The rejectome of acute t-cell mediated rejection in clinical liver transplantation

Rejection remains a major cause of allograft injury and loss in liver transplantation (LT). Mechanisms mediating clinical liver allograft rejection remain elusive, limiting development of new immunosuppressive drugs and biomarker panels for monitoring rejection for decades. Herein, multi-omic data and systems immunology were combined to define the ‘rejectome’ of T-cell mediated rejection (TCMR) in 98 pediatric LT recipients. Spatial proteomics of liver biopsies revealed enrichment of HLADR high and PD1 high T and B-cell subtypes in TCMR. Two peripheral PD1+ T-cell subsets shared expression profiles with T-cells within the alloimmune microenvironment. Plasma proteomics and predictive modeling identified a tissue correlative panel of 11 biomarkers linked to immune function and liver metabolism that differentiates TCMR from no rejection and proteomic profiles in other liver diseases. These data highlight multi-tissue proteomics features of the alloimmune microenvironment during clinical TCMR and suggest that a clinical plasma proteomic ‘liquid biopsy’ can be developed for management of TCMR in LT.