Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion.
Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge. In this setting, IVIG rapidly (<10 minutes) reduced adherent leukocyte numbers and dramatically inhibited interactions between RBCs and WBCs, resulting in improved microcirculatory blood flow and survival of sickle cell "Berkeley" mice. Longer survival correlated positively with blood flow (P=.001) and negatively with the number of adherent leukocytes (P=.001) and RBC-WBC interactions (P=.002). Using multichannel digital fluorescence videomicroscopy, we found that IVIG affected specifically the recruitment of neutrophils. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial.
Chang
Jungshan
J
Mount Sinai School of Medicine, Department of Medicine, Immunobiology Center and Black Family Stem Cell Institute, New York, NY 10029, USA.
Shi
Patricia A
PA
Chiang
Elaine Y
EY
Frenette
Paul S
PS
D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004913:Erythrocytes, Abnormal / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology* / Q000627:therapeutic use; D007155:Immunologic Factors / Q000494:pharmacology*; D036904:Leukocyte Rolling / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D014652:Vascular Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D014699:Venules / Q000378:metabolism / Q000473:pathology
D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors