Innate Immune Receptors that Promote RBC Alloimmunization

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Summary Project 3 Significance: Red blood cell (RBC) transfusion is a powerful therapeutic tool. Despite ABO and Rh(D) matching, leukoreduced RBCs can lead to the induction of recipient alloantibodies against minor antigens; such antibodies may result in delay locating compatible RBC units for therapy, hemolytic transfusion reactions or hemolytic disease of the newborn. Although there have been significant advances in our understanding of the basic rules that govern the induction of adaptive immunity to pathogens and even transplantation, what immunologically determines when someone will respond to an allogeneic unit of RBCs remains largely undefined. Consequently, we cannot predict which transfusion recipients will develop alloantibodies. Identifying the innate immune cells and receptors that regulate immunization to foreign antigens on RBCs will enable us to identify potential immune triggers of alloimmunization during transfusion and, as an extension, targets to inhibit during these therapies to promote immunological tolerance. Innovation: We have developed a murine model system in which we can evaluate the role of particular innate immune stimuli and cells during allogeneic red blood cell transfusion. These models allow us for the first time to dissect the specific receptors and pathways required for the generation of detrimental alloimmunity during transfusion. Our preliminary data strongly suggest that classic sensors of pathogens, the Toll-like receptors (TLRs), also respond to transfused RBCs and instruct the activation of T and B cells to RBC-derived antigens. Approach/Investigators: Using these murine models we will test the hypothesis that T cell priming to RBC alloantigens is defective in the absence of innate immune pathways by eliminating combinations of downstream signaling pathways or particular surface receptors. Dr. Eisenbarth has extensive experience in evaluating the role of innate immune receptors in shaping T cell responses. Dr. Hendrickson is a leader in the RBC alloimmunization field and has developed many of the widely used murine models to study this process. In collaboration, we will address the following specific aims: Aim 1, Determine the mechanism by which MyD88 regulates adaptive immunity to allogeneic RBCs and Aim 2, Identify which Toll-like receptor(s) drive T cell- dependent RBC alloimmunization.