T-cell Control of Airway Remodeling

University Of California, San Diego, La Jolla CA

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Abstract

The acute phase of asthma is characterized largely by rapid cell infiltration in the lungs driven by airborne[unreadable] allergens. However, chronic asthma is characterized by progressive airway remodeling, involving bronchiolar[unreadable] subepithelial fibrosis and an increase in airway smooth muscle (ASM). It has been proposed that the[unreadable] increase in ASM and fibrosis may be the primary factor contributing to long-term airway hypersensitivity and[unreadable] as such its control is of major interest. CD4 T cells secreting Th2 cytokines might be responsible for driving[unreadable] much of the pathology associated with asthma, but most information on the molecular regulation of asthma[unreadable] has been obtained from murine models that only mimic the acute phase1 and do not generally result in[unreadable] fibrosis or increases in ASM. Thus, in terms of chronic asthma and airway remodeling, there is presently little[unreadable] information on the role, contribution, or stage of response where any cell type, including CD4 cells, might be[unreadable] critical. Our overall hypothesis in this application is that CD4 T cells are important contributors to chronic[unreadable] asthmatic reactions and both indirectly through effects on eosinophils and mast cells, and directly through[unreadable] effects on epithelial cells and ASM, they will, regulate progressive airway remodeling over time. We have[unreadable] spent much of the past few years trying to understand the membrane-expressed receptors that regulate T[unreadable] cells, in particular members of the TNF/TNFR superfamily that act as costimulatory receptors. We already[unreadable] have extensive, published and unpublished, data showing the critical importance of two sets of interactions,[unreadable] namely OX40-OX40L and LIGHT-LTbR-HVEM to development of acute asthmatic inflammation. However,[unreadable] there have currently been no studies of any costimulatory molecules and whether they participation in[unreadable] chronic asthma, and specifically regulate airway remodeling. Recent studies have visualized expression of[unreadable] OX40L, LTbR, and HVEM, on smooth muscle, epithelial cells, mast cells, and eosinophils, providing a strong[unreadable] rationale for these ligands and their receptors, OX40 and LIGHT, expressed on T cells to control chronic[unreadable] asthma. By using knockout mice and blocking reagents, and employing novel TCR transgenic systems[unreadable] where we can track antigen-reactive Th2 cells that express or lack OX40 or LIGHT, in mice deficient in either[unreadable] LTbR, HVEM, or OX40L, we will show if and how these novel receptor-ligand systems control airway[unreadable] remodeling.