Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: Relevance of glutathione S-transferase T1 mismatch

Abstract

Antibody-mediated rejection (AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as “minor”, whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis (dnAIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dnAIH with plasma cell (PC)-rich rejection. Antibodies to glutathione S-transferase T1 (GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not disease-specific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are IgG4⁺. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.

Keywords: Glutathione S-transferase T1 mismatch; Liver allograft rejection; Plasma cell-rich rejection; De novo autoimmune hepatitis; Donor-specific antibodies; NewCAST; Cell quantification; IgG4⁺ plasma cell; T lymphocytes

Core tip: The purpose of this review is to update the reader with recent knowledge about a disease of the liver allograft, whose definition has evolved from “de novo autoimmune hepatitis” to “plasma cell-rich rejection”. During the last 20 years, several groups have contributed new data that has prompted the liver transplant community to reconsider several aspects of the disease. It is not the intention of this review to go over details of the histological features or the role of autoantibodies in this disease, which have been well described in other reviews. Instead, more recent aspects, such as the composition of infiltrates in biopsies and T cell involvement will be discussed.