title: Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts.
abstract: Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Baumann
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlue
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.|Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hardtke-Wolenski
authors.affiliation: Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany.|Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lehner
authors.affiliation: Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Barg-Hock
authors.affiliation: Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Klempnauer
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.|Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Taubert
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.|Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D015994:Incidence; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors