New insight into immunological mechanisms of venom immunotherapy.
The early production of IL-10 appears to induce T cell anergy and is an important step in venom immunotherapy. This results in the loss of the abnormal venom-specific T helper type 2 response (reduced proliferation and cytokine production) and a switch from a T helper type 2 dominant to a T helper type 1 dominant cytokine response. As a consequence, there is an increase in specific IgG4, an increase in the specific IgG4:IgE ratio, and over the longer term a decrease in specific IgE. IL-10 is initially produced by allergen-specific T cells, but later by B cells and monocytes. IL-10 initiates anergy in T cells by blocking tyrosine phosphorylation of CD28 and inhibiting the CD28 co-stimulatory signal. IL-10 also inhibits cytokine gene transcription and messenger RNA production. That clinical protection in venom immunotherapy occurs earlier than antibody changes suggests that additional mechanisms may be operative. Decreased basophil mediator release is a candidate and has been demonstrated: it is induced by IL-10 and possibly also related to changes in chemokines and other cytokines. Proliferation and cytokine secretion in anergic T cells can be restored depending on the cytokine milieu. Restimulation in the presence of IL-2, IL-15 and possibly IL-12 leads to a T helper type 1 cytokine pattern (immunity:effective immunotherapy) and with IL-4 a T helper type 2 pattern (persistence of allergy:relapse). The cytokine microenvironment in tissues can thus influence outcome. A variety of new approaches to immunotherapy is being investigated, including peptide therapy. Preliminary data from DNA vaccines, largely in animal models, hold great promise. Immunostimulatory DNA sequences have an adjuvant effect and induce T helper type 1 cytokines, independent of antigen. They may be co-administered with allergen and used to redirect allergen-specific T helper type 2 responses.
Ewan
P W
PW
Department of Allergy and Clinical Immunology, Addenbrooke's Hospital, University of Cambridge Clinical School, Cambridge, UK. pamela.ewan@addenbrookes.nhs.uk
D000485:Allergens / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D001514:Bee Venoms / Q000276:immunology*; D003888:Desensitization, Immunologic / Q000379:methods*; D006801:Humans; D006927:Hymenoptera / Q000276:immunology; D006969:Hypersensitivity, Immediate / Q000517:prevention & control*; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D014862:Wasp Venoms / Q000276:immunology*
D000485:Allergens; D001514:Bee Venoms; D014862:Wasp Venoms; D016753:Interleukin-10