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

Joshua J. Field, Gene Lin, Maureen M. Okam, Elaine Majerus, Jeffrey Keefer, Onyinye Onyekwere, Ainsley Ross, Federico Campigotto, Donna Neuberg, Joel Linden, David G. Nathan

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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 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.

Original languageEnglish (US)
Pages (from-to)3329-3334
Number of pages6
JournalBlood
Volume121
Issue number17
DOIs
StatePublished - Apr 25 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Field, J. J., Lin, G., Okam, M. M., Majerus, E., Keefer, J., Onyekwere, O., Ross, A., Campigotto, F., Neuberg, D., Linden, J., & Nathan, D. G. (2013). Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood, 121(17), 3329-3334. https://doi.org/10.1182/blood-2012-11-465963