Single‐dose intravenous gammaglobulin can stabilize neutrophil Mac‐1 activation in sickle cell pain crisis

Abstract

Intravenous immunoglobulin (IVIG) decreases neutrophil adhesion to endothelium and red blood cell-neutrophil interactions in sickle cell mice undergoing vaso-occlusion. In this Phase I clinical trial of sickle cell anemia (SCA) patients admitted with pain crisis, we evaluated the status of adhesion molecules on neutrophils in control and IVIG-treated subjects pre- and post-infusion up to 800 mg/kg, the same dose used in murine studies. Mac-1 function significantly decreased from baseline in the low-dose IVIG (200–400 mg/kg) cohorts. IVIG-related adverse events may have occurred in the high-dose (600–800 mg/kg) cohorts. There were no significant increases in neutrophil and leukocyte counts, suggesting that IVIG may more selectively inhibit Mac-1 function as opposed to neutrophil adhesion. This study provides the first in-human validation of pre-clinical murine studies that IVIG can decrease Mac-1 function.

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease

“…162,164 Furthermore, a clinical trial using intravenous immunoglobulin infusions to block Fc γ RIII receptor mediation of secondary activity on neutrophils in children with SCD in crisis is in process (ClinicalTrials.gov identifier: NCT01757418). 165 A functional in-vitro adhesion test, such as the SCD biochip, could be a useful tool for measuring patients’ response to treatment. Moreover, the SCD biochip could be adopted as an in-vitro model in which to test therapeutics that target cellular adhesion.…”

Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli

“…Interestingly, a pan-selectin inhibitor, rivipansel (GMI-1070), has been shown in phase II studies to reduce the time to resolution of systemic vaso-occlusive pain crisis and opioid administration in SCD patients (39). In a separate phase I study, intravenous immunoglobulin (IVIG) was shown to inhibit Mac-1 activation on neutrophils in SCD patient blood (40). Recently, an oral P-selectin inhibitor was also shown to improve microvascular blood flow in SCD patients (41).…”

Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology

“…112 IVIG administration in SCD patients in a phase 1 study demonstrates no significant adverse events with doses up to 800 mg/kg, indicating safety and tolerability in acute VOC. 113 Because lower doses show better biomarker and clinical efficacy profiles, the 400 mg/kg dose is selected for further study in an ongoing phase 2 trial (#NCT01757418). Numerous preclinical and early phase clinical studies have demonstrated the benefit of targeting P-selectin.…”