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Division of Immunopathology
Department of Pathophysiology and Allergy Research
Center of Pathophysiology, Infectiology & Immunology

Medical University of Vienna

Vienna General Hospital, AKH, 3Q
Waehringer Guertel 18-20
A-1090 Vienna, Austria

Mucosal tolerance induction: a strategy for prevention and therapy of type I allergy [Wiedermann-Schmidt]

Project summary

Within the last project years we have focused our research on the development of new treatment strategies on the basis of mucosal tolerance induction against multi-sensitivities.
In a mouse model of poly-sensitization to birch and grass pollen allergens we demonstrated that simultaneous tolerance to all allergens was inducible with structurally different multi-allergen constructs: the first one was generated as a polypeptide containing the immunodominant T cell epitopes of the selected allergens, the other one was constructed as an allergen chimer, harbouring one complete allergen as linker for the immunodominant peptides of the other allergens. The underlying mechanisms of immunosuppression, however, differed in dependence of the conformation of the constructs, as polypeptide-induced tolerance seemed to be mediated by cytokine independent pathways while the conformational allergen-chimer induced the production of TGF-ï¢ and IL-10. In the coming project period we aim to further elucidate the underlying mechanisms of poly-tolerance induction by using knock-out mice as well as in vivo and in vitro blockade of surface markers closely associated with the Treg phenotype. Identification of the cell source of regulatory cytokines, phenotypic characterization of Treg cells within inductive and effector sites of tolerance induction, as well as antigen uptake and internalization by dendritic cells shall help to understand the tolerizing pathways induced by structurally different allergen constructs.
Based on the constructed birch and grass pollen chimer, we are in the process of engineering allergen chimers against birch pollen-related food allergies, known to be difficult to treat by conventional immunotherapy. A similar approach is pursued against house dust mite- and animal dander allergens, which are also common in multi-sensitized patients. The goal is to provide an allergen-chimer covering the most frequent allergens for prophylactic intervention against the development of multisensitivities in patients at risk. As primary prevention is thought to be introduced at a very early stage of life to counterbalance possible immune dysregulations, intervention during pregnancy and early postnatal period rather than child-directed intervention might be more effective. Therefore, multi-allergen administration during the pre- peri- and postnatal period will be performed to evaluate the preventive potential of this strategy against multisensitivities in the progeny.
Our preceding studies indicated that therapeutic, in contrast to prophylactic, tolerance induction with multi-allergen constructs is difficult to achieve without the use of additional immunomodulators. Therefore selected adjuvant systems with immunomodulating properties will be used for delivery of poly-allergen constructs. Based on our previous work three candidates, namely cholera toxin B-subunit, virosomes or recombinant lactic acid bacteria are of interest for being tested in our mouse model of poly-sensitization.
As a result of the described functional and mechanistic studies, the most promising approaches shall be further translated into clinical trials.