Early vs. Late Liver Allograft T-Cell Mediated Rejection: A Banff Allograft Pathology Update
Claudia Mescoli et al
Read the full manuscript on SSRN
Abstract
The often smouldering accumulation of alloimmune damage after the initial post-transplant months, categorised as late-TCMR, is difficult to sensitively recognise and monitor because: a) liver injury tests can be insensitive and nonspecific, b) lack of protocol liver biopsy practice delays detection until graft dysfunction manifests and c) late rejection does not usually resemble early-TCMR histologically; differences in tempo and pathogenesis lead to distinct clinical and histologic manifestations. Late- compared with early-TCMR is characterized by more prevalent interface and perivenular inflammatory activity, a lymphocyte-predominant infiltrate and fibrosis, with less conspicuous portal, duct-centered and subendothelial venular inflammation. The traditional Banff RAI scheme that works consistently well to diagnose early-TCMR is less well calibrated to account for these late shifts of inflammatory target and density, risking underdiagnosis of clinically significant late-TCMR. This document lays out the histopathologic characteristics of early- vs. late-TCMR and the rationale for updating the Banff scoring system for liver allograft rejection to better incorporate currently unrepresented histology feature sets correlating with a molecular rejection signature into the Banff rejection scheme.
Join the conversation by providing your comment(s) on the:
Clinical feasibility and utility of the classification
Areas of improvement for clarity and reduction of ambiguity
Inaccuracies and inconsistency
Evidence and knowledge gaps
The comment period will be open until August 31, 2025. All comments will be reviewed and considered by the Banff meeting report author groups prior to finalizing the manuscripts and submission for formal peer review.
How to comment:
Click on the comment box and you will be prompted to create an account
Once your account is created, you will return to the article, please enter your comment and click publish
Make sure to follow the post for updates on new comments and replies
The recognition that the current Banff Rejection Activity Index (RAI) underestimates late-TCMR—particularly interface and perivenular activity—is well supported by emerging molecular and histopathologic data. The emphasis on protocol biopsies, molecular correlations, and integration of non-invasive tools reflects an important step toward more precise and personalized allograft monitoring.
That said, a few considerations may strengthen the proposed framework:
Reproducibility and Simplicity: Incorporating interface and perivenular inflammation is essential, but highly granular schemes may reduce reproducibility across centers. A simplified composite or tiered scoring system (e.g., global impression plus key modifiers) could maintain sensitivity while ensuring day-to-day usability.
Integration of Non-HLA Allo-immunity: While the review acknowledges the role of non-HLA antibodies (AT1R, MICA, others), their practical integration into diagnostic criteria remains limited. Given their association with microvascular inflammation, plasma cell–rich rejection, and fibrosis progression, explicit inclusion in future Banff formulations would be valuable.
Therapeutic Implications and Risk Stratification: Early- and late-TCMR are biologically distinct. Even mild late-TCMR may accelerate fibrosis in pediatric and young adult recipients with decades of expected graft survival, whereas its clinical weight in older recipients may be different. Prospective studies stratified by age, comorbidity, and alloantibody profile will be critical to define intervention thresholds.
Overall, this initiative represents a major advance in codifying the spectrum of late alloimmune injury. Moving forward, prioritizing reproducible scoring, explicit incorporation of non-HLA alloimmunity, and prospective clinicopathologic correlation will help ensure broad applicability and clinical impact.