As noted in the Background and Significance section of the clinical proposal, two studies used clonal culture methodology in semisolid methylcellulose medium supplemented with SCF (and, in one study, IL-9) and reported that CD34+ cells from the blood of asthmatic children gave rise to 5-6-fold higher numbers of MC colonies than did CD34+ cells from normal controls (Mwamtemi 2001;Matsuzaka 2003). These studies did not characterize the putative colony-forming cell subset. Indeed, the identity of the committed MCp in humans has been elusive. Because asthma involves a MC hyperplasia that is induced by unknown mechanisms, it is essential to establish the surface and molecular phenotype of committed MCp in the blood. We propose to verify our preliminary characterization of MCp in Aim 1, and to determine the quantitative relationships between these MCp and the numbers and distribution of MCs in biopsies from patients with severe asthma, as well as the degree of AHR to methacholine and to adenosine monophosphate (AMP) in Aim 2. In parallel with the clinical studies, we will determine whether imatinib therapy alters the numbers or phenotype of this unique cell population. The studies proposed herein will provide the first cytofluorographic and transcriptional definitions of MCp in the human, and will determine the quantitative and functional relationship of this unique cell type to mature MCs in the ainA/ay, and to pathophysiologic outcomes. The development of cytofluorographic criteria for MCp may also provide a surrogate assay that could predict the likely benefit of c- Kit inhibition for asthma and other diseases.
| Cahill, Katherine N; Katz, Howard R; Cui, Jing et al. (2017) KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376:1911-1920 |
| Ono, Emiko; Dutile, Stefanie; Kazani, Shamsah et al. (2014) Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. Am J Respir Crit Care Med 190:886-97 |
| Barnig, Cindy; Cernadas, Manuela; Dutile, Stefanie et al. (2013) Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci Transl Med 5:174ra26 |
| Cummings, Hannah E; Liu, Tao; Feng, Chunli et al. (2013) Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 191:5807-10 |
| Kazani, Shamsah; Israel, Elliot (2011) Update in asthma 2010. Am J Respir Crit Care Med 184:291-6 |
