Expression of Corticosteroid Regulated Genes By Peripheral Blood Mononuclear Cells (PBMCs) in Children from the NIH/Niaid Sponsored Asthma Phenotypes in the Inner City (APIC) Study after One Year of Guidelines-Based Therapy
Sunday, March 6, 2016: 4:45 PM
Concourse Foyer (Convention Center)
Elena Goleva, PhD, Leisa P. Jackson, BS, Baomei Shao, BS, Zheng Hu, BS, Michelle A. Gill, MD PhD, Denise C. Babineau, PhD, Andrew H. Liu, MD FAAAAI, Donald Y.M. Leung, MD PhD FAAAAI
Rationale: The development of peripheral blood markers for characterization of therapeutic responses to corticosteroids in asthma is of great importance.

Methods: PBMC were collected from 125 asthmatic children (ages 6-17) after one-month (Visit 0, V0) and one year (Visit 6, V6) of NAEPP guidelines-based therapy. At V6, patients were categorized as difficult-to-control, easy-to-control and indeterminate per APIC study definition. PBMC expression of glucocorticoid receptor alpha (GRalpha), corticosteroid transactivation (FK binding protein 5 (FKBP5)) and transrepression markers (IL-8, TNFalpha) at baseline and in response to 10-8M fluticasone were determined by RT-PCR. Matched V0 and V6 PBMC data from 95 patients were analyzed. 

Results: 31, 19 and 45 patients were categorized as easy-to-control, indeterminate and difficult-to-control, respectively. PBMC of difficult-to-control as compared to easy-to-control patients had significantly decreased GRalpha at V0 (p=0.05). Compared to easy-to-control patients, corticosteroid-mediated transrepression remained poor in PBMC of difficult-to-control patients at V6, with significantly decreased TNFalpha and IL-8 fold suppression by fluticasone at V6 compared to easy-to-control patients, even after adjusting for TNFalpha or IL-8 fold suppression by fluticasone at V0 (p=0.001 and p=0.02, respectively). Contrary to easy- and difficult-to-control patients, baseline TNFalpha did not decline between V0 and V6 in indeterminate patients (p=0.035 and p=0.008 respectively). Compared to indeterminate subjects, corticosteroid-mediated transactivation improved in the PBMC of difficult-to-control patients at V6, with increased FKBP5 induction by fluticasone at V6 (p=0.03). 

Conclusions: This is the first study to demonstrate reduced responsiveness to corticosteroids in PBMC of difficult-to-control asthma patients over the course of one year of the asthma guidelines-based therapy.