Examination of Initiating Factors that Regulate Red Blood Cell Alloimmunization

Brigham And Women'S Hospital, Boston MA

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Abstract

Summary: Despite being one of the most common interventions in hospitalized patients, red blood cell (RBC) transfusion is not without risk. Exposure to allogeneic RBCs can result in RBC alloimmunization, which can make it difficult to find compatible blood for future transfusions and directly increases the risk of transfusion complications. To develop strategies that can actively inhibit alloimmunization, key initiating factors that drive alloantibody formation against RBC alloantigens must be defined. The overall objective of this proposal is to define key initiating factors that contribute to short- and long-term alloantibody production. Our central hypothesis is that complement serves as a key molecular adjuvant that can drive alloimmunization through a CD4 T cell independent (TI) pathway, but that CD4 T cells are required for long-term alloantibody production. Our hypothesis is formulated on the basis of our recent discovery that while initial anti-KEL IgG antibody formation is TI, in the absence of complement component 3 (C3), anti-KEL IgG antibody formation is completely CD4 T cell dependent (TD), suggesting that RBC surface bound C3 may directly drive TI IgG antibody formation. Consistent with this, complement receptors 1 and 2 (CR1/2) on B cells are required for KEL RBC-induced TI IgG antibody production. Our data also demonstrate that patients with sickle cell disease (SCD) experiencing acute chest syndrome (ACS) are not only much more likely to become alloimmunized, but also experience significant complement activation, suggesting that complement activation may enhance RBC alloimmunization following transfusion during ACS. In contrast, for long-lived alloantibody production to be realized, CD4 T cells must be engaged. Using the same KEL model system, our data demonstrate that despite CD4 T cells not being required for initial IgG alloantibody formation, KEL RBCs activate T follicular helper cells (TFH) and follicular (FO) B cells, and that long-lived alloantibody production is TD. In contrast to the requirement for C3 for TI IgG alloantibody formation, while initial alloantibody formation occurs in the absence of toll-like receptors (TLRs), TLR-signaling is required for persistent alloantibody production. Taken together, these data suggest that KEL RBC transfusion can simultaneously engage two distinct immune pathways through a complement-regulated process. To test this, we will weld pre-clinical and clinical studies to test the following specific aims. Aim 1: Define the role of C3 in driving TI MZ B cell-mediated antibody production. Aim 2: Define the role of TLR signaling and 33D1+ DCs in driving TFH and FO B cell formation and long-lived antibody production. We think that successful completion of these aims will provide a unique opportunity to define key factors that initiate distinct types of RBC alloimmunization with the promise of identifying key targets to prevent RBC alloimmunization.