Induction of ‘blocking’ IgG antibodies during immunotherapy

Abstract

Specific allergen immunotherapy (SIT) to date is the only treatment shown to have long-term benefit in patients with IgE-mediated allergic disorders such as allergic rhinitis. In seasonal rhinitis and asthma, and to a lesser extent in perennial allergic rhinitis, SIT is highly effective in reducing symptoms and medication use in patients who fail to respond adequately to usual pharmacologic treatments and these effects are maintained for at least three years after discontinuation [1][2][3][4][5][6]. Clinical outcomes such as early and late skin, nasal and bronchial reactions have been shown to decrease after treatment. For example, immunotherapy results in a reduction in immediate allergen-induced symptoms and the concentrations of inflammatory mediators in nasal lavage fluid, including histamine and prostaglandin D 2 [7]. The risk/benefit of SIT is less favourable in patients with chronic asthma because of an increased risk of developing IgE-mediated systemic side-effects and, rarely, anaphylaxis. Therefore, delineation of the immunological mechanisms underlying successful immunotherapy, with a view to develop more targeted forms of therapy with maintained efficacy but reduced risk of side-effects, remains an important goal.While the clinical efficacy of SIT is well-documented, the molecular mechanisms are incompletely understood. Current evidence suggests that specific immunotherapy exerts an effect on several aspects of the immune system, including modulation of allergen-specific B cell as well as T cell responses. Studies on the effect of immunotherapy have demonstrated reduced basophil reactivity to allergens [8], reductions in mucosal recruitment of inflammatory cells [9], deviation of Th2 cytokine responses to allergens in favour of Th1 responses [10,[11][12][13] and the induction of IL-10 producing regulatory T cells [14][15][16]. In addition, changes in serum antibody titres in response to immunotherapy have been described, mostly as increases in allergen-specific IgG antibodies, particularly the IgG4 isotype [17,[18][19][20][21][22], sometimes accompanied by blunting of seasonal increases in IgE antibodies.In order to improve safety while maintaining efficacy, attempts have been made to reduce allergen-induced IgE responses during the course of immunotherapy. For example, one therapeutic approach has been the use of novel vaccine adjuvants based on bacterial lipopolysaccharide (LPS). LPS is a bacterial membrane component specific to Gram-negative bacteria, which acts as an immunomodulator by activating the innate immune response. LPS consists of a complex glycolipid composed of a hydrophilic polysaccharide portion and a hydrophobic domain known as lipid A, which contains the adjuvant activity of LPS [23]. The clinical use of LPS is limited because of toxicity, including possible induction of a sepsis-like systemic inflammatory response syndrome. Chemical modifications of LPS have been developed such as a detoxified version of the lipid A moiety of Salmonella minnesota R595 termed monophosphoryl lipid A ...

IgE-Mediated Allergen Presentation and Blocking Antibodies: Regulation of T-Cell Activation in Allergy

“…It has further been suggested that functional properties such as affinity and epitope specificities of the induced IgG, especially IgG4, should be investigated, as changes in these properties may be more relevant for the clinical effect of the antibodies [100, 101]. Only minor differences were found when measuring the avidities of IgG to different allergens, and SIT did not induce any appreciable avidity changes [102].…”

Successful Desensitisation in a Patient with CRIM-Positive Infantile-Onset Pompe Disease

“…Classically used for IgE-mediated reactions (hypersensitivity type I), it has been used for drugs nonIgE-mediated hypersensitivity reactions (Cernadas et al 2010). Despite extensive experience (Castells et al 2008), the underlying molecular and cellular basis is poorly understood but may involve depletion of allergic mediators, modification of signal transduction, generation of allergenspecific T-regulatory cells inducing of a tolerant state in peripheral T cells or 'blocking' IgG antibodies (Cernadas et al 2010;Wachholz and Durham 2003;Akdis and Akdis 2007).…”

Clinical Implications and Facts About Allergic Rhinitis (AR) in Children

“…Fc RII receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIM), they transduce, as a consequence, negative signals preventing cellular activation and release of soluble pro-inflammatory mediators following co-aggregation with FcεRI receptors. (Wachholz et al, 2003;Flicker et al, 2003) SLIT prevented the recruitment of eosinophils in the eyes or in the nose after allergen challenge. (Marcucci et al, 2001;Marcucci et al, 2003;Silvestri et al, 2002) SLIT with grass pollen extracts was shown to decrease local or systemic levels of eosinophil cationic protein (ECP), without any increase in tryptase.…”