New Insights into Immunotherapy for Allergic Disorders
Modular Antigen Translocating (MAT) Molecules: A Novel Allergy Vaccine Strategy
Cezmi A. Akdis
Swiss Institute of Allergy and Asthma Research (SIAF)
University of Zurich
Cezmi A. Akdis, Thomas Kündig, Claudio Rhyner, Mübeccel Akdis, Reto Crameri
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Obere Strasse 22, CH-7270 Davos, Switzerland.
Allergen-specific immunotherapy (SIT) has been used for almost a century as a desensitizing therapy for allergic diseases and represents the only curative and specific way of treatment. Administration of appropriate concentrations of allergen extracts has been shown to be reproducibly effective when patients are carefully selected. However, allergen-SIT faces several problems related to the allergen content of the extracts used, type of the adjuvant, route of application, long duration of treatment, side effects and limited efficacy. Intensive studies are being performed to improve efficacy and safety of allergen-SIT. Based on PTD (protein transduction domain) technology, we have engineered MAT (modular antigen translocation) molecules, aimed to enhance antigen presentation through intracellular targeting of the MHC II presentation pathway. MAT vaccines consist of a cloning cassette, which fuses Tat (transactivator of transcription) peptide to a truncated Ii (invariant chain), which is able to target antigens to the nascent MHC II molecules in the trans-Golgi compartment. To test the efficacy of intracellular targeting, we engineered arrays of MAT-fusions and compared the effects of recombinant allergens, Tat-conjugated allergens and MAT-conjugated allergens for the ability to stimulate T-cell proliferation and cytokine production in human PBMC (peripheral blood mononuclear cell) cultures derived from allergic individuals, and to elicit protective immune responses in mice. MAT–vaccines induced a strong proliferation of PBMCs at a low concentration and induced a Th2 to a Tregulatory/Th1 cell shift in the cytokine profile, reflecting those reported in successfully desensitized allergic individuals. In mouse models of allergy, we showed that MAT–vaccines are highly efficient in desensitizing mice and protect them from anaphylactic shock. The technology is applicable not only for the treatment of allergies, but also for the development of preventive vaccines in general.