TY - JOUR
T1 - Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson
AU - Field, Joshua J.
AU - Lin, Gene
AU - Okam, Maureen M.
AU - Majerus, Elaine
AU - Keefer, Jeffrey
AU - Onyekwere, Onyinye
AU - Ross, Ainsley
AU - Campigotto, Federico
AU - Neuberg, Donna
AU - Linden, Joel
AU - Nathan, David G.
N1 - Funding Information:
This study was supported by National Heart, Lung, and Blood Institute grants RC2HL101367 and R34HL108757 and a grant from Astellas Pharma (D.G.N.). The authors also acknowledge the support provided by Clinical and Translational Science Awards at all participating institutions.
Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/4/25
Y1 - 2013/4/25
N2 - Adenosine A2A receptor (A2AR) agonists reduce invariant natural killer T (iNKT) cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A2AR agonist regadenoson in adults with SCD. The target dose was 1.44 mg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kB (phospho-NF-kB p65), interferon-g (IFN-g), and A2AR. Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-kB p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-g expression was also significantly higher compared with controls (P 5 .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-kB p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P 5 .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 mg/kg/h during pVOC decreases activation of iNKT cells without toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01085201.
AB - Adenosine A2A receptor (A2AR) agonists reduce invariant natural killer T (iNKT) cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A2AR agonist regadenoson in adults with SCD. The target dose was 1.44 mg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kB (phospho-NF-kB p65), interferon-g (IFN-g), and A2AR. Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-kB p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-g expression was also significantly higher compared with controls (P 5 .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-kB p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P 5 .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 mg/kg/h during pVOC decreases activation of iNKT cells without toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01085201.
UR - http://www.scopus.com/inward/record.url?scp=84879350342&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-11-465963
DO - 10.1182/blood-2012-11-465963
M3 - Article
C2 - 23377438
AN - SCOPUS:84879350342
SN - 0006-4971
VL - 121
SP - 3329
EP - 3334
JO - Blood
JF - Blood
IS - 17
ER -