James C. Zimring, MD, PhD, the Thomas W. Tillack Professor of Experimental Pathology, was awarded a $11.3 million program project P01 grant from the National Heart, Lung, and Blood Institute for the next five years to research mechanisms of alloimmunization to transfused red blood cells (RBCs).
Transfusion is the most common invasive inpatient procedure, with close to five million patients transfused each year in the United States alone, approximately one in every 70 individuals. In addition to the very well-known ABO and RhD molecules, there are over 380 known variant molecules, called alloantigens, on RBCs that differ amongst people. Upon transfusion, some recipients mount antibody responses against alloantigens, making them no longer able to receive transfusions from donors that carry the antigens. This is especially a problem in patients who require chronic transfusion like people suffering from sickle cell anemia, beta thalassemia, and myelodysplastic syndrome, among other diseases.
Specialized transfusion medicine services monitor antibodies in every patient who is transfused, identify the antigens the antibodies recognize, and then isolate units of RBCs that lack the antigens and are safe to transfuse. However, compatible units of RBCs can become increasingly difficult to identify as patients become immunized to more and more antigens. In some cases, insufficient compatible blood is available nationwide, leading to the morbidity of delayed or insufficient transfusion or even mortality in extreme cases.
In cases of pregnancy, maternal antibodies that recognize RBC alloantigens on fetal RBCs, can lead to fetal illness or death. Why some patients but not others become alloimmunized after transfusion is unknown and mechanisms of RBC alloimmunization are only partially understood. There are currently no methods to predict which patients will become alloimmunized by transfusion nor are there any therapeutic interventions other than avoiding exposure to RBC antigens.
Dr. Zimring will lead a multidisciplinary team across multiple institutions to identify genetic and environmental factors that regulate immune responses to transfused RBCs with the goal of predicting and preventing RBC alloimmunization.
Although applicable to transfusion in general, the projects have a special focus on RBC alloimmunization in sickle cell disease. Co-investigators for this research project include Chance John Luckey, MD, PhD, University of Virginia; Krystalyn E Hudson, PhD, Columbia University; and Vivien Sheehan, MD, PhD, Emory University.