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.

The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection

“…It may be present in around 8–15% of the patients who present persistent or de novo DSA, specially targeting HLA class II [ 2 , 10 ]. Most patients are diagnosed as cAMR in protocol biopsies [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 13 , 14 , 15 , 19 , 20 , 21 ], tolerance-inducing weaning protocols [ 3 , 5 , 8 , 14 , 15 , 22 ], as well as biopsies performed in inexorable immunosuppression cessation secondary to infections (Epstein-Barr Virus, EBV; Cytomegalovirus, CMV), malignancies (post-transplant lymphoproliferative disease, PTLD) or non-compliance [ 2 , 3 , 4 , 5 , 6 , 8 , 9 , 10 , 12 , 13 , 14 , 19 , 23 , 24 ].…”

“…DSA suggests the presence of antibodies against the liver allograft, but some patients with positive DSA have no signs of rejection in liver biopsies and some cAMR patients have no detectable DSA. Such patients may have antibodies against non-HLA minor antigens such as glutathione S-transferase T1 (GSTT1) and IgG4 DSA [ 15 , 21 ].…”

Incidence of de novo autoimmune hepatitis in children and adolescents with increased autoantibodies after liver transplantation: a meta‐analysis

“…Additionally, the measurement methods and cutoff value of positive autoantibodies differed among the studies. It was difficult to estimate the effect of immunosuppression after liver transplantation on elevated autoantibodies and occurrence of de novo AIH [27] because of the small number of studies and control groups. Therefore, more further studies will be needed to obtain comparative results.…”

De Novo Autoimmune Hepatitis After Liver Transplantation: Natural History and Diagnosis

“…dnAIH has been reported to occur in up to 7% of post-liver transplant patients. Glutathione S-transferase T1 (GSTT1) mismatch [3][4][5][6][7] has been reported to play a role in dnAIH with antibodies against glutathione S-transferase being found in 100% of patients with dnAIH [4], however, not enough research has been done on the subject provide a more detailed understanding of its role in the pathogenesis of dnAIH.…”