Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection

Abstract

T cell-mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. We reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6-year follow-up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79-1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78-1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderateto-severe early TCMR (HR, 2.85; 95% CI, 1.55-5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87-6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35-2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23-2.37; P = 0.001). Thus, these data suggest that the timing and histologic grade of TCMR determine its impact on patient and allograft survival. Early mild TCMR episodes after LT do not adversely impact patient or allograft survival provided that they are adequately treated. The occurrence of late TCMR carries deleterious effects with increased longterm risk of graft loss and decreased survival. Patients with moderate-to-severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow-up.

Liver transplantation: Rejection and tolerance

“…Earlier data from 3 North American centers that performed surveillance biopsies demonstrated that the incidence of liver TCMR was 66% within the first year . With standardized tacrolimus‐based immunosuppression, this incidence appears to have been reduced to approximately 37.1% in the more recent era . The vast majority of the TCMR occurs within the first 6 weeks.…”

“…(6) With standardized tacrolimus-based immunosuppression, this incidence appears to have been reduced to approximately 37.1% in the more recent era. (7) The vast majority of the TCMR occurs within the first 6 weeks. Although mild elevation in liver enzymes typically accompanies TCMR, the sensitivity and specificity of abnormal tests are relatively low.…”

Late T cell–mediated rejection may contribute to poor outcomes in adolescents and young adults with liver transplantation

“…As previously observed, in LT, late L‐TCMR was often associated with lower immunosuppression levels, including non‐adherence 7,8 . L‐TCMR was more refractory to immunosuppressive therapy, and the evolution of L‐TCMR might result in chronic rejection or zone 3 fibrosis 9‐11 .…”

“…Late TCMR was defined as TCMR characterized by central veins or perivenular inflammation and an onset later than 3 months after LT in accordance with the Banff criteria and past literature (Figure 1). 8,10,15 Although either 3 months or 6 months can be used to define L‐TCMR due to the lack of a clear criterion for time‐to‐onset of L‐TCMR, 9 we adopted 3 months because steroid administration is stopped 3 months after the LT in accordance with our immunosuppression protocol described below. The L‐TCMR grades ranged from minimal or indeterminate to severe in accordance with the previously proposed criteria 10 .…”

“…L‐TCMR was more refractory to immunosuppressive therapy, and the evolution of L‐TCMR might result in chronic rejection or zone 3 fibrosis 9‐11 . Furthermore, recent investigations have demonstrated that L‐TCMR was associated with increased long‐term risk of graft loss and decreased graft survival in adult LT 8 . Therefore, it is hypothesized that graft survival in AYA patients after LT may be associated with L‐TCMR occurrence.…”