Targeting Fel d 1 to FcγRI induces a novel variation of the TH2 response in subjects with cat allergy

Background: Induction of CD4(+) T cells that produce IL-10 or IFN-gamma is central to the protective effects of conventional allergen immunotherapy. Objective: We examined the T-cell modulatory capacity of a fusion protein (H22-Fel d 1) that targets Fel d 1 to the high-affinity IgG receptor (Fc gamma RI) on antigen-presenting cells. Methods: Monocyte-derived dendritic cells pulsed with H22-Fel d 1 were analyzed for surface phenotype and cytokine secretion by flow cytometry and cytometric bead assay, respectively. CD4(+) T cells generated after coculture with H22-Fel d 1-pulsed dendritic cells were analyzed at the single-cell level by flow cytometry after intracellular cytokine staining. The T-cell repertoire was compared for subjects with (IgE(+)) and without cat allergy (IgE(neg)IgG(neg)), including subjects with a modified T(H)2 response (IgE(neg)IgG(+)). Results: H22-Fel d 1 induced a semimature phenotype in dendritic cells in conjunction with a selective increase in IL-5(+) and IL-10(+) CD4(+) T cells compared with nonreceptor-targeted Fel d 1. Amplified T cells included diverse subtypes characteristic of THO (IL-5(+)IFN-gamma(+)), regulatory T(H)1 (IL-10(+)IFN-gamma(+)) and regulatory T(H)2 (IL-10(+)IL-5(+)) cells. T-cell qualitative changes were restricted to subjects with allergy and were distinct from a modified T(H)2 response. Blocking IL-10 induced by H22-Fel d 1 selectively increased IL-5(+) CD4(+) T cells, suggesting that T(H)2 responses were controlled. Conclusion: Targeting Fel d 1 to Fc gamma RI induces a novel variation of the T(H)2 response that incorporates major elements of a protective T-cell response.