title: 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 μg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-κB (phospho-NF-κB p65), interferon-γ (IFN-γ), 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-κB p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-γ expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-κB 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 μg/kg/h during pVOC decreases activation of iNKT cells without toxicity.
authors: BloodCenter of Wisconsin, 8733Watertown Plank Road, Milwaukee, WI 53226, USA. joshua.field@bcw.edu
authors: Joshua J
authors: JJ
authors: Field
authors: Gene
authors: G
authors: Lin
authors: Maureen M
authors: MM
authors: Okam
authors: Elaine
authors: E
authors: Majerus
authors: Jeffrey
authors: J
authors: Keefer
authors: Onyinye
authors: O
authors: Onyekwere
authors: Ainsley
authors: A
authors: Ross
authors: Federico
authors: F
authors: Campigotto
authors: Donna
authors: D
authors: Neuberg
authors: Joel
authors: J
authors: Linden
authors: David G
authors: DG
authors: Nathan
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D055611:Natural Killer T-Cells / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011687:Purines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D051996:Transcription Factor RelA / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D043705:Receptor, Adenosine A2A; D051996:Transcription Factor RelA; C430916:regadenoson; D007371:Interferon-gamma
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