Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson.

ABSTRACT: 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 ?g/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-?B (phospho-NF-?B p65), interferon-? (IFN-?), 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-?B p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-? expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-?B p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P = .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 ?g/kg/h during pVOC decreases activation of iNKT cells without toxicity.

SUBMITTER: Field JJ 

PROVIDER: S-EPMC3637009 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature