This research is designed to determine the extent to which the adverse effects of the transfusion of stored RBCs result from the acute delivery of iron to the monocyte-macrophage system. Although transfusion is effective in treatment of symptomatic anemia, there is increasing evidence that RBC transfusions increase rates of infection, morbidity, and mortality in hospitalized patients. Our preliminary data in mice and humans strongly suggest that this is indeed the case, and that iron is the most likely culprit in producing these adverse effects. By current FDA standards, a unit of stored red blood cells (RBC) is clinically acceptable for transfusion if as much as 25% of the RBC are cleared within 24 hours, thereby delivering a substantial dose of iron to the monocyte-macrophage system. The central hypothesis of this proposal is that iron, acting both intracellularly in phagocytes and extracellularly as plasma non-transferrin bound iron (NTBI), is responsible for the adverse effects associated with stored RBC transfusions. To accomplish our aims, we will use well-characterized mouse models of transfusion and sepsis. This research has three Specific Aims:
Aim #1 : To test the hypothesis that the pro-oxidant effects of increased intracellular iron levels are responsible for the observed pro-inflammatory state following transfusion of older, stored RBCs.
Aim #2 : To test the hypothesis that the acute clearance of older stored RBCs alters T helper (TH) cell differentiation towards TH17 cells.
Aim #3 : To test the hypothesis that NTBI released following the acute clearance of older stored RBCs increases the severity of infection in models of monobacterial infection and polymicrobial sepsis. Thus, this proposal will define the mechanism of the iron insult in Aim #1, characterize the immune response to this insult in Aim #2, and study the clinical consequences of this insult in Aim #3. The insights gained from this project will guide future pre-clinical studies evaluating novel therapeutic approaches in human transfusion medicine. This project, along with a well-developed career development plan, including four distinguished mentors and advisors, will provide the applicant with a training vehicle in immunology and iron biology, which will advance his research career to that of an independent investigator.

Public Health Relevance

The ultimate goal of this project is to determine whether iron is responsible for the adverse effects associated with transfusions of older, stored red blood cells. The insights gained from completing this proposal will have an impact on the current practice of blood transfusion and will provide the foundation for developing rationally- designed approaches to improve the quality of human donor blood and of human transfusion therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (ZHL1)
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Welniak, Lisbeth A
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Hod, Eldad A; Francis, Richard O; Spitalnik, Steven L (2017) Red Blood Cell Storage Lesion-Induced Adverse Effects: More Smoke; Is There Fire? Anesth Analg 124:1752-1754
Bandyopadhyay, Sheila; Brittenham, Gary M; Francis, Richard O et al. (2017) Iron-deficient erythropoiesis in blood donors and red blood cell recovery after transfusion: initial studies with a mouse model. Blood Transfus 15:158-164
L'Acqua, Camilla; Bandyopadhyay, Sheila; Francis, Richard O et al. (2015) Red blood cell transfusion is associated with increased hemolysis and an acute phase response in a subset of critically ill children. Am J Hematol 90:915-20
Hod, Eldad A (2015) Red blood cell transfusion-induced inflammation: myth or reality. ISBT Sci Ser 10:188-191
Prestia, Kevin; Bandyopadhyay, Sheila; Slate, Andrea et al. (2014) Transfusion of stored blood impairs host defenses against Gram-negative pathogens in mice. Transfusion 54:2842-51
Berra, Lorenzo; Pinciroli, Riccardo; Stowell, Christopher P et al. (2014) Autologous transfusion of stored red blood cells increases pulmonary artery pressure. Am J Respir Crit Care Med 190:800-7
Wojczyk, Boguslaw S; Kim, Nina; Bandyopadhyay, Sheila et al. (2014) Macrophages clear refrigerator storage-damaged red blood cells and subsequently secrete cytokines in vivo, but not in vitro, in a murine model. Transfusion 54:3186-97
Spitalnik, Steven L (2014) Stored red blood cell transfusions: iron, inflammation, immunity, and infection. Transfusion 54:2365-71
Francis, R O; Jhang, J S; Pham, H P et al. (2013) Glucose-6-phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks. Vox Sang 105:271-82
Callan, M B; Patel, R T; Rux, A H et al. (2013) Transfusion of 28-day-old leucoreduced or non-leucoreduced stored red blood cells induces an inflammatory response in healthy dogs. Vox Sang 105:319-27

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