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Blood, 15 October 2003, Vol. 102, No. 8, pp. 2862-2867.
Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2003-04-1029.
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IMMUNOBIOLOGY
Anti-D initially stimulates an Fc-dependent leukocyte oxidative burst and subsequently suppresses erythrophagocytosis via interleukin-1 receptor antagonist
Malini D. Coopamah,
John Freedman, and
John W. Semple
From the Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital; Department of Pharmacology, University of Toronto; Department of Medicine, University of Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto; Canadian Blood Services; and the Toronto Platelet Immunobiology Group, Toronto, ON, Canada.
Previous results have demonstrated that anti-D therapy in children with chronic auto-immune thrombocytopenic purpura (AITP) induced a significant increase in several pro- and anti-inflammatory plasma cytokines within 2 hours of administration. To investigate the biologic basis of these early in vivo responses, we developed a flow cytometric assay to measure Fc-dependent responses of human peripheral leukocytes with fluorescently labeled and anti-D–opsonized red blood cells (RBCs). When anti-D–opsonized RBCs were incubated with peripheral blood leukocytes, the earliest detectible event observed was a significant oxidative burst in both monocytes (P < .05) and granulocytes (P < .0001), characterized by the production of hydrogen peroxide (H2O2), peroxynitrite (ONOO–), superoxide (O –2), and hydroxyl (OH) by 10 minutes which declined by 1 hour. By 2 hours, the opsonized RBCs were phagocytosed, particularly by granulocytes (P < .001), but the phagocytosis subsequently declined by 6 hours of incubation. The decline in phagocytosis was correlated with a significant production of interleukin-1 receptor antagonist (IL1ra) by both monocytes (P = .036) and granulocytes (P = .0002) within 4 hours. None of these events occurred if the RBCs were coated with anti-D F(ab)'2 fragments. When recombinant IL1ra was titrated into the assay, phagocytosis of the opsonized RBCs was significantly inhibited (P = .002). Taken together, these results suggest that at least one mechanism of action of anti-D is via the production of the anti-inflammatory cytokine IL1ra which can negatively regulate the ability of leukocytes to phagocytose opsonized cells.
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