Amelioration of ovalbumin-induced allergic airway disease following Der p 1 peptide immunotherapy is not associated with induction of IL-35

Abstract

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of T(H)2 cells and decreased interleukin (IL)-17⁺ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3⁺ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.

Mechanisms of Peptide Immunotherapy in Allergic Airways Disease

“…This observation is supported by the results of murine studies in which no increase in the absolute numbers of Foxp3 1 T cells was observed in the lungs of mice after successful peptide therapy (19). On the basis of an assessment of the intensity of Foxp3 staining (20), however, peptide immunotherapy may increase the amount of this regulatory transcription factor per cell, resulting in enhanced suppressive capability. To date, to the best of our knowledge, no functional suppression assays have been performed in the model in question to formally test this hypothesis.…”

“…The functional significance of this increase remains to be determined, as does the role of whole allergen challenge after therapy in the induction of antibody responses in the study by Tarzi and colleagues. In a model of peptide immunotherapy in which mice sensitized to both HDM allergens and OVA were treated with HDM peptides, a significant decrease in the numbers of CD19 1 B cells was observed in lung tissue digests (20). However, no decreases in allergen-specific IgE were observed in the sera of these animals.…”

“…Additional support for these observations has been provided through in vivo experimental models (19,20). Mice jointly sensitized to HDM allergens and ovalbumin (OVA) were treated with peptides from the HDM allergen Der p 1 (20). In addition to downregulating HDM responses, Der p 1 peptide therapy reduced inflammatory responses to OVA rechallenge, demonstrating the induction of intermolecular tolerance.…”

“…More recently, my research group has obtained unpublished data demonstrating the upregulation of IL-10 production in response to allergen proteins not represented in the peptide therapy, thereby providing some evidence to support the induction of intermolecular tolerance. Additional support for these observations has been provided through in vivo experimental models (19,20). Mice jointly sensitized to HDM allergens and ovalbumin (OVA) were treated with peptides from the HDM allergen Der p 1 (20).…”

Distinct Roles of the Anaphylatoxins C3a and C5a in Dendritic Cell–Mediated Allergic Asthma

“…In absence of a model allowing to test directly the proliferation of T cell clones in response to HDM Ag, we used a surrogate model (41), in which BMDCs were stimulated with a mixture of HDM and OVA in the presence of CFSE-labeled CD4 + T cells from OVA-TCR transgenic DO11.10/ Rag2 2/2 for 4-9 d. As expected, T cells strongly proliferated, as evidenced by the decreased CFSE signal 4 d after coculture. C5aR1 2/2 BMDCs were equally potent in driving CD4 + T cell proliferation (Fig.…”