title: Transfusion-induced alloimmunization and platelet refractoriness in a mouse model: mechanisms and interventions.
abstract: BACKGROUND
  Platelet (PLT) transfusions can be an essential therapy for patients with thrombocytopenia to maintain hemostasis. However, some patients become alloimmunized to antigens on PLTs (typically HLA), which can prevent efficacy of PLT transfusion due to antibody-mediated clearance. In extreme cases, patients with alloimmunization to multiple HLAs can become "refractory" to PLT transfusion, such that insufficient compatible PLT units can be found to meet transfusion needs.
  
  
  METHODS
  An in vivo murine model of PLT-induced alloimmunization was refined so as to include both transfusion with allogeneic leukoreduced PLTs and studies of posttransfusion PLT recoveries, allowing assessment of alloimmunization and refractoriness. Basic mechanisms of antibody-mediated PLT clearance were investigated using recipients missing either the C3 complement gene or the common gamma chain for Fc receptors. In addition, the efficacy of using costimulatory blockade as a therapeutic intervention was assessed by testing CTLA4-Ig administration before PLT transfusion.
  
  
  RESULTS
  Fcγ receptors (but not complement C3) are required for alloantibody-mediated PLT refractoriness. In addition, levels of anti-MHC predict the extent of refractoriness in a given animal. Finally, costimulatory blockade as a therapeutic modality prevents transfusion-induced PLT refractoriness.
  
  
  CONCLUSIONS
  Together these findings introduce new experimental methods, basic mechanistic understanding, and a potential therapeutic intervention for alloimmunization to MHC-based antigens on transfused PLTs.
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Hayley R
authors.initials: HR
authors.lastname: Waterman
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kapp
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Adam
authors.initials: A
authors.lastname: Munday
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Katherine
authors.initials: K
authors.lastname: Odem-Davis
authors.affiliation: Bloodworks NW Research Institute, University of Washington School of Medicine, Seattle, Washington.|Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington.|Department of Medicine, Division of Hematology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D007518:Isoantibodies / Q000097:blood / Q000276:immunology*; D016014:Linear Models; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017713:Platelet Transfusion / Q000009:adverse effects*; D065227:Transfusion Reaction / Q000276:immunology*
chemical_list: D015415:Biomarkers; D006649:Histocompatibility Antigens; D007518:Isoantibodies