Regulation of RBC Alloimmunization by Different Types of Recipient Inflammation

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DESCRIPTION (provided by applicant): The candidate for this career development award is a Pediatric Hematologist with specialized clinical training in Transfusion Medicine. Her career goal is to become an independent physician scientist researcher, capable of bridging the gap from basic bench research to translational medicine. The goal of this proposal is to advance the basic science understanding of red blood cell (RBC) alloimmunization, while providing the candidate with the basic science researchtraining required to become an independent investigator. RBC alloimmunization is a clinically ignificant problem in some chronically transfused patients, especially those with hemoglobinopathies. Once a patient becomes alloimmunized to multiple RBC antigens, locating compatible blood for future transfusions can be difficult (and sometimes not possible). There is wide variability in immune responses to transfused RBCs, and factors that influence rates of RBC alloimmunization are poorly understood. The candidate has reported the novel finding that recipient inflammation affects rates of RBC alloimmunization. While a viral-like stimulus (polyinosinic polycytidylic acid, poly (I:C)) increases alloimmunization, a bacterial-like stimulus (lipopolysaccharide, LPS) decreases alloimmunization. The proposed research utilizes cutting-edge immunological tools (including well defined model RBC antigens, TCR and BCR transgenic and knockout mice) to perform cellular and molecular elucidations of how different types of inflammation regulate RBC alloimmunization. The candidate has taken advantage of resources in multiple departments at Emory University, including the Division of Pediatric Hematology/Oncology/BMT, Center for Transfusion and Cellular Therapies, and Immunology and Pathogenesis Program. She has assembled a multi-specialty mentoring committee and a comprehensive career development plan. The culmination of this mentored research training will be extensive basic science training in RBC immunology and the basis for an independent career as a physician scientist. RELEVANCE (See instructions): The public health knowledge gained by the proposed research will provide a mechanistic understanding for the rational development of targeted therapeutic interventions to decrease rates of RBC alloimmunization. This research will thus potentially impact the 5% of transfusion recipients that become alloimmunized to RBCs (with 14 million units of RBCs being transfused annually in the US).