title: Sickle cell disease (SCD), iNKT cells, and regadenoson infusion.
abstract: A humanized murine sickle cell-disease (SCD) model (NY1DD) has been used to study ischemia/reperfusion injury (IRI) in sickle cell anemia, and iNKT cells (a very small subset of murine and human T cells) have been found to instigate such injury in this model. Furthermore, levels of activated iNKT cells are generally elevated in the circulation of patients with SCD. Because activated iNKT cells are rich in adenosine A2A receptors which, when agonized, down-regulate the inflammatory cytokine expression that characterizes the cells, we have conducted a phase 1 trial of a constant infusion of low-dose regadenoson (an adenosine analogue with high A2A receptor specificity) to determine its safety and the capacity of a safe dose to down-regulate circulating iNKT cells in patients with SCD. We have found two dose rates that are both safe and effective and now plan a controlled Phase 2B clinical trial to determine whether our highest dose, administered as a 48-hour constant infusion, will induce faster remission in both painful vaso-occlusive crisis (pVOC) and acute chest syndrome (ACS).
authors.affiliation: Dana-Farber Cancer Institute, Boston MA, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Nathan
authors.forename: Joshua
authors.initials: J
authors.lastname: Field
authors.forename: Gene
authors.initials: G
authors.lastname: Lin
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Elaine
authors.initials: E
authors.lastname: Majerus
authors.forename: Onyinye
authors.initials: O
authors.lastname: Onyekwere
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keefer
authors.forename: Maureen
authors.initials: M
authors.lastname: Okam
authors.forename: Ainsley
authors.initials: A
authors.lastname: Ross
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000473:pathology*; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D055611:Natural Killer T-Cells / Q000473:pathology*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058908:Adenosine A2 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; C430916:regadenoson