Inhibition of iNKT cells by adenosine A2A receptor activation in patients with sickle cell disease (45.1)

Abstract

Abstract Invariant natural killer T (iNKT) cells comprise a minor subset of lymphocytes that are activated by CD1d-restricted lipid antigens produced by pathogens or by the host in response to ischemia reperfusion-injury (IRI). Sickle cell disease (SCD) causes IRI due to chronic widely disseminated vaso-occlusion. IRI and SCD cause iNKT cell activation and release of IFN-γ that triggers an inflammatory cascade with recruitment and activation of other leukocytes to propagate tissue inflammation and injury. In mice with SCD, deletion of iNKT cells or inhibition of their activation with anti-CD1d antibodies or adenosine A2A receptor (A2AR) agonists inhibits tissue inflammation and injury at steady state or during evoked disease exacerbations. People with SCD have increased numbers of a subset iNKT cells that express cellular activation markers including activated NFκB (phospho-p65). The activated iNKT cell-subset concordantly displays elevated A2ARs that cause activated iNKT cells to become hypersensitve to inhibition by adenosine. Infusion of very low doses (1.5 nM in blood) of the A2AR agonist regadenoson into SCD patients results in no cardiovascular effects, but a rapid inhibition of iNKT cell NFκB and a reduction in A2AR immunoreactivity. We plan to initiate a clinical trial to determine if regadenoson infusion reduces the severity and duration of vaso-occlusive pain crises or acute chest syndrome in SCD patients.