In treatment of paediatric rare liver diseases, liver transplantation (LT) is the standard-of-care therapy, improving prognosis and quality of life for children with terminal liver failure. In long-term care of these children, the ultimate goal is to secure optimal transplant function while minimizing toxicity of immunosuppressive treatment over many decades. However, multiple centres have reported on hepatitis and fibrosis in protocol biopsies observed in healthy paediatric transplant recipients with normal liver function tests. The pathological relevance of these subclinical lesions in liver allografts and its impact on patient and graft outcome has remained uncertain. In a recent publication in Gastroenterology, a group led by Sandy Feng and Alberto Sanchez-Fueyo lead us to rethink the importance of subclinical inflammatory lesions in long-term stable liver transplant recipients (DOI: 10.1053/j.gastro.2018.08.023).

Subclinical chronic liver transplant injury: a new entity?

In the study by Feng et al[1], 157 children, transplanted at ≤ 6 years of age for non-viral and non-autoimmune liver disease received screening liver biopsy for an immunosuppression withdrawal study (iWITH) more than 4 years after liver transplantation. These patients received LT predominantly for biliary atresia (55%) and had stable liver tests while being on CNI monotherapy. Liver biopsies were scored by a central pathologist and sorted into three clusters. Feng et al. carried out transcriptional and cytometric analyses of liver tissue samples. Further, transcriptional patterns, clinical and serological data including donor-specific HLA antibodies were assessed and correlated with histological phenotype.

All children had normal aminotransferases (ALT 27.6 ±13.57 U/l and gamma-GT 17.4 ±7.93 U/l. However, the histopathological assessment revealed a high proportion of inflammation and fibrosis: Lymphocytic inflammation was found in periportal (59% mild and 5% moderate) and perivenular zones (17% mild) including interface activity (21% mild; 1 % moderate). Based on unsupervised hierarchical cluster analysis, three distinct histopathological phenotypes were determined: Cluster 1, portal inflammation with interface activity +/- fibrosis (n=34); cluster 2, significant fibrosis without interface activity (n=45); cluster 3, near normal histology (n=78). Transcriptional gene analysis of the liver tissue revealed a module of genes whose expression correlated with portal inflammation and interface activity (cluster 1). The module was enriched in genes that are known to regulate T-cell mediated rejection of liver allografts. The transcript levels correlated significantly with the magnitude of leukocyte infiltration. Patients in cluster 1 had also the highest prevalence of donor-specific HLA class II antibodies. Further, patients with high class II DSA (MFI sum >20000) were at increased risk of significant fibrosis and portal inflammation. Further, DSA correlated significantly with C4d staining. However, the authors did not observe a significant enrichment in specific gene signatures described for antibody-mediated rejection. Class II DSA were associated with mRNA expression of T cell chemokines such as CCL8 and CYCL9. The authors propose a contributory role for DSA, in the purpose of a mixed process influenced by both humoral sensitisation and T-cell alloreactivity.

This publication contributes to our concept of longterm management of liver-transplanted children with rare liver diseases. The paper by Feng’s group adds to our understanding of a recently observed histological finding as evidence of subclinical T-cell mediated rejection potentially increasing the risk of graft loss. Studies in long-term survivors after paediatric LT showed an unexpectedly high prevalence of chronic graft hepatitis and fibrosis[2]. This long-term graft injury is associated with a high risk of developing progressive graft fibrosis 10 years after LT, and up to 25% of patients need re-transplantation[3]. This study and a similar study in adults[4] define this type of chronic graft injury as subclinical rejection, a new entity in paediatric liver transplantation. Recognising subclinical rejection as a prevalent condition with potential influence on graft loss raises further questions about natural history and optimal immunosuppressive therapy[5]. However, evidence is not yet sufficiently clear to support an intensification of immunosuppressive therapy upon detecting subclinical rejection. An interventional randomized clinical trial comparing patient groups with chronic graft hepatitis treated either by intensified immunosuppressive therapy or continued standard immunosuppression could lead to further insights. Currently, no clear recommendation can be made. In addition, alternative immunomodulating approaches including hematopoietic stem cell transplantation[6], application of mesenchymal stem cells[7] or regulatory T-cells[8] may contribute to achieving donor-specific tolerance. The understanding of subclinical chronic liver transplant injury and new approaches to immunomodulation may help to define personalized immunosuppression decision making with the ultimate goal of achieving “life-long” graft survival in liver transplanted children. The global Graft Injury Group (http://www.graftinjurygroup.org/) network endorsed by ERN RARE LIVER is one example of a multicentre platform offering the infrastructure to plan and conduct multi-center trials in this vulnerable group of patients.

References

  1. Feng, S., Bucuvalas, J.C., Demetris, A.J., et al., Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants. Gastroenterology, 2018.
  2. Evans, H.M., Kelly, D.A., McKiernan, P.J., et al., Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology, 2006. 43(5): p. 1109-17.Paediatric Gastroenterology and Hepatology
  3. Scheenstra, R., Peeters, P.M., Verkade, H.J., et al., Graft fibrosis after pediatric liver transplantation: ten years of follow-up. Hepatology, 2009. 49(3): p. 880-6.
  4. Londono, M.C., Souza, L.N., Lozano, J.J., et al., Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients. J Hepatol, 2018. 69(3): p. 626-634.
  5. Miloh, T., Barton, A., Wheeler, J., et al., Immunosuppression in pediatric liver transplant recipients: Unique aspects. Liver Transpl, 2017. 23(2): p. 244-256.
  6. Hartleif, S., Lang, P., Handgretinger, R., et al., Outcomes of pediatric identical living-donor liver and hematopoietic stem cell transplantation. Pediatric Transplantation, 2016. 20(7): p. 888-897.
  7. Hartleif, S., Schumm, M., Doring, M., et al., Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study. Stem Cells International, 2017.
  8. Todo, S., Yamashita, K., Goto, R., et al., A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology, 2016. 64(2): p. 632-43.

Steffen Hartleif MD, Ekkehard Sturm MD PhD
I. Department of Medicine, University Hospital Tübingen, Germany.
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