Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Joshua J. Field1,2,
  2. Gene Lin3,
  3. Maureen M. Okam4,5,
  4. Elaine Majerus6,
  5. Jeffrey Keefer7,
  6. Onyinye Onyekwere8,
  7. Ainsley Ross4,
  8. Federico Campigotto9,
  9. Donna Neuberg9,
  10. Joel Linden3, and
  11. David G. Nathan5,9,10
  1. 1BloodCenter of Wisconsin, Milwaukee, WI;
  2. 2Medical College of Wisconsin, Milwaukee, WI;
  3. 3La Jolla Institute for Allergy and Immunology, San Diego, CA;
  4. 4Brigham and Women’s Hospital, Boston, MA;
  5. 5Harvard Medical School, Boston, MA;
  6. 6Washington University School of Medicine, St. Louis, MO;
  7. 7Johns Hopkins School of Medicine, Baltimore, MD;
  8. 8Howard University College of Medicine, Washington, DC;
  9. 9Dana-Farber Cancer Institute, Boston, MA; and
  10. 10Boston Children’s Hospital, Boston, MA

Key Points

  • The fraction of invariant NKT cells demonstrating activation is increased during painful crises compared with steady state.

  • Regadenoson, an adenosine A2A receptor agonist, decreases the fraction of activated invariant NKT cells during painful crises.

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. This trial was registered at www.clinicaltrials.gov as #NCT01085201.

  • Submitted November 6, 2012.
  • Accepted January 22, 2013.
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