期刊
BLOOD
卷 121, 期 17, 页码 3329-3334出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-11-465963
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类别
资金
- National Heart, Lung, and Blood Institute [RC2HL101367, R34HL108757]
- Astellas Pharma
- Clinical and Translational Science Awards
Adenosine A(2A) receptor (A(2A)R) 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(2A)R agonist regadenoson in adults with SCD. The target dose was 1.44 mu g/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kappa B (phospho-NF-kappa B p65), interferon-gamma (IFN-gamma), and A(2A)R. 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-kappa B p65 and A(2A)R expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-gamma expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-kappa 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 mu g/kg/h during pVOC decreases activation of iNKT cells without toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01085201.
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