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New tools for allergen-specific immunotherapy: cellular mechanisms of allergen uptake and presentation
Lämpligt för studenter inom det biomedicinska området eller närliggande utbildningsprofiler.
Project description: Specific immunotherapy (SIT) is the only curative treatment in use for allergic disease. This therapy is however time-consuming, expensive and not without risks for adverse side effects. To overcome the limitations of current SIT, this project aims to develop new strategies to improve the therapy. For this purpose, it is essential to understand the mechanisms for how an allergen induces an allergic immune response and how this response may be modified and skewed towards a ¿non-allergic¿ response. By changing the molecular nature and delivery conditions of an allergen, we hypothesize that we can influence on how an allergen is recognised by the immune system. This will in turn influence the T-cell response evoked and thus if the result will be an allergic response or not. The antigen-presenting cell (APC) taking up and presenting the allergen to the T-cell plays a key role in this process. Hence, in this project we will focus on the mechanisms for uptake and antigen presentation of allergens by APC:s.
Dendritic cells (DC) are the most potent APC. Our model system for allergen uptake and presentation is monocyte-derived DC from peripheral blood and purified T-cells from the same donors. The allergens we use in this study are the major cat allergen Fel d 1 and the major birch pollen allergen Bet v 1. Both are produced as recombinant proteins. Fel d 1 has been coupled to carbohydrate particles as a possible alternative to administer allergen and to obtain adjuvant effects in SIT. Two hypoallergenic derivatives of Bet v 1 are used in the study, i.e. the Bet v 1 has been modified so that the B-cell epitopes are disrupted while the T-cell epitopes are preserved. Hypoallergenic derivatives have been suggested as new tools for improvement of SIT-protocols. The influence on DC and T-cell responses of the allergens and the modified allergen preparations are evaluated using flow cytometry, confocal laser scanning microscopy, T-cell proliferation assays and cytokine measurements by ELISpot or flow cytometry. The aim is to clarify what signals the DCs give to the T-cell after uptake and presentation of allergens compared to hypoallergens or carbohydrate particle-coupled allergens in allergic and healthy subjects.
In another ongoing project we are examining the allergen-specific T-cell response during SIT. An immunotherapy study has been carried out in which birch pollen allergic patients were treated with Bet v 1 hypoallergens or with placebo. Peripheral blood mononuclear cells (PBMC) were prepared and frozen before and after the treatment. These cells are now used for allergen stimulation in vitro to elucidate the mechanisms for how SIT induces unresponsiveness to allergens.
Allergy to common inhalant allergens is an increasing problem in our society and almost one third of the population is affected. Therefore we need curative therapies to treat allergic diseases. The overall aim of this project is to learn how we can target allergens to be presented to the immune system in a ¿non-allergic¿ fashion in order to generate new tools for immunotherapy of allergic disease.
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