Synchronous immune alterations mirror clinical response during allergen immunotherapy

Abstract

Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS)trial demonstrated that 2years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1year after discontinuation. We sought to examine in the GRASS trial the time course of immunologic changes during 2years of sublingual and subcutaneous immunotherapy and for 1year after treatment discontinuation. We performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding). All 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2years of allergen desensitization, followed by reversal at 3years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific TH2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1year after discontinuation. Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific TH2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1year after discontinuation might be an early indicator of a protolerogenic mechanism.