Development of new treatment strategies for allergic disease

Background
Allergic diseases affect 25-30% of the population in industrialised countries. Allergy to inhaled environmental antigens (allergens) is a common cause of asthma, a chronic inflammatory disease of the lung. Efficient treatment of allergy is thus important in order to prevent the development of allergic inflammation and asthma. Allergen specific immunotherapy (ASIT) is the only treatment in use that affects the cause of the allergy, gives long lasting relief of allergic symptoms and prevents development of asthma. Allergen-specific regulatory T-cells controlling the allergen specific immune response are activated during the course of ASIT.

Objective
The overall project aim is to provide new treatment strategies for allergic disease with improved safety and efficacy. In order to achieve this we need to acquire knowledge on how inflammation affects the regulatory mechanisms controlling the immune response to allergens.

Project description
We have previously shown that regulatory T-cells able to control an immune response towards allergens are activated and expand during inflammation. Meanwhile, the inflammation counteracts regulatory mechanisms. We are interested in the balance between these processes and study the immune response to allergens in a couple of ongoing studies involving patients with allergic asthma. Blood from the patients is collected after various types of treatments, e.g. allergen provocation. Isolated blood cells are stimulated in vitro with allergen and subsequently we investigate which regulatory cells and mediators that control the immune response.
Our strategy for obtaining improved ASIT is to activate immunoregulating mechanisms during the treatment. In a human in vitro system and in a mouse model for allergy to cat we test if allergens linked to immunomodulating substances are able to stimulate these mechanisms and counteract the allergic immune response. The major cat allergen Fel d 1 has been linked to various immunomodulators, e.g. Vitamin D3. Other modulators and adjuvants will also be evaluated in these systems. In the allergy model we can treat sensitized mice with promising immune-modulating Fel d 1 constructs and examine their effect on experimentally induced allergic inflammation and airway symptoms. The mouse model also allows us to investigate mechanisms of action for the immunomodulating constructs.

Thesis project
When you perform your thesis project you will be part of the research group during 20 weeks. You will join an ongoing research project and under supervision you will be responsible for a defined part of the project. You will also take part in other regular activities in the research group, e.g. research seminars and journal clubs. Methods which you will use are mainly immunological and cell biological techniques; e.g. cell culture, cell isolation, ELISA, flow cytometry, quantitative PCR, application of a disease model in mice. During the last part of your project period you will prepare a thesis in accordance with the guidelines of your university program. To be eligible you should have studied at least one advanced course in immunology.

Selected publications
Thunberg, S., Gafvelin, G., Grönneberg, R., Grunewald, J., Nord, M., Eklund, A. & van Hage, M. (2010) “Allergen provocation increases TH2-cytokines and FOXP3 expression in the asthmatic lung” Allergy 65(3), 311-318.

Neimert-Andersson, T., Thunberg, S., Swedin. L., Dahlén, SE., Jacobsson-Ekman, G., Wiedermann, U., Scheynius, A., Grönlund, H., van Hage, M. & Gafvelin, G. (2008) Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy. Allergy, 63, 518–526

Gafvelin, G., Parmley, S., Neimert-Andersson, T., Blank, U., Eriksson, TJL., van Hage, M. & Punnonen, J. (2007) Hypoallergens for allergen-specific immunotherapy by directed molecular evolution of mite group 2 allergens. J. Biol. Chem. 282(6), 3778-87

Thunberg, S., Akdis, M., Akdis, C.A., Trollmo, C., Malmström, V., Grönneberg, R., van Hage, M. & Gafvelin, G. (2007) Immune regulation by CD4(+)CD25(+) T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls. Clin Exp Allergy 37, 1127-36