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Förslaget inkom 2006-10-19

Mechanisms for regulation of the allergic immune response as targets for allergen-specific immunotherapy

Background: During the last decades a dramatic increase in prevalence of allergic diseases has been observed in our society. The most frequent type is IgE-mediated allergy, which is caused by IgE antibodies against otherwise harmless environmental antigens, i.e. allergens. The production of specific IgE by B-cells is stimulated by allergen-specific T-helper cells (Th), which can be divided into different subtypes according to their cytokine profiles. The Th2 cells are the Th-cells mainly responsible for stimulating IgE-production. Allergy is thus commonly considered to be a ¿Th2-disease¿. Recently a number of evidences suggest that regulatory T-cells (Treg) play an important immunomodulatory role, giving a balanced, non-allergic response to allergens.
Today, specific immunotherapy (SIT) is the only curative treatment for allergic disease in use. This therapy is however time-consuming, resource-demanding 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 general aim of our research is to dissect regulatory mechanisms controlling allergy and to explore ways of intervention of allergic reactions by targeting regulatory mechanisms. The goal is to develop new strategies for treatment of allergic disease.
Projects: Our research group consists of one professor, one associate professor, one post doc, three PhD students and one technician and our lab is situated at the department of Medicine, Clin. Immunology and Allergy unit, Karolinska Institutet, at Karolinska University hospital in Solna. Several other research groups studying similar research problems also work at the same department. Our group study regulatory immune mechanisms in order to learn how to activate these mechanisms, which normally control and suppress the allergic immune response towards allergens. In one project we are investigating how Treg cells control the immune response to allergens in allergic and healthy individuals. For this purpose, blood cells from allergic patients and healthy controls are collected and the cells stimulated with allergens in vitro. The mechanisms for how Tregs control the allergic immune response are then investigated. In a second project we focus on factors that modulate the T-cell response to allergens and decide between a balanced response and a Th2-dominated allergic immune response. One such factor is the bacterial wall component lipopolysaccharide (LPS), which interacts with toll-like receptor 4 (TLR-4) and CD14 on antigen-presenting cells. We are also evaluating a novel allergen carrier and adjuvant for allergen-specific immunotherapy (SIT), carbohydrate-based particles (CBP). A major cat allergen has been coupled to CBPs and will be assessed in a human system for their effect on dendritic cells and T-cell responses. Finally, at the present we are establishing a mouse model for cat allergy where we can test the therapeutic potency of different cat allergen preparations. This allergy model will be used to test new approaches to manipulate an allergic immune response in SIT.
Methods: The 20 credits project work will address a defined problem within some of the described projects. Many different methods will be employed, depending on the project. Cell fractioning and culture, isolation of Treg cells, in vitro differentiation of dendritic cells, cell analyses by flow cytometry, cell proliferation assays, cytokine production (e.g. ELISA, intracel


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