The costimulatory T-cell molecule ICOS as a novel therapeutic target for allergic airway disease

• Applicant: Professor Dr. Andreas Hutloff
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2007 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 57198407

T cells initiate and maintain allergic airway inflammation by facilitating cellular infiltration and humoral immune responses. Activation, differentiation, and effector cell function of T cells is directed by so-called costimulatory molecules that deliver critical signals modulating the antigen-specific signal of the T-cell receptor (TCR). Considering their pivotal impact on T-cell regulation, costimulatory molecules are promising targets for therapeutic intervention in allergic diseases. Many of these costimulatory molecules have been identified only recently. So far, little is known about their specific role in the regulation of the immune response, especially for allergic airway inflammation. According to current understanding, the Inducible Co-Stimulatory T cell molecule, ICOS, is one of the most promising candidates for an in vivo blocking strategy to treat allergic airway inflammation, because it specifically regulates the effector phase of Th2 cells and is important for the regulation of immunoglobulin production by B cells. We are especially interested in the local production of allergen-specific IgE in lung tissues. Only recently we showed that ICOS is mainly involved in this process. However, the exact cell interactions, time, and mode of ICOS costimulation during allergic airway inflammation is still not fully understood. To learn more about the role of T and B cells for the pathophysiology of airway inflammation, we want to establish a mouse model for allergic airway inflammation in which it will be possible to track antigen-specific T and B cells in vivo at any stage of the allergic response and analyse them on a single-cell level. This system will be crucial to defining the exact role of ICOS costimulation in allergic airway inflammation, which is a prerequisite for the development of therapeutic strategies. As a new therapeutic strategy, we plan to interfere with ICOS costimulation using blocking monoclonal antibodies in our mouse model and test different routes and time points of application. Studies will also include a chronic airway inflammation model and delayed treat-ment regime to mimick more closely the clinical setting in patients. Taken together, this project will deliver important information on the pathophysiology of allergic airway inflammation and the applicability of T cell costimulation blockade for the treatment of allergic diseases.

• DFG Programme: Research Grants
• Participating Person: Dr. Katja Beier