title: Transfusion of murine red blood cells expressing the human KEL glycoprotein induces clinically significant alloantibodies.
abstract: BACKGROUND
  Red blood cell (RBC) alloantibodies to nonself antigens may develop after transfusion or pregnancy, leading to morbidity and mortality in the form of hemolytic transfusion reactions or hemolytic disease of the newborn. A better understanding of the mechanisms of RBC alloantibody induction, or strategies to mitigate the consequences of such antibodies, may ultimately improve transfusion safety. However, such studies are inherently difficult in humans.
  
  
  METHODS
  We recently generated transgenic mice with RBC-specific expression of the human KEL glycoprotein, specifically the KEL2 or KEL1 antigens. Herein, we investigate recipient alloimmune responses to transfused RBCs in this system.
  
  
  RESULTS
  Transfusion of RBCs from KEL2 donors into wild-type recipients (lacking the human KEL protein but expressing the murine KEL ortholog) resulted in dose-dependent anti-KEL glycoprotein immunoglobulin (Ig)M and IgG antibody responses, enhanced by recipient inflammation with poly(I:C). Boostable responses were evident upon repeat transfusion, with morbid-appearing alloimmunized recipients experiencing rapid clearance of transfused KEL2 but not control RBCs. Although KEL1 RBCs were also immunogenic after transfusion into wild-type recipients, transfusion of KEL1 RBCs into KEL2 recipients or vice versa failed to lead to detectable anti-KEL1 or anti-KEL2 responses.
  
  
  CONCLUSIONS
  This murine model, with reproducible and clinically significant KEL glycoprotein alloantibody responses, provides a platform for future mechanistic studies of RBC alloantibody induction and consequences. Long-term translational goals of these studies include improving transfusion safety for at-risk patients.
authors.affiliation: Department of Pathology, Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University, Atlanta, Georgia; Puget Sound Blood Center Research Institute, Seattle, Washington.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Stowell
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Girard-Pierce
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Smith
authors.forename: Kate L
authors.initials: KL
authors.lastname: Henry
authors.forename: C Maridith
authors.initials: CM
authors.lastname: Arthur
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
mesh_terms: D000743:Anemia, Hemolytic / Q000235:genetics / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics; D001787:Blood Group Incompatibility / Q000235:genetics / Q000276:immunology; D017707:Erythrocyte Transfusion / Q000379:methods*; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis*; D007626:Kell Blood-Group System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011070:Poly I-C
chemical_list: D007518:Isoantibodies; D007626:Kell Blood-Group System; D011070:Poly I-C