T cells at the time of allergen injections. In addition, SIT generates CD4(+)CD25(+)FOXP3(+) T cells that contribute to the suppression of airway eosinophilia upon allergen challenges. Therefore, enhancing Treg cell number or their activity during and after SIT could be of clinical relevance to improve the therapeutic effects of SIT.

Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma.

The prevalence of allergic diseases has increased dramatically during the last four decades and is paralleled by a striking increase in iron intake by infants in affluent societies. Several studies have suggested a link between increased iron intake and the marked increase in prevalence of allergic diseases. We hypothesized that the increased iron intake by infants offers an explanation for the increased prevalence of allergic disease in industrialized societies during the past four decades. A well-established mouse model of ovalbumin (OVA)-driven allergic asthma was used to test the effects of differences in iron intake and systemic iron levels on the manifestations of allergic asthma. Surprisingly, iron supplementation resulted in a significant decrease in airway eosinophilia, while systemic iron injections lead to a significant suppression of both allergen-induced airway eosinophilia and hyperreactivity compared to placebo. In contrast, mice fed on an iron-deprived diet did not show any difference in developing experimentally induced allergic asthma when compared to those fed on an iron-sufficient control diet. In contrast to our hypothesis, airway manifestations of allergic asthma are suppressed by both increased levels of iron intake and systemic iron administrations in the mouse model.