Asthma is a complex inflammatory disease thought to reflect a dysregulated Immune state established at the epithelial interface in the lung. Although subgroups of patients with different types of Inflammation have been described, allergic asthma, as represented by increased numbers of innate and adaptive IL-4/IL-13- expressing cells, remains highly prevalent. Despite this Insight, understanding the process(es) by which allergic asthma is Initiated will require studies in mice, where recent findings Implicate crosstalk between the lung epithelia and innate immune cells. An innate non-B, non-T, non-NK lymphocyte population present in mice and humans has gained attention through the capacity to respond to epithelial cytokines IL-25 and IL- 33 by release of large amounts of IL-13 and IL-5. Using cytokine reporter mice that accurately function-mark immune cells, we have succeeded in tracking and deleting these cells, which we designate innate helper type-2 or iH2 cells, through their capacity to generate either of these cytokines. Given the central role of IL- 13 and IL-5 In mediating tissue alterations important in asthma and allergic immunity, we propose two specific alms to study the function ofthese cells in allergic lung Inflammation.
Specific Aim 1. To establish lineage and function marking of iH2 cells In order to reveal their quantitative contributions to allergic lung immunity during physiologic challenges and to compare this with cytokine- mediated activation.
Specific Aim 2. To assess the functional requirements for IH2 cells during allergic challenges and In immune homeostasis, and to examine the physical positioning ofthese cells in lung tissues In situ. Insights from these two Specific Alms will be used to guide the choices of probes and profiles that will enable the study ofthese cells In bronchoaiveolar lavage and airway samples collected from patients with allergic asthma. (LAY SUMMARY). Asthma remains the most prevalent chronic debilitating disease of childhood and a major contributor to health care costs in the United States. These studies seek to understand the early steps required to generate an inflammatory lung response resembling asthma using model systems In mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107202-02
Application #
8526522
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$398,516
Indirect Cost
$144,684
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bando, Jennifer K; Liang, Hong-Erh; Locksley, Richard M (2015) Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat Immunol 16:153-60
Simpson, Laura J; Patel, Sana; Bhakta, Nirav R et al. (2014) A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production. Nat Immunol 15:1162-70
Thomas, Molly F; L'Etoile, Noelle D; Ansel, K Mark (2014) Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways. Trends Genet 30:298-307
Peters, Michael C; Mekonnen, Zesemayat K; Yuan, Shaopeng et al. (2014) Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol 133:388-94
Jackson, Daniel J; Hartert, Tina V; Martinez, Fernando D et al. (2014) Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 11 Suppl 3:S139-45
Baumjohann, Dirk; Ansel, K Mark (2014) MicroRNA regulation of the germinal center response. Curr Opin Immunol 28:6-11
von Moltke, Jakob; Locksley, Richard M (2014) I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis. Curr Opin Immunol 31:58-65
Locksley, Richard M; Fahy, John V (2014) Asthma and the flu: a tricky two-step. Immunol Cell Biol 92:389-91
Van Dyken, Steven J; Mohapatra, Alexander; Nussbaum, Jesse C et al. (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and ?? T cells. Immunity 40:414-24
Bronevetsky, Yelena; Ansel, K Mark (2013) Regulation of miRNA biogenesis and turnover in the immune system. Immunol Rev 253:304-16

Showing the most recent 10 out of 16 publications