This grant alms to understand the chemoattractant pathways that control the recruitment of Th2 effector lymphocytes into the airways in human asthma. Since allergen-specific Th2 cells play a key role in the pathogenesis of asthma, understanding the mechanisms that control their specific recruitment into the ain/vay has the potential to lead to new more specific therapies for allergic asthma while leaving overall T cellmediated lung immunity to viruses and other import human pathogens intact. In the 3.5 years of this R37 award, we have made significant progress towards this goal, and have also made some important related discoveries concerning chemokine control of Treg trafficking into the allergic lung and the ability of lung dendritic cells to imprint lung homing of T cells. In this project period, this grant has supported our work resulting in 9 original publications (7 from the Pis laboratory), 6 reviews, 1 commentary and 2 book chapters. In the prior funding period, we have identified CCR4 as an important chemokine receptor that participates in the control of Th2 cell recruitment into the airways in asthma. We also found that Tregs are recrOited into the lung in allergic pulmonary inflammation via a CCR4-dependent pathway where they have the ability to s.uppress allergic pulmonary inflammation. Since CCR4 only accounts for -50% of the Th2 cell trafficking signals, we clearly need to identify the other relevant chemoattractant pathways. In addition, since CCR4 is also important for Treg cell recruitment into the lung, the identification of additional chemokine pathways that participate in Th2 cells trafficking into the allergic lung could allow the specific targeting of Th2 cells, leaving Treg recruitment intact. In the MERIT extension period we will generate a CCL17 and CCL22 dual reporter mouse to determine the pattern of CCR4 ligand expression in the lung and lymph node in allergic pulmonary inflammation. We will also image the influence of chemokines on Th2, Treg and DC interactions in the lung using confocal and multiphtoton intravital microscopy. In addition, we will determine the chemokine receptors responsible for lung-specific homing and identify the lung DC subset that imprints lung-specific homing. In the prior funding period, our analysis of human T cells recruited into the airway following allergen challenge was restricted to bulk T cells, which include many bystander T cells. In our extension period, we will build upon our work using MHC class II allergen-specific tetramers to precisely define the chemokine receptor phenotype of allergen-specific T cells recruited into the lung. This is very important because in order to define the chemoattractant receptor pathways critical for pathogenic T cell recruitment into the airway in asthma, we need to define the relevant pathway for the critical cell, the allergen-specific T cell.
Asthma is an allergic disease of the lung that is increasing in prevalence and severity, especially among children, despite current therapies. Asthma is caused by the inappropriate activation and accumulation of T cells in the lung, where they drive the asthmatic response through the'release of potent inflammatory mediators. The goal of this grant is to identify the key proteins that control the accumulation of these pathogenic T cells in the lung, which will define excellent new targets for therapeutic intervention.
|Adams, David C; Hariri, Lida P; Miller, Alyssa J et al. (2016) Birefringence microscopy platform for assessing airway smooth muscle structure and function in vivo. Sci Transl Med 8:359ra131|
|Ling, Morris F; Luster, Andrew D (2016) Allergen-Specific CD4(+) T Cells in Human Asthma. Ann Am Thorac Soc 13 Suppl 1:S25-30|
|Kelly, Vanessa J; Winkler, Tilo; Venegas, Jose G et al. (2015) Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge. PLoS One 10:e0143976|
|Severa, Martina; Islam, Sabina A; Waggoner, Stephen N et al. (2014) The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8. J Immunol 192:2291-304|
|Chow, Melvyn T; Luster, Andrew D (2014) Chemokines in cancer. Cancer Immunol Res 2:1125-31|
|Okamoto, Ryo; Mandal, Kalyaneswar; Ling, Morris et al. (2014) Total chemical synthesis and biological activities of glycosylated and non-glycosylated forms of the chemokines CCL1 and Ser-CCL1. Angew Chem Int Ed Engl 53:5188-93|
|Griffith, Jason W; Luster, Andrew D (2013) Targeting cells in motion: migrating toward improved therapies. Eur J Immunol 43:1430-5|
|Ochkur, Sergei I; Protheroe, Cheryl A; Li, Wen et al. (2013) Cys-leukotrienes promote fibrosis in a mouse model of eosinophil-mediated respiratory inflammation. Am J Respir Cell Mol Biol 49:1074-84|
|Afshar, Roshi; Strassner, James P; Seung, Edward et al. (2013) Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation. J Allergy Clin Immunol 131:1644-52|
|Hariri, Lida P; Applegate, Matthew B; Mino-Kenudson, Mari et al. (2013) Volumetric optical frequency domain imaging of pulmonary pathology with precise correlation to histopathology. Chest 143:64-74|
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