Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants

• Type of Material: Article
• Authors: Sandy Feng, University of California San Francisco; John C. Bucuvalas, Cincinnati Children's Hospital Medical Center; Anthony J. Demetris, University of Pittsburgh; Bryna E. Burrell, Immune Tolerance Network; Katherine M. Spain, Rho, Inc.; Sai Kanaparthi, Immune Tolerance Network; John C. Magee, University of Michigan; David Ikle, Rho, Inc.; Andrew Lesniak, University of Pittsburgh; Juan J. Lozano, Carlos III Health Institute; Estella M. Alonso, Ann & Robert H Lurie Children's Hospital; Robert A Bray, Emory University; Nancy E. Bridges, National Institute of Allergy and Infectious Diseases; Edward Doo, Emory University Hospital; Howard Gebel, Emory University; Nitika Arora Gupta, Emory University; Ryan W. Himes, Texas Children’s Hospital; Annette M. Jackson, Johns Hopkins University; Steven J. Lobritto, Columbia University; George V. Mazariegos, Children’s Hospital of Pittsburgh of UPMC; Vicky L. Ng, Transplant & Regenerative Medicine Center; Elizabeth B. Rand, Children's Hospital of Philadelphia; Averell H. Sherker, Ann & Robert H Lurie Children's Hospital; Shikha Sundaram, University of Colorado; Yumirle P. Turmelle, St Louis Children's Hospital; Alberto Sanchez-Fueyo, Kings College
• Language: English
• Date: 2018-12-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 AGA Institute
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2018.08.023
• Title of Journal or Parent Work: Gastroenterology
• ISSN: 0016-5085
• Volume: 155
• Issue: 6
• Start Page: 1838
• End Page: +
• Grant/Funding Information: This research was primarily supported by U01-AI-100807 awarded by the National Institute of Allergy and Infectious Diseases (NIAID); and the National Institute for Diabetes and Digestive and Kidney Diseases.; In addition, the research was also performed as a project of the Clinical Trials in Organ Transplantation in Children (U01-AI-104347), a collaborative clinical research project headquartered at NIAID; and as a project of the Immune Tolerance Network (UM1AI109565), an international clinical research consortium headquartered at the Benaroya Research Institute; and supported by NIAID.
• Keywords: HLA ANTIBODIES; DYSFUNCTION; HEPATITIS; IMMUNOSUPPRESSION WITHDRAWAL; DSA; Immune Response; HUMAN-LEUKOCYTE ANTIGEN; ALLOANTIBODIES; Prognostic Factor; Gastroenterology & Hepatology; Life Sciences & Biomedicine; ALT; ANTIBODY-MEDIATED REJECTION; R PACKAGE; GRAFT FIBROSIS; Science & Technology; GENE-EXPRESSION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Background & Aims: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles. Methods: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data. Results: The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell–mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3. Conclusion: In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.