A number of disease states require chronic transfusion of RBCs, including sickle cell anemia, alpha and beta thalassemia, aplastic anemia, renal failure, myeloproliferative disorders, bone marrow and solid organ transplantation and chronic anemia of various etiologies. However, a major impediment to the use of chronic RBC transfusion therapy is the induction of alloantibodies to blood group antigens present on donor RBCs but absent on recipient erythrocytes (RBC alloimmunization). When chronically transfused patients accumulate enough clinically significant antibodies that essentially all available units are incompatible, the patient is required to either forego the beneficial and/or life saving effects of transfusion or receive a unit of 'least incompatible' blood, risking a potentially fatal hemolytic transfusion reaction. Thus, the development of antibodies to blood group antigens is a serious problem that can be a matter of 'life and death' in chronically transfused patients. Interestingly, despite the presence of hundreds of blood group antigens on transfused RBCs, some patients do not become alloimmunized while others make strong antibody responses to foreign RBC antigens. The factors and mechanisms that determine whether a transfused patient will be alloimmunized are poorly understood. Using a novel murine model of RBC immunization, we have observed that recipient inflammation plays a pivotal role in antibody responses to transfused RBCs and that distinct sub-types of inflammation can result in a significant enhancement of both the frequency and magnitude of RBC immunization. Moreover, RBC transfusion in uninflammed recipients not only fails to elicit an antibody response, but leads to immunological tolerance. These findings suggest a novel mechanism for regulation of antibody responses to transfused RBCs in humans, and to the best of our knowledge, provide the first evidence of the role of inflammation in RBC immunization. The overall objective of these studies is to generate a detailed mechanistic understanding of how recipient inflammation regulates immunity vs. tolerance to antigens on transfused RBCs. The data generated will both further our basic understanding of RBC immunization and lay the technical and conceptual groundwork for the rational development of therapeutic interventions to prevent RBC immunization.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL086773-04
Application #
8342006
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2008-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$274,483
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hayek, Salim S; Ko, Yi-An; Awad, Mosaab et al. (2017) Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study. Kidney Int Rep 2:425-432
Hammadah, Muhammad; Al Mheid, Ibhar; Wilmot, Kobina et al. (2017) The Mental Stress Ischemia Prognosis Study: Objectives, Study Design, and Prevalence of Inducible Ischemia. Psychosom Med 79:311-317
Qi, Zhen; Roback, John D; Voit, Eberhard O (2017) Effects of Storage Time on Glycolysis in Donated Human Blood Units. Metabolites 7:
Hammadah, Muhammad; Alkhoder, Ayman; Al Mheid, Ibhar et al. (2017) Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress. Int J Cardiol 243:47-53
Hammadah, Muhammad; Al Mheid, Ibhar; Wilmot, Kobina et al. (2017) Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes. Circ Res 120:1130-1138
Uppal, Karan; Walker, Douglas I; Jones, Dean P (2017) xMSannotator: An R Package for Network-Based Annotation of High-Resolution Metabolomics Data. Anal Chem 89:1063-1067
Pakvasa, Mitali A; Winkler, Anne M; Hamrick, Shannon E et al. (2017) Observational study of haemostatic dysfunction and bleeding in neonates with hypoxic-ischaemic encephalopathy. BMJ Open 7:e013787
Hayek, Salim S; Klyachkin, Yuri; Asfour, Ahmed et al. (2017) Bioactive Lipids and Circulating Progenitor Cells in Patients with Cardiovascular Disease. Stem Cells Transl Med 6:731-735
Patel, Ravi M; Knezevic, Andrea; Shenvi, Neeta et al. (2016) Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 315:889-97
Auletta, J J; Devine, S M; Waller, E K (2016) Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden? Bone Marrow Transplant 51:333-43

Showing the most recent 10 out of 47 publications