Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion

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Alloimmunization to transfused RBCs remains a major problem for the large number of patients who require transfusion (approximately 1 out of 70 people (~5,000,000 patients) annually in the USA alone). Although a barrier to transfusion in multiple settings, alloimmunization is particularly problematic for patients with sickle cell disease (SCD) due to 1) the increased rate of alloimmunization (up to 30%), 2) the need for chronic transfusion, and 3) the risk of undetected (or new) alloantibodies causing potentially catastrophic hyperhemolysis. There are very few effective therapeutic interventions to prevent RBC alloimmunization (e.g., extensive antigen matching). For all transfusion indications, patients tend to be either “responders” that develop alloantibodies over time with ongoing transfusion or “non-responders” with no detectable alloantibodies even after many transfusions. Currently, we cannot predict which patients are likely to be responders and become alloimmunized. This P01 focuses on addressing the persistent problem of RBC alloimmunization for the large number of patients who require transfusions and are at risk for alloimmunization. The program is structured around a central core (Core A) that will collect longitudinal samples from a cohort of 2000 patients with SCD (at steady state, at time of transfusion, and one-month post-transfusion) linked to detailed clinical information, including RBC alloimmunization. Projects 1-3 combine novel translational murine models with clinical samples from Core A while Project 4 uses samples from Core A to test hypotheses through an omics-based approach and generates data on pathways studied in Projects 1-3. In this way, the proposed program creates a synergy of approaches with the ability to translate murine findings into humans and model human findings in mice. Using the samples from Core A as a common resource, four projects are proposed. Project 1 builds on a novel observation that a mouse model of SLE recapitulates increased RBC alloimmunization observed in humans with SLE and utilizes the model and samples from Core A to test the mechanistic role of TLR7, TLR9 and anti-nucleic acid antibodies in RBC alloimmunization. Project 2 builds on our novel observation that multiple purinergic signaling pathways regulate RBC alloimmunization in mice and utilizes mouse models and samples form Core A to test the mechanistic role of CD73, AMP, Adora1, adenosine and Adora2b in RBC alloimmunization. Project 3 proposes mechanistically driven studies in pre-clinical models and human studies to expand upon our novel finding that reticulocytes (in donor RBC units or in transfusion recipients) are a risk factor for RBC alloimmunization. Project 4 will investigate the underlying genetic risk factors that predispose a given patient with SCD through analysis of whole genome sequencing and the specific molecular drivers of alloimmunization to a given transfusion through analysis of single cell RNASeq data. This P01 is designed to have near-term benefits of guiding clinical practice by discovering predictors of responder/non-responder patients and longer-term benefits of elucidating mechanisms of RBC alloimmunization to allow rational targets for therapy development.