Allergen-immunostimulatory oligodeoxynucleotide conjugate: a novel allergoid for immunotherapy

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Abstract
To summarize the data of both preclinical studies and initial clinical trials of a novel allergoid for allergen specific immunotherapy. This allergoid consists of allergen covalently coupled to immunostimulatory oligodeoxynucleotide DNA sequences. Recently, immunostimulatory oligodeoxynucleotide sequences, also called unmethylated cytosin-guanine dinucleotide motifs, have been discovered that act as strong T helper 1 response inducing adjuvants in mice. Although mixing allergens with immunostimulatory DNA sequences induces T helper 1 responses in T helper 2 biased mice, the allergens in such mixes could still cause anaphylactic reactions when used in humans which is one of the reasons why immunotherapy has gradually been falling out of favor. Therefore, we made allergen-immunostimulatory oligodeoxynucleotide conjugates and investigated their immunogenicity and allergenicity in animal models of allergy. These conjugates were highly immunogenic for inducing T helper 1-like antiallergen responses and reversed T helper 2 responses and symptoms of asthma in mouse models. They were also less allergenic, as shown by the reaction with human immunoglobulin E antibodies and by histamine release from basophils of allergic patients. Preliminary phase I and II trials in ragweed allergic patients showed that allergen-immunostimulatory oligodeoxynucleotide conjugates are well tolerated, less allergenic and induce immunoglobulin G antiallergen antibodies more rapidly than allergen extracts without significantly increasing the immunoglobulin E titer. Allergen-immunostimulatory DNA conjugates induce T helper 1 and down regulate preexisting T helper 2 anti-allergen responses in mice. Initial phase I and II trials in ragweed allergic patients showed that ragweed allergen-DNA conjugates are well tolerated and induce a rapid immunoglobulin G but not E response. The data show that allergen-DNA conjugates are a novel type of allergoid that have great potential for a safe and potent form of allergen specific immunotherapy.