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.
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).
|Stowell, Sean R; Girard-Pierce, Kathryn R; Smith, Nicole H et al. (2014) Transfusion of murine red blood cells expressing the human KEL glycoprotein induces clinically significant alloantibodies. Transfusion 54:179-89|
|Girard-Pierce, Kathryn R; Stowell, Sean R; Smith, Nicole H et al. (2013) A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation. Blood 122:1793-801|
|Stowell, Sean R; Henry, Kate L; Smith, Nicole H et al. (2013) Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model. Blood 122:1494-504|
|Hendrickson, Jeanne E; Hod, Eldad A; Perry, Jennifer R et al. (2012) Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease. Transfusion 52:231-40|
|Smith, Nicole H; Hod, Eldad A; Spitalnik, Steven L et al. (2012) Transfusion in the absence of inflammation induces antigen-specific tolerance to murine RBCs. Blood 119:1566-9|
|Smith, Nicole H; Henry, Kate L; Cadwell, Chantel M et al. (2012) Generation of transgenic mice with antithetical KEL1 and KEL2 human blood group antigens on red blood cells. Transfusion 52:2620-30|
|Hod, Eldad A; Brittenham, Gary M; Billote, Genia B et al. (2011) Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood 118:6675-82|
|Hendrickson, Jeanne E; Hod, Eldad A; Cadwell, Chantel M et al. (2011) Rapid clearance of transfused murine red blood cells is associated with recipient cytokine storm and enhanced alloimmunogenicity. Transfusion 51:2445-54|
|Patel, Seema R; Hendrickson, Jeanne E; Smith, Nicole H et al. (2011) Alloimmunization against RBC or PLT antigens is independent of TRIM21 expression in a murine model. Mol Immunol 48:909-13|
|Hendrickson, Jeanne E; Hod, Eldad A; Hudson, Krystalyn E et al. (2011) Transfusion of fresh murine red blood cells reverses adverse effects of older stored red blood cells. Transfusion 51:2695-702|
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