title: Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro.
abstract: Bee venom phospholipase A2 (PLA) is the major allergen in bee sting allergy. It displays three peptide and a glycopeptide T cell epitopes, which are recognized by both allergic and non-allergic bee venom sensitized subjects. In this study PLA- and PLA epitope-specific T cell and cytokine responses in PBMC of bee sting allergic patients were investigated before and after 2 mo of rush immunotherapy with whole bee venom. After successful immunotherapy, PLA and T cell epitope peptide-specific T cell proliferation was suppressed. In addition the PLA- and peptide-induced secretion of type 2 (IL-4, IL-5, and IL-13), as well as type 1 (IL-2 and IFN-gamma) cytokines were abolished, whereas tetanus toxoid-induced cytokine production and proliferation remained unchanged. By culturing PBMC with Ag in the presence of IL-2 or IL-15 the specifically tolerized T cell response could be restored with respect to specific proliferation and secretion of the type 1 T cell cytokines, IL-2 and IFN-gamma. In contrast, IL-4, IL-5, and IL-13 remained suppressed. Treatment of tolerized T cells with IL-4 only partially restored proliferation and induced formation of distinct type 2 cytokine pattern. In spite of the allergen-specific tolerance in T cells, in vitro produced anti-PLA IgE and IgG4 Ab and their corresponding serum levels slightly increased during immunotherapy, while the PLA-specific IgE/IgG4 ratio changed in favor of IgG4. These findings indicate that bee venom immunotherapy induces a state of peripheral tolerance in allergen-specific T cells, but not in specific B cells. The state of T cell tolerance and cytokine pattern can be in vitro modulated by the cytokines IL-2, IL-4, and IL-15, suggesting the importance of microenvironmental cytokines leading to success or failure in immunotherapy.
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
authors.forename: C A
authors.initials: CA
authors.lastname: Akdis
authors.forename: M
authors.initials: M
authors.lastname: Akdis
authors.forename: T
authors.initials: T
authors.lastname: Blesken
authors.forename: D
authors.initials: D
authors.lastname: Wymann
authors.forename: S S
authors.initials: SS
authors.lastname: Alkan
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.forename: K
authors.initials: K
authors.lastname: Blaser
mesh_terms: D000485:Allergens / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001514:Bee Venoms / Q000627:therapeutic use*; D017635:Clonal Anergy / Q000276:immunology*; D000939:Epitopes; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D010741:Phospholipases A / Q000276:immunology*; D054467:Phospholipases A2; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000485:Allergens; D001514:Bee Venoms; D000939:Epitopes; D007074:Immunoglobulin G; D007378:Interleukins; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010741:Phospholipases A; D054467:Phospholipases A2