Research objectives and content
It is widely accepted that eosinophils are critical effector cells in bronchial mucosal damage in asthma. I wish to identify cells in bronchial biopsies from asthmatics and controls, which transcribe and translate mRNA for the "CC chemokines", eotaxin, RANTES MCP-3 and MCP-4. These newly discovered peptides are potent eosinophil chemoattractants. Professor Kay's group have developed novel technology which allows identification of the phenotype of chemokine- and cytokine-producing cells. I will study both allergic (extrinsic) and non-allergic (intrinsic) asthma and, as controls, use material from atopic non- asthma (mostly allergic rhinitis) and non-atopic normal subjects. Preliminary data shows mRNA-positive cells for eotaxin, RANTES and MCP-3 in bronchial biopsies from allergic asthma. The specific hypotheses are as follows: (I) There is increased gene expression of CC chemokines in both atopic asthma and non-atopic asthma (when compared to atopic non-asthmatics and non-atopic normal controls) and that this is related to disease severity as measured by the FEV1, methacholine PC20 and the symptom scores. (2) The cells expressing mRNA and protein product for CC chemokines include T cells, macrophages, epithelial cells, endothelial cells, eosinophils and mast cells. (3) CC chemokine gene-expression is related to the numbers of eosinophils infiltrating the bronchial mucosa. (4) There are different patterns of CC chemokine expression between atopic and non atopic asthma.
Training content (objective, benefit and expected impact)
The objective is to learn the methods of molecular immunopathology as they relate to the study of asthma. This is a growing and important disease in Europe and world wide. It will be possible to set up these techniques when I return to Greece - at which time I will be able to enlarge further and expand the important scientific questions being addressed in this proposal. Thus I will learn the techniques of in situ hybridisation and immunohistochemistry and relate these to high quality objective clinical measurements.
Links with industry / industrial relevance (22)
The Allergy and Clinical Immunology Group at the NHLI have substantive links with industry, particularly in the general field of eosinophils and T cells in asthma. They are currently evaluating monoclonal antibody treatment directed against CD4+ T cells in chronic severe asthma as well as the anti-eosinophil properties of leukotriene receptor antagonists.