Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2018; 24(29): 3239-3249
Published online Aug 7, 2018. doi: 10.3748/wjg.v24.i29.3239
Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: Relevance of glutathione S-transferase T1 mismatch
Isabel Aguilera, Elena Aguado-Dominguez, Jose Manuel Sousa, Antonio Nuñez-Roldan
Isabel Aguilera, Elena Aguado-Dominguez, Antonio Nuñez-Roldan, Department of Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
Jose Manuel Sousa, Digestive and Liver Diseases Service, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
Author contributions: Aguilera I contributed to this paper with the conception, literature review and drafting; Aguado-Dominguez E contributed with literature review, original data and drafting; Sousa JM and Nuñez-Roldan A contributed with critical revision of the manuscript and approval of the final version.
Supported by Andalusian Government, Proyecto de Excelencia, No. CTS-7846; and Spanish Ministry of Economy, Instituto de Salud Carlos III, No. 11/857 and No. 17/1403.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Isabel Aguilera, PhD, Research Fellow, Senior Scientist, Department of Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Avda Manuel Siurot s/n, Sevilla 41013, Spain.
Telephone: +34-955923120
Received: May 3, 2018
Peer-review started: May 4, 2018
First decision: May 17, 2018
Revised: June 28, 2018
Accepted: June 30, 2018
Article in press: June 30, 2018
Published online: August 7, 2018

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.