Insect venom immunotherapy induces interleukin‐10 production and a Th2‐to‐Th1 shift, and changes surface marker expression in venom‐allergic subjects

Abstract

The current study was carried out to elucidate the immunoregulatory changes induced by venom immunotherapy (VIT) in bee or wasp allergic subjects. All subjects included in this study had a history of severe systemic allergic reactions to stings of the respective insect as well as positive skin tests with the respective venom or venom-specific IgE in the sera. Parameters assessed in peripheral blood mononuclear cells (PBMC) before and after initiation of VIT (rush therapy reaching a maintenance dose of 100 micrograms venom injected subcutaneously within 1 week) were expression of CD3, CD4, CD8, CD45RA, CD45RO, interleukin (IL)-2 receptor (R) alpha, IL-4R, IL-12R, Fc epsilon RII, CD40, and CD40 ligand (CD40L), cells producing interferon (IFN)-gamma and IL-10 after stimulation with phorbol 12-myristate 13-acetate + ionomycin in the presence of monensin measured by flow cytometry; secretion of IFN-gamma, IL-4, and IL-10 measured by ELISA (IFN-gamma and IL-10 were additionally measured by PCR), and proliferation after stimulation with the respective venom. Significant decreases were observed after VIT for proliferative response to venom and venom + IL-4, IL-4 secretion, Fc epsilon RII, CD40, and CD40L expression. Significant increases were observed after VIT for IFN-gamma concerning the amount secreted and the number of producing cells, and IL-10, IL-10 was mainly produced by CD4+ cells that were negative for IFN-gamma, but some double-positive (IL-10 and IFN-gamma) cells were always detected. Addition of blocking anti-IL-10 antibodies, but not isotype control antibodies, prevented down-regulation of proliferation (but not IL-4 secretion) and further enhanced IFN-gamma secretion after VIT. These data indicate that in insect venom allergic subjects, VIT not only induces a rapid shift in cytokine expression from Th2 to Th1 cytokines, but also leads to induction of the immunosuppressive cytokine IL-10, which may be important for the limitation of potentially harmful allergen-specific Th1 responses. The described changes in cytokine expression may be responsible for subsequent increases in allergen-specific IgG and decreases in IgE production, as well as suppressive activity observed in earlier studies.

IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

“…IT has been related to a shift in T cell responses from Th2 to Th1 (15). In our animal model, we confirmed that frequencies of IFN-g-producing CD4 + T cells are increased in lung and draining lymph nodes following IT indicative of a Th1 shift present also in this model (Fig.…”

“…IT causes the production of IgG Abs that are supposed to block mast cell degranulation and compete with IgE for the allergen (13). Furthermore, a shift from the pathogenic Th2 to Th1 cells was described that regulates the Th2-mediated inflammation via IFN-g (14,15). Furthermore, regulatory T (Treg) cells have been associated with the effectiveness of IT.…”

“…Both subsets, Foxp3 + and Foxp3 2 Treg cells, play a role in IT. Some studies identified IL-10 production (15,(18)(19)(20), and some studies discovered FOXP3 + Treg cells in IT-treated human subjects (21,22) or both populations (23).…”

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.…”

Characterization of T Cell Responses to Hev b 3, an Allergen Associated with Latex Allergy in Spina Bifida Patients

“…Recently the mechanisms operative in SIT have been elucidated. It has been shown that during the administration of increasing doses of allergen, a shift from a typical allergic Th2-response to Th1 could be detected (immunodeviation) and that allergen-specific T cell responses were suppressed (tolerance induction) (17)(18)(19)(20)(21). It was concluded that strategies aiming in the correction of the allergic immune response should target allergenspecific T lymphocytes.…”