Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model

Abstract

When successful, human leukocyte antigen (HLA)-matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex-matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8 ؉ T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.

Antigen Modulation Confers Protection to Red Blood Cells from Antibody through Fcγ Receptor Ligation

“…FcgR KO mice (Fcer1g) were purchased from Taconic Farms All mice were used at 8 to 14 wk of age. HOD mice consisted of transgenic animals (FVB background) expressing a fusion protein HEL, Ova, and Duffy b (also known as HOD mice) (27). All breeding (including FcgR KO and C3 KO mice) was performed by the Emory University Department of Animal Resources Husbandry Services, and all procedures were performed according to approved Institutional Animal Care and Use Committee protocols.…”

“…It is for this reason that transfer of a distinct RBC population into an Ag 2 recipient allows examination of specific consequences, including cellular clearance and the potential development of protection against Ab-mediated removal, without the confounding variables of cell division or synthesis of additional protein. In this study, we use a recently described RBC Ag-Ab system using RBCs that express a unique model Ag: the hen egg lysozyme (HEL)-OVA-Duffy (HOD) Ag (27,28). Using this system, we describe RBCs escaping destruction by Abs through Ag modulation.…”

Supportive care in severe and very severe aplastic anemia

“…Whether this association is still true when efficiently leukocyte-depleted blood products are used 47 is not clear. 48 Universal leuko-reduction of blood products has reduced patient alloimmunization, 47,[49][50][51] although further studies are needed to confirm the impact on, for example, outcome after SCT. Allosensitization is mostly due to residual leukocytes in transfused blood products, although a study in mice indicates that mHAs on donor erythrocytes may contribute to allosensitisation.…”

“…Allosensitization is mostly due to residual leukocytes in transfused blood products, although a study in mice indicates that mHAs on donor erythrocytes may contribute to allosensitisation. 48 An erythrocyte-dependent immunization against mHAs is not eliminated by leukocyte depletion. 48 A restrictive transfusion policy should be applied, in particular in patients who are candidates for allogeneic BMT.…”

“…48 An erythrocyte-dependent immunization against mHAs is not eliminated by leukocyte depletion. 48 A restrictive transfusion policy should be applied, in particular in patients who are candidates for allogeneic BMT. [44][45][46]52 However, a planned transplantation is no reason to withhold an otherwise indicated transfusion.…”