Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A_2A receptor agonist regadenoson

Adenosine A_2A receptor (A_2AR) 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 A_2AR 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 A_2AR. 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 A_2AR 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.