The Significance of Donor-Specific HLA Antibodies in Rejection and Ductopenia Development in ABO Compatible Liver Transplantation

Abstract

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

Donor-Specific HLA Antibodies in Living Versus Deceased Donor Liver Transplant Recipients

“…Consequently, it is reasonable to hypothesize that, given the nature of the procedure, DDLT recipients may be more sensitive to the detrimental effects of HLA antibodies in comparison to LDLT recipients. That said, similar to recent reports, DSA is likely to have an impact in both donor settings because our multivariate analysis demonstrated an independent association between DSA and graft failure regardless of donor type (5)(6)(7)(8)10,(19)(20)(21).…”

“…Although early studies suggested correlations between positive crossmatches and graft loss in LT, liver recipients have been routinely transplanted without regard for HLA antibodies for years (1,25). Not until the recent seminal work of multiple investigators has the interest in alloantibodies in LT become reinvigorated (6,7,10,20,26,27). Significant associations have been made between preformed and de novo DSA and liver transplant rejection, alloimmune hepatitis and patient and graft survival (4)(5)(6)(7)(8)(9)(10)19,21,26).…”

“…Although older studies did not find a correlation between graft survival and DSA (1-3), more recent data using advanced techniques such as solid-phase antibody testing have found new associations between DSA with high mean fluorescent intensity (MFI) and rejection, alloimmune hepatitis and long-term patient and graft survival (4)(5)(6)(7)(8)(9)(10). Most of the studies, however, have been single center and retrospective in nature.…”

Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation

“…Antibody-mediated injury may coincide with, or augment, bouts of acute cellular rejection with positive donor-specific antibodies and C4d staining observed in roughly 50% of specimens exhibiting cellular rejection (12-19 of 28, depending on pattern). 92 Other studies have shown C4d staining with many other allograft abnormalities not related to rejection, including chronic hepatitis, vascular injury, or bile duct injury. 84,95,97 Therefore, C4d staining should be interpreted with caution and has no particular significance without the correct clinical context and congruent histopathologic changes in the biopsy.…”

“…84,85 Within the population of ABO-compatible grafts, recipients with known, preformed lymphocytotoxic antibodies to the donor (positive cross-matches) are at higher risk for developing ABMR, 86-90 whereas cross-match-negative transplants appear to have minimal risk of isolated ABMR. 89,91,92 In this context, unlike heart or kidney, the diagnosis of isolated ABMR in liver is rare and one of exclusion. Diagnostic criteria are not as well established compared with other solid organ transplants, but histopathologic changes suggesting ABMR (see Table 1), C4d immunostaining, and donor-specific antibody detection should all be combined to evaluate for the possibility of ABMR.…”