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The adenosine A 2A receptor agonist regadenoson decreases activation of invariant NKT cells in human sickle cell subjects
Author(s) -
Lin Gene,
Field Joshua,
Neuberg Donna,
Nathan David,
Linden Joel
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1119.2
Subject(s) - agonist , medicine , immunology , inflammation , natural killer t cell , adenosine , receptor , endocrinology , t cell , immune system
Sickle cell disease (SCD) is associated with widely disseminated vaso‐occlusion caused by hyper‐adherent sickle red blood cells and leukocytes. Recurrent episodes of ischemia reperfusion‐injury in the vasculature of SCD individuals promote a pro‐inflammatory state. In a mouse model of SCD, adenosine A 2A receptor (A 2A R) activation significantly decreases pulmonary inflammation and dysfunction. Similar protective effects are produced by depleting invariant NKT (iNKT) cells or by blocking CD1d restricted activation of iNKT cells, indicating that A 2A R agonists mediate their anti‐inflammatory effects primarily by inhibiting iNKT cell activation. We have initiated a clinical trial to investigate the safety and efficacy of a selective A 2A R agonist, regadenoson, in human SCD subjects. Our findings indicate that iNKT cells in blood from normal subjects are fewer in number and less activated than from subjects with SCD. Furthermore, activated iNKT cells from SCD subjects are CD4+ and express elevated levels of phospho‐NFκB (P‐NFκB), CD69, and the A 2A R. Most significantly, infused regadenoson was observed to diminish iNKT cell expression of P‐NFκB and other activation markers in a time dependent manner. These results imply that A 2A R signaling and NFκB regulate iNKT cell activation and that selective A 2A R agonists may be useful for treating acute vaso‐occlusion in SCD.