Innate and adaptive immune responses to transfused alloantigens

Abstract

Over 300 different variant alloantigens on red blood cells (RBCs) have been described in humans. Thus, anytime a transfusion of non-autologous RBCs is given, the recipient is exposed to myriad RBC alloantigens. Despite such exposures, on average only 3–6% of transfused humans develop a measurable RBC alloantibody. Once a recipient is alloimmunised to at least one antigen, they are much more likely to become alloimmunised to additional specificities; in contrast, patients who are not alloimmunised tend not to become alloimmunised, despite multiple transfusions. Using murine models, we have reported that exposure of recipients to Toll-like receptor (TLR) agonists, which are known to induce inflammation and activate innate immunity, significantly increase both rates and magnitude of alloimmunisation. Moreover, transfusion of uninflamed mice not only produces no measurable alloimmunisation, but then makes mice non-responsive to a subsequent transfusion in the presence of TLR agonists, which would otherwise result in alloimmunisation. In aggregate, these studies implicate innate immune activation as a regulatory switch of responder/non-responder biology, in a mouse model. Both published and new data will be presented, in both murine models and also limited human studies, exploring the role of innate immune activation in adaptive immunisation to RBC transfusion. Over 300 different variant alloantigens on red blood cells (RBCs) have been described in humans. Thus, anytime a transfusion of non-autologous RBCs is given, the recipient is exposed to myriad RBC alloantigens. Despite such exposures, on average only 3–6% of transfused humans develop a measurable RBC alloantibody. Once a recipient is alloimmunised to at least one antigen, they are much more likely to become alloimmunised to additional specificities; in contrast, patients who are not alloimmunised tend not to become alloimmunised, despite multiple transfusions. Using murine models, we have reported that exposure of recipients to Toll-like receptor (TLR) agonists, which are known to induce inflammation and activate innate immunity, significantly increase both rates and magnitude of alloimmunisation. Moreover, transfusion of uninflamed mice not only produces no measurable alloimmunisation, but then makes mice non-responsive to a subsequent transfusion in the presence of TLR agonists, which would otherwise result in alloimmunisation. In aggregate, these studies implicate innate immune activation as a regulatory switch of responder/non-responder biology, in a mouse model. Both published and new data will be presented, in both murine models and also limited human studies, exploring the role of innate immune activation in adaptive immunisation to RBC transfusion.