Refractoriness to treatment is a major cause of asthma-related morbidity and mortality. Refractory asthma accounts for the bulk of the direct cost for asthma. There is a general consensus that asthma is heterogeneous and that the same treatment will not work for all. Treatments that failed in general asthma population were found beneficial to a specific endotype of asthma (e.g. anti-IL5 antibody in eosinophilic asthma). For this reason identification of mechanism-based subtypes (endotypes) of asthma and development of mechanism-targeted treatment are of paramount importance. Using flow cytometry-based characterization of bronchoalveolar lavage (BAL) cells we have recently reported the identification of a novel endotype of asthma that is characterized by the dominance of dual positive Th2/Th17 cells in the airways. This Th2/Th17 predominant endotype distinguishes itself from the Th2 predominant and Th2/Th17 low endotypes with more severe asthma and greater refractoriness to treatment including steroids. The objective of this proposal is to study this Th2/Th17 predominant endotype of severe refractory asthma. We propose 4 specific aims.
Under specific aim 1 we will characterize dual positive Th2/Th17 cells in airways from asthmatic patients and define the phenotype of Th2/Th17 predominant asthma. We will perform bronchoalveolar lavage, endobronchial biopsy and brushing in refractory asthmatic patients. We will characterize the cytokine and surface marker profile of BAL Th2/Th17 cells by flow cytometry and RNA-seq. Through analyses of tissue histopathologic, pulmonary physiologic, immunologic & clinical features we will identify unique phenotypic characteristics that are associated with the production of Th17 cytokines by Th2/Th17 cells.
Specific aim 2 will examine the mechanism of development of airway Th2/Th17 cells in asthma. We will examine the role of IL1? and danger-associated molecular patterns in transdifferentiation of Th2 cells into Th2/Th17 cells.
Under specific aim 3 we will delineate the signaling mechanism of steroid resistance of Th2/Th17 cells. The cytokines that induce Th2/Th17 cells also activate the MEK and p38 MAPK signaling pathways. We will examine the role of these signaling molecules in induction of steroid resistance. We will examine MEK regulation of the glucocorticoid receptor-associated co-repressor SMRT, p38 regulation of glucocorticoid receptor phosphorylation, and the consequences of these events for steroid resistance.
Specific aim 4 will examine the role of IL1? and IL8 in the pathogenesis of neutrophilic asthma, another steroid resistant form of refractory asthma. We will also examine the role of Th2 cytokines in preventing neutrophil influx into the airways in Th2/Th17 predominant asthma. The study is important because it identifies and characterizes a novel endotype of severe refractory asthma. We will perform invasive procedures and examine bronchoalveolar lavage cells and bronchial tissue for vast majority of experiments, which has direct relevance for asthma. The delineation of the molecular mechanism of Th2/Th17 cell development and its steroid resistance will pave the way for clinical trials of already existing therapeutic agents in Th2/Th17 endotype of severe refractory asthma.

Public Health Relevance

Asthma is a heterogeneous disease, which means it has multiple causes and multiple forms of manifestation. Response to treatment in asthma varies depending upon the cause. Despite growing understanding in fundamental immunologic mechanisms of asthma, our knowledge about mechanism-based subgroups of asthma is superficial, which hinders therapeutic progress. In this proposal we have identified a new subgroup of asthma with a distinct immunologic mechanism and possible link to infection. A successful completion of this project will help determine clinical benefits for this subgroup of asthma from certain drugs that are already available in the market for other diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL126895-01A1
Application #
9029107
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Noel, Patricia
Project Start
2016-04-20
Project End
2020-03-31
Budget Start
2016-04-20
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Alam, Rafeul; Good, James; Rollins, Donald et al. (2017) Airway and serum biochemical correlates of refractory neutrophilic asthma. J Allergy Clin Immunol 140:1004-1014.e13
Verma, Mukesh; Liu, Sucai; Michalec, Lidia et al. (2017) Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations. J Allergy Clin Immunol :
Liu, Weimin; Liu, Sucai; Verma, Mukesh et al. (2017) Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol 139:1548-1558.e4
Katial, Rohit K; Martucci, Michael; Burnett, Trever et al. (2016) Nonsteroidal anti-inflammatory-induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 138:579-85
Irvin, Chaoyu; Zafar, Iram; Good, James et al. (2014) Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol 134:1175-1186.e7