Selective Therapeutic Targeting of iNKT Cell-Mediated Inflammation in Sickle Cell Anemia

Sickle cell anemia is a genetic disorder of red blood cells caused by a point mutation in the β-globin gene (HBB; β^{6 glu>val}). Sickle hemoglobin (HbS; α₂β^S2) polymerizes upon deoxygenation leading to the two main pathophysiologic features of sickle cell anemia: hemolysis and vasoocclusion. We now understand vaso-occlusion to be a complex, multicellular process involving erythrocytes, leukocytes, platelets, endothelial cells, and soluble coagulation and inflammatory factors. Ischemia-reperfusion injury (IRI), which is thought to underlie the pathogenesis of the vaso-occlusive complications, is also associated with a profound pro-inflammatory environment. This inflammation causes activation, adhesion, and migration of leukocytes that can sustain and propagate vaso-occlusion. Thus, inflammation can be considered a cause of vaso-occlusion as well as a consequence. Inflammation has long been considered a therapeutic target in this disease, and several investigators have tested corticosteroids for the treatment of painful vaso-occlusive events and acute chest syndrome. Although corticosteroid therapy can shorten vaso-occlusive events, it can also precipitate “rebound” painful events, which decreases the net benefit.

In search of a better treatment, Field and colleagues have begun to explore a finely targeted approach to anti-inflammatory therapy in sickle cell anemia. Based on the knowledge that invariant natural killer T (iNKT) cells appear to be key to propagating the inflammatory cascade associated with IRI and that iNKT cells are both increased in number and activated in sickle cell anemia, they conducted a phase I trial of regadenoson to decrease iNKT activation during painful events. iNKT cells are a rare subset of lymphocytes that link innate and adaptive immune responses, and they express high amounts of adenosine A2A receptors (A2AR) upon activation.¹  Regadenoson is a selective A2AR agonist used to induce myocardial hyperemia for imaging, but its anti-inflammatory actions occur at drug concentrations 10 to 100 times lower than its cardiovascular actions. As such, a low-dose infusion of regadenoson has the potential to decrease inflammation yet avoid cardiovascular side effects.

Field and colleagues studied iNKT cell activation and administered regadenoson as a low-dose, 24-hour infusion (1.44 mcg/kg/hour, determined during a dose-finding phase) to 12 adults with sickle cell anemia – six at steady-state and six during a painful vaso-occlusive event. iNKT activation was assessed by analyzing the degree of expression of NF-κB, A_2AR, and IFN-γ by flow cytometry. They found that iNKT activation was highest during painful events compared with steady-state and normal controls. During painful events, regadenoson infusion reduced iNKT activation to levels similar to steady-state and normal controls, chiefly as measured by reduced expression of NF-κB. The infusion of regadenoson was well tolerated at all dose levels. The only potentially dose-limiting toxicity was transient bradycardia (heart rate = 49 bpm) while asleep at the 0.6 mcg/kg/hr dose level, but this event was adjudicated not to be medication-related. Heart rate and blood pressure were a concern because bolus doses of regadenoson used for myocardial imaging cause vasodilation; however, both were relatively stable throughout the regadenoson infusion, showing only normal physiologic variation, and the infusion did not interfere with the provision of usual medical care for the patients with pain.