Allergen-specific subcutaneous immunotherapy in allergic asthma: immunologic mechanisms and improvement

Abstract

Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4(+) T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and IL-13. Allergen-specific immunotherapy (SIT) is currently the only treatment with a long-term effect via modifying the natural course of allergy by interfering with the underlying immunological mechanisms. However, although SIT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of the symptoms. Improvement of SIT is needed to enhance its efficacy in asthmatic patients. Herein, the immunoregulatory mechanisms underlying the beneficial effects of SIT are discussed with the ultimate aim to improve its treatment efficacy.

Keywords: IL-10; IgE; Th2 lymphocytes; allergic asthma; dendritic cell; eosinophilia; hyperresponsiveness; immunotherapy; regulatory T cells.

Fig. 1

Schematic representation of the pathophysiology of allergic asthma. In genetically predisposed individuals, primary exposure to an allergen leads to activation of Th2 lymphocytes and stimulation of IgE synthesis. Later on, exposure causes immediate release of the biologically active mediators (histamine, leukotrienes) via mast cell degranulation and further activation of Th2 cells with resulting eosinophil inflammation and AHR.

Fig. 2

Schematic representation of the potential immune deviation leading to the beneficial effects of SIT. Allergen SIT results in both a shift in allergen-specific T-cells from Th2 to Th0/Th1 responses and the generation of IL-10 and TGF-β producing T regulatory (Treg) cells. Allergen-specific Th1 immune responses protect against the development of allergic disorders by inducing the production of IFN-γ, which inhibits the development of Th2 cells. The regulatory cytokines IL-10 and TGF-β induce switching of B cell responses in favor of IgG4 antibodies and IgA antibodies, respectively, and suppress IgE production. IL-10 and TGF-β directly or indirectly suppress effector cells of allergic inflammation such as mast cells and eosinophils thereby preventing release of mediators and late-phase inflammation. Sold gray arrows represent immune response pathway to natural exposure; dotted arrows represent immune response pathway to IT; blocked lines represent inhibition.

Fig. 3

Hypothetical scheme of the proposed mechanisms contributing to the induction of tolerance by SIT. (A) Natural exposure to an allergen leads to activation of Th2 cells. (B) nTreg cells are generated in thymus, but can also develop from conventional CD4⁺ T-cells by specific condition or signals. nTreg cells induce IDO expression on dendritic cell (IDO⁺DC). This is partially mediated via the interaction of CTLA-4 expressed on nTreg and CD80 (B7) expressed on DC. (C) IDO catalyzes the initial and rate-limiting step of tryptophan degradation. (D) IDO expressing DC induces development of Treg after allergen IT by a mechanism at present not completely defined. (E) 1,25(OH)₂D₃ inhibits transcription factor NF-κB thereby inhibiting maturation of DC and resulting in tolerogenic DC, which direct the induction of Treg cells. Treg cells suppressed Th2 responses and effector cells by the release of immunoregulatory cytokines IL-10 and TGF-β. (F) The role of allergen-specific IgA is unclear. Dotted arrows represent immune response pathway to SIT; blocked lines represent inhibition.