The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre-and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

Preformed donor-specific human leukocyte antigen antibodies (DSAs) are considered a contraindication to the transplantation of most solid organs other than the liver. Conflicting data currently exist on the importance of preformed DSAs in rejection and patient survival after liver transplantation (LT). To evaluate preformed DSAs in LT, we retrospectively analyzed prospectively collected samples from all adult recipients of primary LT without another organ from January 1, 2000 to May 31, 2009 with a pre-LT sample available (95.8% of the patients). Fourteen percent of the patients had preformed class I and/or II DSAs with a mean fluorescence intensity (MFI) 5000. Preformed class I DSAs with an MFI 5000 remained persistent in only 5% of patients and were not associated with rejection. Preformed class II DSAs with an MFI of 5000 to 10,000 remained persistent in 23% of patients, and this rate increased to 33% for patients whose MFI was 10,000 (P < 0.001). Preformed class II DSAs in multivariable Cox proportional hazards modeling were associated with an increased risk of early rejection [hazard ratio (HR) 5 1.58; p = 0.004]. In addition, multivariate modeling showed that in comparison with no DSAs (MFI < 1000), preformed class I and/or II DSAs with an MFI 5000 were independently correlated with the risk of death (HR 5 1.51; p = 0.02). The role of donor-specific human leukocyte antigen antibodies (DSAs) in liver transplantation (LT) has long been debated. [1][2][3][4][5] Early analyses revealed the liver's ability to absorb preformed DSAs; some were absorbed without consequence, and others resulted in preservation injury and/or vanishing bile duct syndrome. [4][5][6][7][8] Early clinical data based on cytotoxic crossmatching were united in leading to the conclusion of an absence of hyperacute rejection (with rare exception), but they were divided with respect to conclusions about short-term and longer term outcomes. 1,9,10 However, in the 1980s, graft failure rates were high and limited the analysis of long-term outcomes. Stratification by crossmatch strength in the early 1990s first elucidated increased 1-month graft failure rates in crossmatch-positive patients (29%) versus low-level crossmatch-positive and crossmatchnegative patients (16%). 2,3,9 In fact, "rejection was the most common cause of primary liver allograft failure" in patients with a positive crossmatch. 2 Recent technological improvements have resulted in mounting evidence that antibody-mediated rejection occurs in LT patients; single-antigen bead analyses have found correlations between preformed DSAs and Additional Supporting Information may be found in the online version of this article.Abbreviations: AIH, autoimmune hepatitis; CNI, calcineurin inhibitor; DSA, donor-specific human leukocyte antigen antibody; HLA, human leukocyte antigen; HR, hazard ratio; IgG, immunoglobulin G; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MFI, mean fluorescence intensity; NASH, nonalcoholic steatohepatitis; NS, not significant; PBC, primary bil...

In contrast to kidney transplantation where donorspecific anti-HLA antibodies (DSA) negatively impact graft survival, correlation of DSA with clinical outcomes in patients after orthotopic liver transplantation (OLT) has not been clearly established. We hypothesized that DSA are present in patients who develop chronic rejection after OLT. Prospectively collected serial serum samples on 39 primary OLT patients with biopsy-proven chronic rejection and 39 comparator patients were blinded and analyzed for DSA using LABScreen R single antigen beads test, where a 1000 mean fluorescence value was considered positive. In study patients, the median graft survival was 15 months, 74% received ≥ one retransplant, 20% remain alive and 87% had ≥ one episode of acute rejection. This is in contrast to comparator patients where 69% remain alive, and no patient needed retransplant or experienced rejection. Thirty-six chronic rejection patients (92%) and 24 (61%) comparator patients had DSA (p = 0.003). Chronic rejection versus comparator patients had higher mean fluorescence intensity (MFI) DSA. Although a further study with larger numbers of patients is needed to identify clinically significant thresholds, there is an association of high-MFI DSA with chronic rejection after OLT.Key words: Chronic allograft rejection, donor-specific antibodies, HLA antibodies, Liver Transplantation Abbreviations: DSA, donor-specific anti-HLA antibodies; HCV, hepatitis C; MFI, mean fluoresce intensity; MELD, model for end-stage liver disease; OLT, orthotopic liver transplantation.

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Bortezomib therapy effectively abrogates anti-HLA antibodies. Hence, removal of antibodies, by proteasome inhibition, represents a new treatment strategy for transplantation and may have benefit in autoimmune-related disease.