Anti-D initially stimulates an Fc-dependent leukocyte oxidative burst and subsequently suppresses erythrophagocytosis via interleukin-1 receptor antagonist.

Abstract

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.

• Authors: Malini D Coopamah, John Freedman, John W Semple
• Journal: Blood (Blood) Vol. 102 Issue 8 Pg. 2862-7 (Oct 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12829590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• IL1RN protein, human
• Immunoglobulin Fragments
• Immunoglobulins
• Interleukin 1 Receptor Antagonist Protein
• Reactive Oxygen Species
• Rho(D) Immune Globulin
• Sialoglycoproteins

Topics

• Cytokines (biosynthesis, metabolism)
• Dose-Response Relationship, Drug
• Erythrocytes (metabolism)
• Flow Cytometry
• Granulocytes (metabolism)
• Humans
• Immunoglobulin Fragments (metabolism)
• Immunoglobulins (metabolism)
• Interleukin 1 Receptor Antagonist Protein
• Leukocytes (drug effects, metabolism)
• Monocytes
• Phagocytosis
• Reactive Oxygen Species
• Respiratory Burst
• Rho(D) Immune Globulin (administration & dosage, therapeutic use)
• Sialoglycoproteins (metabolism)
• Time Factors