The full extent of factors responsible for histocompatibility is not entirely understood. Despite continuous efforts, solid organ transplants with apparent ideal histocompatibility matching can still fail, and avenues outside of the human leukocyte antigen (HLA) system are being explored. Currently, there are only a few non-HLAs that have been studied and sought out for their contribution to solid organ transplantation, and the goal of this investigation was to add red blood cell (RBC) antigens to that growing list. The influence of RBC antigen alloimmunization on solid organ transplantation outside of the ABO blood group system is not well known, but the clinical significance of transfusion-associated RBC alloimmunization is widely recognized and applied in standard transfusion medicine practice. RBC antigens that have been identified outside of RBCs are termed histoblood group antigens. Detection of these antigens in deceased donor tissues will designate additional non-HLA histocompatibility for transplant recipients, especially for those that have pre-formed non-ABO RBC alloantibodies in suspected cases of antibody-mediated rejection (AMR). This investigation aimed to identify the (i) frequency of non-ABO RBC alloantibodies in transplant patients and (ii) detect histoblood group epitopes in deceased donor tissues to further characterize non-HLA expression. To do this, serum of transplant patients was tested for the presence and specificity of commonly encountered, non-ABO RBC antibodies, and immunohistochemistry (IHC) was used to identify select histoblood group epitopes in deceased donor tissues (heart, lung, kidney, and pancreas). The total study population had 5% of patients testing positive for non-ABO RBC antibodies. Clinically significant antibodies identified were anti-K, and anti-Fya. A clinically insignificant, nonspecific cold reacting antibody was also detected. The results obtained for the reported clinically significant antibodies align within documented characteristics; these antibodies are commonly encountered, and target antigens that have higher immunogenicity. Immunodetection used in this investigation further classified the location of histoblood group antigens from the MNS, Rh, Kell, Lewis, Duffy, Kidd, XG, Chido/Rodgers, and Knops blood group systems. IHC data collected in this investigation reveals that the expression of histoblood group antigens in deceased donor tissues (heart, lung, kidney, and pancreas) is comparable to that of healthy individuals. Additionally, this investigation provides further details for the detection of histoblood group antigens in tissue substructures where comparable IHC data were unavailable, e.g., in intercalated discs (heart), bronchial epithelium (lung), and urothelium (kidney), and new data for the detection of both Ss (GYPB) and Kell antigens outside of RBCs. This study offers new evidence for the frequency of non-ABO RBC antibodies in transplant patients, and for the distribution of histoblood group antigens on deceased donor tissues. These data facilitate consideration of non-ABO RBC antibodies, when present, in cases of suspected AMR when HLA donor-specific antibodies (DSAs) are absent.
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