title: Antibody specific for the glycophorin A complex mediates intravenous immune globulin-resistant anemia in a murine model.
abstract: BACKGROUND
  Therapy for patients with autoimmune hemolytic anemia (AHA) remains a major challenge. Patients with glycophorin A (GPA)-specific immunoglobulin G antibodies can have severe hemolysis, which may occur by mechanisms independent from traditional macrophage-dependent Fcγ receptor (FcγR)-mediated extravascular hemolysis. As intravenous immune globulin (IVIG) is known to display its beneficial effects in FcγR-mediated cytopenias, and IVIG responses in AHA are inconsistent at best, we sought to gain insight into the mechanism of anemia by a GPA complex-specific monoclonal antibody (TER119) in a mouse model of immune hemolytic anemia and evaluate the therapeutic effect of IVIG.
  
  
  METHODS
  The anemic effect of the TER119 antibody was studied in vitro by incubation of mouse RBC with the antibody and in vivo by infusing the antibody into normal mice versus mice genetically deficient for the Fc receptor γ chain (Fcγ), complement C3, mice naturally deficient in complement C5, and splenectomized mice. IVIG efficacy in anemia was determined by treating mice with an intensive IVIG dosing regimen.
  
  
  RESULTS
  The TER119-mediated anemia was independent of classical FcγR-, C3-, and C5-dependent mechanisms, but occurred by a mechanism consistent with RBC agglutination. In accordance with agglutination, the presence of the spleen accelerated the anemia observed but anemia could still occur in splenectomized mice. IVIG did not significantly affect the induction of anemia by TER119.
  
  
  CONCLUSIONS
  The mechanism of anemia induced by AHA-causing antibodies may be an important factor to consider in the response to therapy with IVIG.
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Hasan
authors.initials: H
authors.lastname: Ghaffar
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Jen
authors.forename: Alan H
authors.initials: AH
authors.lastname: Lazarus
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D005260:Female; D006021:Glycophorins / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D000906:Antibodies; D006021:Glycophorins; D016756:Immunoglobulins, Intravenous