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

被引：121

作者：

Feng, Sandy ^{[1
]}

Bucuvalas, John C. ^{[2
]}

Demetris, Anthony J. ^{[3
]}

Burrell, Bryna E. ^{[4
]}

Spain, Katherine M. ^{[5
]}

Kanaparthi, Sai ^{[4
]}

Magee, John C. ^{[6
]}

Ikle, David ^{[5
]}

Lesniak, Andrew ^{[3
]}

Lozano, Juan J. ^{[7
]}

Alonso, Estella M. ^{[8
]}

Bray, Robert A. ^{[9
]}

Bridges, Nancy E. ^{[10
]}

Doo, Edward ^{[9
,11
]}

Gebel, Howard M. ^{[9
]}

Gupta, Nitika A. ^{[12
]}

Himes, Ryan W. ^{[13
]}

Jackson, Annette M. ^{[14
]}

Lobritto, Steven J. ^{[15
]}

Mazariegos, George V. ^{[16
]}

Ng, Vicky L. ^{[17
]}

Rand, Elizabeth B. ^{[18
]}

Sherker, Averell H. ^{[8
]}

Sundaram, Shikha ^{[19
]}

Turmelle, Yumirle P. ^{[20
]}

Sanchez-Fueyo, Alberto ^{[21
]}

机构：

[1] Univ Calif San Francisco, Dept Surg, Div Transplantat, San Francisco, CA 94143 USA

[2] Cincinnati Childrens Hosp Med Ctr, Pediat Liver Care Ctr, Cincinnati, OH 45229 USA

[3] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[4] Immune Tolerance Network, Bethesda, MD USA

[5] Rho Inc, Chapel Hill, NC USA

[6] Univ Michigan, Dept Surg, Sect Transplant Surg, Ann Arbor, MI 48109 USA

[7] Carlos III Hlth Inst, Biomed Res Ctr Hepat & Digest Dis, Barcelona, Spain

[8] Ann & Robert H Lurie Childrens Hosp Chicago, Siragusa Transplantat Ctr, Chicago, IL 60611 USA

[9] Emory Univ Hosp, Dept Pathol, 1364 Clifton Rd NE, Atlanta, GA 30322 USA

[10] NIAID, Transplantat Branch, Div Allergy Immunol & Transplantat, Rockville, MD USA

[11] NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA

[12] Emory Univ, Sch Med, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Atlanta, GA 30322 USA

[13] Texas Childrens Hosp, Sect Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[14] Johns Hopkins Univ, Dept Med, Div Immunogenet & Transplantat Immunol, Baltimore, MD USA

[15] Columbia Univ, Med Ctr, Dept Surg, Ctr Liver Dis & Transplantat, New York, NY USA

[16] Childrens Hosp Pittsburgh UPMC, Hillman Ctr Pediat Transplantat, Pittsburgh, PA USA

[17] Transplant & Regenerat Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[18] Childrens Hosp Philadelphia, Liver Transplant Program, Philadelphia, PA 19104 USA

[19] Univ Colorado, Sch Med, Childrens Hosp Colorado, Div Gastroenterol Hepatol & Nutr, Aurora, CO USA

[20] St Louis Childrens Hosp, Div Gastroenterol Hepatol & Nutr, St Louis, MO 63178 USA

[21] Kings Coll London, Inst Liver Studies, London, England

来源：

GASTROENTEROLOGY | 2018年 / 155卷 / 06期

关键词：

ALT; DSA; Immune Response; Prognostic Factor; ANTIBODY-MEDIATED REJECTION; HUMAN-LEUKOCYTE ANTIGEN; HLA ANTIBODIES; IMMUNOSUPPRESSION WITHDRAWAL; GENE-EXPRESSION; GRAFT FIBROSIS; R PACKAGE; ALLOANTIBODIES; DYSFUNCTION; HEPATITIS;

D O I：

10.1053/j.gastro.2018.08.023

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 g-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.

引用

页码：1838 / +

页数：21

共 61 条

[51] Significance analysis of microarrays applied to the ionizing radiation response [J].

Tusher, VG ;

Tibshirani, R ;

Chu, G .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (09) :5116-5121

[52] Dynamics of Allograft Fibrosis in Pediatric Liver Transplantation [J].

Venturi, C. ;

Sempoux, C. ;

Quinones, J. A. ;

Bourdeaux, C. ;

Hoyos, S. P. ;

Sokal, E. ;

Reding, R. .

AMERICAN JOURNAL OF TRANSPLANTATION, 2014, 14 (07) :1648-1656

[53] Novel Histologic Scoring System for Long-Term Allograft Fibrosis After Liver Transplantation in Children [J].

Venturi, C. ;

Sempoux, C. ;

Bueno, J. ;

Ferreres Pinas, J. C. ;

Bourdeaux, C. ;

Abarca-Quinones, J. ;

Rahier, J. ;

Reding, R. .

AMERICAN JOURNAL OF TRANSPLANTATION, 2012, 12 (11) :2986-2996

[54] NanoStringNorm: an extensible R package for the pre-processing of NanoString mRNA and miRNA data [J].

Waggott, Daryl ;

Chu, Kenneth ;

Yin, Shaoming ;

Wouters, Bradly G. ;

Liu, Fei-Fei ;

Boutros, Paul C. .

BIOINFORMATICS, 2012, 28 (11) :1546-1548

[55] Evolution and Clinical Pathologic Correlations of De Novo Donor-Specific HLA Antibody Post Kidney Transplant [J].

Wiebe, C. ;

Gibson, I. W. ;

Blydt-Hansen, T. D. ;

Karpinski, M. ;

Ho, J. ;

Storsley, L. J. ;

Goldberg, A. ;

Birk, P. E. ;

Rush, D. N. ;

Nickerson, P. W. .

AMERICAN JOURNAL OF TRANSPLANTATION, 2012, 12 (05) :1157-1167

[56] Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation [J].

Wozniak, Laura J. ;

Hickey, Michelle J. ;

Venick, Robert S. ;

Vargas, Jorge H. ;

Farmer, Douglas G. ;

Busuttil, Ronald W. ;

McDiarmid, Sue V. ;

Reed, Elaine F. .

TRANSPLANTATION, 2015, 99 (07) :1416-1422

[57] Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations [J].

Yaari, Gur ;

Bolen, Christopher R. ;

Thakar, Juilee ;

Kleinstein, Steven H. .

NUCLEIC ACIDS RESEARCH, 2013, 41 (18) :e170

[58]

Yanik EL, 2017, PEDIATRICS, V5, P139

[59] DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis [J].

Yu, Guangchuang ;

Wang, Li-Gen ;

Yan, Guang-Rong ;

He, Qing-Yu .

BIOINFORMATICS, 2015, 31 (04) :608-609

[60] clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters [J].

Yu, Guangchuang ;

Wang, Li-Gen ;

Han, Yanyan ;

He, Qing-Yu .

OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY, 2012, 16 (05) :284-287

← 1 2 3 4 5 6 7 →