The costimulatory T-cell molecule ICOS as a novel therapeutic target for allergic airway disease
Final Report Abstract
We successfully established a novel murine airway inflammation model which allows to track antigen-specific T and B cells in the lung-draining lymph nodes as well as the inflamed lung tissue using immunohistology and flow cytometry. In this model allergen-specific, transgenic T and B cells are adoptively transferred into syngeneic, immunocompetent hosts. Intranasal application of the cognate allergen leads to activation of the transgenic T and B cells in the lung-draining lymph nodes. Subsequently, both cell types emigrate into the lung tissue. There, high frequencies of cytokine producing T cells and immunoglobulin producing B cells are found in large clusters. Repeated allergen challenge generates a chronic inflammation, where switched memory B cells can still be found in the tissue several weeks after the last allergen application. Long-lived plasma cells are mainly found in the bone marrow at this stage. We used our system to analyze the role of the inducible costimulator ICOS for allergic airway inflammation. Clinical signs of airway inflammation (lung infiltration with lymphocytes and granulocytes, IgE titers) are strongly reduced in ICOS knock-out mice. As the major biological effect ICOS regulates the general pool size of allergen-specific T and B cells. In the lymph node, ICOS regulates differentiation of T follicular helper cells and germinal center B cells. In the lung tissue, ICOS has an important role for T cell cytokine production and the generation of IgA plasmablasts and memory cells.
Publications
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2009. BCG priming of dendritic cells enhances T regulatory and Th1 function and suppresses allergen-induced Th2 function in vitro and in vivo. Int Arch Allergy Immunol 150:210-220
Ahrens, B., C. Gruber, R.D. Rha, T. Freund, D. Quarcoo, A. Awagyan, A. Hutloff, A.M. Dittrich, U. Wahn, and E. Hamelmann
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2009. Lipopolysaccharide stimulation of dendritic cells induces interleukin-10 producing allergen-specific T cells in vitro but fails to prevent allergic airway disease. Exp Lung Res 35:307-323
Ahrens, B., T. Freund, R.D. Rha, A.M. Dittrich, D. Quarcoo, A. Hutloff, and E. Hamelmann
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2012. Prenatal allergen exposures prevent allergen-induced sensitization and airway inflammation in young mice. Allergy 67
Gerhold, K., A. Avagyan, E. Reichert, C. Seib, D.V. Van, E.O. Luger, A. Hutloff, and E. Hamelmann
