Induction of ‘blocking’ IgG antibodies during immunotherapy

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 [1–6]. 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 D2 [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, 11–13] and the induction of IL-10 producing regulatory T cells [14–16]. 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, 18–22], 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 (MPL). MPL retains immunostimulatory properties without the potential toxic systemic side-effects of LPS [24]. MPL stimulates Th1-type antigen specific responses in rodent models including preferential induction of IgG antibodies while inhibiting IgE [24–27]. These properties make it potentially useful as an adjuvant for allergen-specific immunotherapy. Studies in mice have shown that co-administration of MPL with a ragweed pollen vaccine results in enhanced IgG2b responses, suggesting a strong Th1-inducing bias as an adjuvant for promoting ragweed-specific antibodies [28]. Moreover, MPL treatment of rats reduced antigen-specific IgE responses upon booster injections in hypersensitized animals. These results suggest that co-application of MPL with allergen vaccine during SIT could result in enhancement of Th1 responses while downregulating allergen-specific IgE responses, thereby improving efficacy and reducing potential side-effects. A controlled trial of grass pollen extract containing an MPL adjuvant was successful in reducing nasal and ocular symptoms and requirement for rescue medication when compared to a placebo group [29]. In addition, there was an increase in allergen-specific IgG antibody titres and a blunting of seasonal increases in allergen-specific IgE in the actively treated group. Significant increases in specific IgG antibodies may be of clinical importance by preventing IgE-mediated activation of mast cells, which contribute to the early-phase response in allergic inflammation. However, quantitative changes in IgG antibody do not always correlate with clinical protection [18, 19, 30]. For this reason, the role of IgG in immunotherapy has been questioned and it is not clear whether the significant increases in IgG have a causal role in alleviating symptoms or simply represent a bystander effect, occurring as a consequence of high allergen exposure. To refute a role for allergen-specific IgG on the basis of a lack of correlation between clinical response and quantity of antibody is probably too simplistic. Michils et al. [20] investigated the IgG antibody response to venom immunotherapy and observed increases in IgG titres following IT. However, the investigators also reported for the first time that this was preceded by a rapid change in the fine specificity of IgG antibodies. In a more recent study, the same investigators reported that allergen-specific IgG isolated from patients allergic to bee venom displayed a fine specificity spectrum to the major bee venom allergen that was distinct from that of allergen-specific IgG derived from individuals protected either naturally or by successful immunotherapy [31]. These data complement findings from murine models of immunotherapy, where the administration of high concentrations of allergen has been shown to alter antibody affinity and specificity as Clin Exp Allergy 2003; 33:1171–1174