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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL103756-04
Application #
8442306
Study Section
Special Emphasis Panel (ZHL1-CSR-U (M1))
Program Officer
Welniak, Lisbeth A
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$131,085
Indirect Cost
$9,710
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Hubbard, Andrea C; Bandyopadhyay, Sheila; Wojczyk, Boguslaw S et al. (2013) Effect of dietary iron on fetal growth in pregnant mice. Comp Med 63:127-35
Hod, Eldad A; Spitalnik, Steven L (2011) Harmful effects of transfusion of older stored red blood cells: iron and inflammation. Transfusion 51:881-5
Jang, Jung-Eun; Hod, Eldad A; Spitalnik, Steven L et al. (2011) CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions. J Clin Invest 121:1397-401