Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

Abstract

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.

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.…”

“…Evidence for intramolecular tolerance was obtained in a study where PBMCs were archived before and after peptide immunotherapy with a prototype mixture containing 12 peptides from Fel d 1. An additional four peptides not administered to the patients in that study were also available to test recall responses posttherapy (19). The results showed that, in addition to modulating the immune response to the treatment peptides themselves, peptide therapy also modified the response to nontreatment peptides from the same allergen, thereby providing an example of intramolecular tolerance in a clinical setting.…”

“…The dependence of in vitro suppression on IL-10 was not evaluated in this model; however, blockade of IL-10 receptors with a monoclonal antibody in a murine model demonstrated that suppression of multiple inflammatory outcomes was dependent on this cytokine (19).…”

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

“…Previous work providing PIT between airway challenges suggested therapeutic benefit in experimental models in which allergenexperienced T cells should predominate (15). Here we have followed the fates of defined, allergen-experienced Th2 populations to show definitively that PIT can be highly effective in controlling the pathogenic activity of such cells in AAI.…”

“…In animal studies, PIT can effectively reduce or prevent CD4 + T-cell-driven diseases (10)(11)(12)(13)(14)(15). Encouraging findings have also been reported in allergic patients (16)(17)(18)(19)(20).…”