Recipient priming to one RBC alloantigen directly enhances subsequent alloimmunization in mice

Individuals that become immunized to red blood cell (RBC) alloantigens can experience an increased rate of antibody formation to additional RBC alloantigens following subsequent transfusion. Despite this, how an immune response to one RBC immunogen may impact subsequent alloimmunization to a completely different RBC alloantigen remains unknown. Our studies demonstrate that Kell blood group antigen (KEL) RBC transfusion in the presence of inflammation induced by poly (I:C) (PIC) not only enhances anti-KEL antibody production through a CD4⁺ T-cell-dependent process but also directly facilitates anti-HOD antibody formation following subsequent exposure to the disparate HOD (hen egg lysozyme, ovalbumin, fused to human blood group antigen Duffy b) antigen. PIC/KEL priming of the anti-HOD antibody response required that RBCs express both the KEL and HOD antigens (HOD × KEL RBCs), as transfusion of HOD RBCs plus KEL RBCs or HOD RBCs alone failed to impact anti-HOD antibody formation in recipients previously primed with PIC/KEL. Transfer of CD4⁺ T cells from PIC/KEL-primed recipients directly facilitated anti-HOD antibody formation following (HOD × KEL) RBC transfusion. RBC alloantigen priming was not limited to PIC/KEL enhancement of anti-HOD alloantibody formation, as HOD-reactive CD4⁺ T cells enhanced anti-glycophorin A (anti-GPA) antibody formation in the absence of inflammation following transfusion of RBCs coexpressing GPA and HOD. These results demonstrate that immune priming to one RBC alloantigen can directly enhance a humoral response to a completely different RBC alloantigen, providing a potential explanation for why alloantibody responders may exhibit increased immune responsiveness to additional RBC alloantigens following subsequent transfusion.