The lung Is a unique epithelial surface at which inhaled particles, be they inert, bacteria or viral, are trapped in very close proximity to the bloodstream and in a filigree of epithelial surfaces. This presents unique spatial challenges for the T cells of the immune system to properly survey these antigens. Like many epithelial tissues, a selection of Immune macrophage and dendritic cells are poised within and beneath the surface to engulf and either neutralize, or to induce a more profound response to the Insult. During inflammatory insults including those of allergic but also bacterial or viral insults, the lung microenvironment physically changes. This new Project 2 will use live-imaging of viable lung and airways to determine how antigens traffic Into the lung and subsequently activate T cells, focusing the majority of effort upon a mouse model of asthma. The primary Issue being addressed is how inflammatory environments create a feedback loop that promotes accelerated immune responses and thus an enhanced inflammatory environment. We hypothesize that inflammation in the lung airway and aveolae creates a hyperreactive milieu for T lymphocyte priming. This milieu in turn is highly facilltative for synaptic interactions and thus increased production of lung remodeling factors Including cytokines. We propose that there are three distinct components of this. First, that there is a shift in the numbers, localization, antigen uptake and trafficking features between tolerizing phagocytic macrophages and highly immunogenic dendritic cells. The features of inflammatory antigens as well as the features of a remodeled milieu are both proposed to be directly responsible for the shift in the nature of APC which interact with T cells. Second, a shift In local polyclonal and antigen-specific regulatory T cells,modulated in part by the changes in APC population, subsequently modulates the activation of T cells. Finally, that T cells and their APC are modulated by airway remodeling and inflammation induced by agents such as Mycoplasma pulmonis or mast cell depletion. Thus, inflammation creates a fertile stimulatory ground for responses to inhaled antigens.

Public Health Relevance

The lung is the site of allergic as well as protective immune responses. Yet, we have little understanding of how antigen presentation leads to discrimination within this vital organ. Our studies will examine how this occurs spatially and temporally. The project will interface with Project 1 and 3 of this PPG by virtue of a common focus on remodeling factors that drive changes in the lung microenvironment during inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024136-35
Application #
8646944
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
35
Fiscal Year
2014
Total Cost
$321,842
Indirect Cost
$112,756
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kim, Minah; Nitschké, Maximilian; Sennino, Barbara et al. (2017) Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms. Cancer Res :
Nitschké, Maximilian; Bell, Alexander; Karaman, Sinem et al. (2017) Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations. Am J Pathol 187:1984-1997
Shepherd, Joanna; Fisher, Matthew; Welford, Abigail et al. (2017) The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate. Oncotarget 8:95648-95661
Baluk, Peter; Yao, Li-Chin; Flores, Julio C et al. (2017) Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract. JCI Insight 2:
Caughey, George H (2016) Mast cell proteases as pharmacological targets. Eur J Pharmacol 778:44-55
Lyons, Jonathan J; Yu, Xiaomin; Hughes, Jason D et al. (2016) Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet 48:1564-1569
Headley, Mark B; Bins, Adriaan; Nip, Alyssa et al. (2016) Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513-7
Pinkard, Henry; Stuurman, Nico; Corbin, Kaitlin et al. (2016) Micro-Magellan: open-source, sample-adaptive, acquisition software for optical microscopy. Nat Methods 13:807-809
Korhonen, Emilia A; Lampinen, Anita; Giri, Hemant et al. (2016) Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest 126:3495-510
Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430

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