Transfusion of minor histocompatibility antigen–mismatched platelets induces rejection of bone marrow transplants in mice

Abstract

Bone marrow transplantation (BMT) represents a cure for nonmalignant hematological disorders. However, compared with the stringent conditioning regimens used when performing BMT to treat hematological malignancies, the reduced intensity conditioning regimen used in the context of nonmalignant hematological disorders leads to substantially higher rates of BMT rejection, presumably due to an intact immune system. The relevant patient population typically receives transfusion support, often including platelets, and the frequency of BMT rejection correlates with the frequency of transfusion. Here, we demonstrate that immunity to transfused platelets contributes to subsequent BMT rejection in mice, even when the BMT donor and recipient are MHC matched. We used MHC-matched bone marrow because, although immunity to transfused platelets is best characterized in relation to HLA-specific antibodies, such antibodies are unlikely to play a role in clinical BMT rejection that is HLA matched. However, bone marrow is not matched in the clinic for minor histocompatibility antigens, such as those carried by platelets, and we report that transfusion of minor histocompatibility antigen-mismatched platelets induced subsequent BMT rejection. These findings indicate previously unappreciated sequelae of immunity to platelets in the context of transplantation and suggest that strategies to account for minor histocompatibility mismatching may help to reduce the chance of BMT rejection in human patients.

Mechanisms of Alloimmunization and Subsequent Bone Marrow Transplantation Rejection Induced by Platelet Transfusion in a Murine Model

“…However, we have also previously reported that in vivo clearance of mHA expressing targets is variable when measured after platelet transfusion (but prior to BMT) and does not statistically predict BMT rejection (20). In contrast, the current findings and our previous experiments demonstrate that in vivo clearance of donor targets approaches roughly 100% after BMT rejection (20). Combined, these data suggest that LR-PLT transfusions prime recipients for a donor mHA alloresponse that differentiates into to a full effector alloresponse during the BMT.…”

“…To test the respective roles of CD4 + and CD8 + T cells in rejection of an MHC-matched BMT in LR-PLT transfused recipients, we made use of our previously described model of MHC-matched:mHA-mismatched BMT (20). In this system, C57BL/6J (H-2 b ) recipients are transfused twice, a week apart, with BALB/c (H-2 d ; MHC- and mHA-mismatched) LR-PLT concentrates (Figure 1A).…”

“…Exposure to mHAs on transfused platelets appears to be required, as neither naïve mice nor mice receiving syngeneic transfusions reject BMT (20). However, we have also previously reported that in vivo clearance of mHA expressing targets is variable when measured after platelet transfusion (but prior to BMT) and does not statistically predict BMT rejection (20). In contrast, the current findings and our previous experiments demonstrate that in vivo clearance of donor targets approaches roughly 100% after BMT rejection (20).…”

“…LR-PLT products and Whole Blood were harvested as previously described (20). LR-PLT transfusions contained 1 × 10 8 total platelets and were transfused through the tail-vein.…”

Red blood cell-incompatible allogeneic hematopoietic progenitor cell transplantation

“…In mouse models, pretransplant exposure to red cells or platelets can induce rejection of transplanted HLA-compatible BM cells as a result of alloimmunization against mHLAs. 44, 45 Bean et al 46,47 reported that irradiation of blood products could prevent immunization to minor dog leukocyte antigens (minor canine histocompatibility antigen) with reduced risk of graft rejection in canine models of dog leukocyte antigen-compatible related and unrelated donor transplants. However, similar studies of the effect of incompatibility for platelet alloantigens in human HPC transplantation have not yielded similar observations.…”