Noval Adjuvants for Specific Immunotherapy of IgE-mediated Allergy

The allergic immune response can be characterized as an excessive Th2-like immune response to environmental antigens. Cytokines produced in connection with Th1 responses are known to display antagonistic effects to those produced by cells of the Th2 type. lt is therefore tempting to speculate that adjuvants leading to Th1-like immune response could - when injected together with allergens during immunotherapy - positively influence the course of the disease. The aim of this project will be to investigate novel adjuvants for their capacity to induce Th1-biased immune responses or tolerance to allergens. We plan to use these adjuvants together with well characterized recombinant model allergens in an animal model of Type 1 allergy. Moreover, the effects of the chosen adjuvants will be evaluated in an in vitro system using human allergen-reactive T lymphocyte cultures. Immunostimulatory sequences (ISS) are DNA motifs (CpG) which appear very frequent in bacterial but are suppressed in mammalian DNA. ISS activate the human immune system by inducing cytokine production in antigen presenting cells. The cells secrete high amounts of IFN-gamma and IL-12, cytokines which are known to direct the immune response towards Th1. The induction of peripheral tolerance by coupling the allergen to tolerogens could also represent an effective way to intervene in an allergic immune situation. Cholera toxin B subunit (CTB) mediates the binding to epithelial cells and represents an efficient carrier-delivery system for induction of peripheral tolerance. CTB has been used as oral vaccine in different disease models. lt is tempting to speculate that allergen/CTB conjugates could induce a state of peripheral tolerance to the allergenic protein. Polycationic compounds are enhancers of transport of proteins into APCs. The mechanism of action has not been entirely resolved, but may differ for distinct polycations. The efficient targeting of high doses of allergen/polycations to antigen presenting cells could lead to a high density of allergen-peptide MHC complexes and thereby promote Th1-like immune responses.

The prevalence of allergies has increased steadily during the last decades. Though we possess antiallergic drugs which are very effective, the treatment with these medicaments is definitely not a causative therapy form as only the symptoms are reduced. The only treatment that influences the immunological mechanisms underlying allergy, is specific immunotherapy, i.e. specific allergy vaccination. In this case, increasing doses of allergens (allergy elicitors) are administered by injection, with the ultimative aim of tolerizing the patient against the agent. A typical allergy vaccine consists of an allergen extract (e.g. from pollens, house dust mites or insect venom) and an adjuvans. The adjuvans is an additive which influences the duration, strength and quality of the immune response induced by the extract-vaccine. In this project different novel adjuvants for immunotherapy were evaluated. It was our aim to develop allergy vaccines which antagonize the characteristic allergic immune response. We have tested several substances. The experiments were performed in an in-vitro model with human cells (isolated from peripheral blood) and in an mouse model of inhalant allergy, which has been established in our Institute. We found that fragments of bacterial DNA induced special "antiallergic" effects by binding to specific receptors. They inhibit the production of IgE antibodies, the typical antibody response in allergic individuals, and lead to an antiallergic milieu in the immune system. Moreover, epidemiologic studies demonstrate that contact with certain bacterial products early in life has protective effects against the later development of allergies. In synopsis with the literature we therefore recommend to start clinical trials with these substances.