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 We already have extensive, published and unpublished, data showing the critical importance of two sets of interactions, namely OX40-OX40L and LIGHT-LTbR-HVEM to development of acute asthmatic inflammation.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

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of California San Diego
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Mehta, Amit K; Gracias, Donald T; Croft, Michael (2018) TNF activity and T cells. Cytokine 101:14-18
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