Transfusion of murine red blood cells expressing the human KEL glycoprotein induces clinically significant alloantibodies

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. Study Design and Methods We recently generated transgenic mice with RBC ‐specific expression of the human KEL glycoprotein, specifically the KEL 2 or KEL 1 antigens. Herein, we investigate recipient alloimmune responses to transfused RBCs in this system. Results Transfusion of RBCs from KEL 2 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 KEL 2 but not control RBCs . Although KEL 1 RBCs were also immunogenic after transfusion into wild‐type recipients, transfusion of KEL 1 RBCs into KEL 2 recipients or vice versa failed to lead to detectable anti‐ KEL 1 or anti‐ KEL 2 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.