Human leukocyte antigen antibodies in liver retransplantation

In this issue of Liver Transplantation, Angeline Goh and Paul Terasaki (Terasaki Foundation Laboratory, Los Angeles, CA), in collaboration with investigators from the Ospedale Maggiore Policlinico (Regina Elena, Italy), report on the clinical significance of preformed human leukocyte antigen (HLA) antibodies in patients receiving a second liver allograft. This retrospective study used single HLA antigen beads on a Luminex platform to examine, for the first time, the presence of HLA class I and class II antibodies in sera from a cohort of adult and pediatric liver retransplant recipients. This method of HLA antibody detection has the benefit of greater sensitivity than other techniques, such as enzyme linked immunosorbent assay and complement-dependent cytotoxicity (CDC) antibody testing. Over 70% of the patients in this study had detectable HLA antibodies prior to the second transplant, and this likely reflects previous sensitization either by the first liver allograft or by blood product transfusions. Within their adult population, the authors discovered that the presence of HLA class I antibodies was associated with significantly poorer second graft survival (hazard ratio 1⁄4 2), which was defined as either patient death or the receipt of a third liver allograft. Interestingly, the deleterious effect of HLA class I antibodies on graft survival was most pronounced in the early posttransplant period (within 1 year). A similar effect was not observed in the cohort of pediatric retransplant recipients, and this was attributed to the limited population size. On the basis of these findings, the authors advocate crossmatch testing for liver allograft recipients considered for retransplantation. Surprisingly, however, the CDC crossmatch results for the patients in this study were almost exclusively negative, even with HLA antibodies specific to the second liver donor detected prior to retransplantation in approximately 25% of the recipients. However, it is not far-fetched to speculate that if HLA antigens are shared between the first and second donors, putative donor-specific HLA antibodies against the second liver might be adsorbed within the first allograft. This would certainly decrease the chances of eliciting a positive CDC crossmatch. The degree of HLA similarities between donors is not reported in this study. Allograft loss due to anti-HLA antibodies is typically due to either acute or chronic antibody-mediated rejection (AMR); however, AMR of either type is an infrequent occurrence in the liver in comparison with extrahepatic allografts. Direct cytotoxic injury of allograft endothelial cells by activation of the complement cascade has been long recognized to manifest as acute AMR. High-titer, preformed donor-specific antibodies (DSAs) can rapidly damage the allograft after reperfusion and result in hyperacute AMR. Alternatively, preformed or de novo DSAs can also induce acute AMR, which can occur both early and late after transplant and may coexist with cellular rejection. Acute AMR is typically diagnosed on the basis of allograft dysfunction, the presence of circulating DSAs, histological evidence of tissue damage, and evidence of complement activation, which is most commonly detected by the staining of allograft biopsy tissue for C4d. Anti-HLA antibodies are generally acknowledged to contribute to chronic allograft rejection. However, the underlying mechanisms are less clear, mainly because the process progresses slowly and may not be