Red blood cell alloimmunisation: induction of immunity and potential mitigation strategies

Millions of RBC units are transfused throughout the world annually. Even though each RBC unit contains multiple foreign donor antigens, only a minority of transfusion recipients will develop detectable RBC alloantibodies. Some factors that influence humoral immune responsiveness to transfused RBC s are obvious, including the necessity of being exposed to a foreign antigen that the immune system can process and present. Mathematically, however, every RBC transfusion meets those criteria. Thus, it remains unclear why some patients form alloantibodies (‘responders’), while others may be transfused hundreds of times without becoming alloimmunised (‘non‐responders’). Studies in humans have found an association with CD 4+ T‐cell markers and responsiveness to transfused RBC s, and have also identified acute or chronic inflammatory disease states as risk factors for alloantibody development. Studies in animal models, which allow single variables to be isolated, have led to an understanding of the critical role played by dendritic cells in transfusion‐associated RBC alloimmunisation. Murine studies have further established that non‐responsiveness to transfused RBC s equates to antigen‐specific tolerance in some settings: alloantibodies develop to RBC s expressing some blood group antigens only when the initial RBC exposure occurs in close association with a danger signal. Additional studies are needed in humans and in animal models to further understand the complex variables that determine when and how a humoral immune response may be initiated against transfused RBC antigens, such that strategies for preventing alloimmunisation and its harmful effects in transfusion and pregnancy scenarios can be developed.