Grass Pollen Immunotherapy Induces Mucosal and Peripheral IL-10 Responses and Blocking IgG Activity

Abstract

T regulatory cells and IL-10 have been implicated in the mechanism of immunotherapy in patients with systemic anaphylaxis following bee stings. We studied the role of IL-10 in the induction of clinical, cellular, and humoral tolerance during immunotherapy for local mucosal allergy in subjects with seasonal pollinosis. Local and systemic IL-10 responses and serum Ab concentrations were measured before/after a double-blind trial of grass pollen (Phleum pratense, Phl P) immunotherapy. We observed local increases in IL-10 mRNA-positive cells in the nasal mucosa after 2 years of immunotherapy, but only during the pollen season. IL-10 protein-positive cells were also increased and correlated with IL-10 mRNA+ cells. These changes were not observed in placebo-treated subjects or in healthy controls. Fifteen and 35% of IL-10 mRNA signals were colocalized to CD3+ T cells and CD68+ macrophages, respectively, whereas only 1–2% of total CD3+ cells and 4% of macrophages expressed IL-10. Following immunotherapy, peripheral T cells cultured in the presence of grass pollen extract also produced IL-10. Immunotherapy resulted in blunting of seasonal increases in serum allergen Phl p 5-specific IgE, 60- to 80-fold increases in Phl p 5-specific IgG, and 100-fold increases in Phl p 5-specific IgG4. Post-immunotherapy serum exhibited inhibitory activity, which coeluted with IgG4, and blocked IgE-facilitated binding of allergen-IgE complexes to B cells. Both the increases in IgG and the IgG “blocking” activity correlated with the patients’ overall assessment of improvement. Thus, grass pollen immunotherapy may induce allergen-specific, IL-10-dependent “protective” IgG4 responses.

The IgE-facilitated allergen binding (FAB) assay: Validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses

“…Patients receiving allergen-specific immunotherapy have been shown to have increased concentrations of allergen-specific IgG4 antibodies in their serum (Gehlhar et al, 1999;Jutel et al, 2003;Nouri-Aria et al, 2004;Djurup et al, 1987). However assays that detect only immunoreactive IgG4 are unlikely to predict clinical efficacy (Djurup et al, 1987;Muller et al, 1989;Ewan et al, 1993;Bodtger et al 2005).…”

“…Moreover, using a simplified assay where allergenIgE complexes bound to the surface of B cells were detected by flow cytometry (IgE-FAB), we demonstrated that the vigour of proliferative responses by T cell clones reflect the binding of allergen-IgE complexes (Wachholz et al, 2003). Using this assay we further established that inhibition of allergen-IgE binding occurs with the addition of serum from subjects receiving grass pollen immunotherapy (Wachholz et al, 2003 andNouri-Aria et al, 2004).…”

“…Cellular changes include immune deviation favouring T helper (Th) 1 responses (Wachholz et al, 2002), and the induction of regulatory cells producing interleukin (IL)-10 (Francis et al, 2003). Treatment is associated also with the induction of allergen-specific serum IgG4 antibodies (Gehlhar et al, 1999;Jutel et al, 2003;Nouri-Aria et al, 2004). IgG4 antibodies are thought to have blocking activities as they compete with IgE for binding to mast cells, basophils and other IgE receptor-expressing cells (Garcia et al, 1993).…”

Influence of polyphenols on allergic immune reactions: mechanisms of action

“…Just recently, evidence has been provided that increased proportions of Treg cells have been found in grass pollen allergics after IT (81) and in IT-treated hay fever patients (82) . This last evidence coupled to the ability of polyphenols to induce Treg cell activation may lead to the formulation of a combined therapy by IT and polyphenols for the treatment of those allergic diseases which are less responsive to IT treatment alone.…”

Early Cytokine Modulation after the Rapid Induction Phase of Sublingual Immunotherapy with Mite Monomeric Allergoids

“…In particular, immunosuppressive IL-Ia can induce specific unresponsiveness (anergy) in peripheral T cells (9,17,(19)(20)(21) and was followed by the IT-induced Thz/Thl switch (22)(23), with a decrease in IL-4 and an increase in IFN-y production in patients undergoing IT. Such changes appear late during the course of SLIT.…”