Does the Innate Immune System Determine Alloimmunization in Response to Red Blood Cell Transfusion?

Transfusions of red blood cells (RBCs), especially given as part of chronic transfusion programs, are increasingly used as disease-modifying therapy for patients with sickle cell disease (SCD). The increased use of chronic transfusions over the past decade has been driven by expanded indications, with the major contributor being primary stroke prevention in children who are identified through transcranial Doppler ultrasonography screening programs.  Also contributing to the increase in transfusions in patients with SCD is the wider availability of methods to limit and monitor transfusional iron loading, including oral iron chelators, automated erythrocytapheresis, and magnetic resonance imaging to quantify tissue iron. Despite these advances, alloimmunization to RBCs remains a vexing problem, even when extended antigen-matched products (e.g., Rh C-, D-, and E-matched units) are used. Depending on the degree of matching, clinically significant alloimmunization may occur in 10 to 30 percent of chronically transfused patients with SCD. Alloantibodies are problematic because they complicate RBC cross-matching, delay availability of blood products, increase the labor and cost of providing compatible units, shorten RBC survival, and potentially cause hemolytic transfusion reactions (that in some cases can be life-threatening). Occasionally, severe alloimmunization can preclude the use of chronic transfusions altogether, leaving patients with few therapeutic alternatives.

Thus, a key clinical question remains: Why do some chronically transfused individuals with SCD become alloimmunized? Previously identified risk factors for alloimmunization include the degree of antigenic discordance between the recipient and donor, the extent of donor-recipient antigen matching of transfused products, the patient’s age at the time of first transfusion, and the overall transfusion burden. Recent work has also suggested that the genetic complexity of the Rh locus, specifically variant alleles that are not detected by serologic methods, result in alloimmunization despite extended antigen matching. The current study by Dr. Hui Zhong and colleagues from the New York Blood Center and the University of Pennsylvania investigated the role of the recipient’s immune response to hemin.  Senescent red cells that are phagocytosed by macrophages of the reticuloendothelial system undergo degradation.  During this process, the heme moiety that dissociates from globin is metabolized to hemin, the ferric state of heme with a chloride ligand, and subsequently converted to biliverdin by heme oxygenase-1 (HO-1), in a reaction that releases iron and generates carbon monoxide. By studying T cells and monocytes from two groups of transfused SCD patients (alloimmunized and non-alloimmunized), Dr. Zhong and coworkers found that hemin induced differential polarization of CD4⁺T cell subsets.  This process was dependent on HO-1 in monocytes suggesting that a degradation product(s) of hemin mediates the T cell subset polarization. The difference in polarization was most evident using CD16⁺ monocyte-enriched fractions, where exposure to hemin increased Treg expansion and inhibited Th1 proliferation in non-alloimmunized patients with SCD, but had little effect on Treg/Th polarization in the alloimmunized group (Figure). Moreover, following exposure to hemin, both higher baseline levels of HO-1 in CD16⁺ monocytes and a more robust anti-inflammatory T-cell polarization profile was observed in samples from the non-alloimmunized SCD patients compared with those from the alloimmunized group (Figure).