Biliary Epithelial Senescence in Cellular Rejection Following Live Donor Liver Transplantation

Archana Rastogi; Neha Nigam; Ramakrishna Gayatri; Chhagan Bihari; Viniyendra Pamecha

doi:10.1016/j.jceh.2022.08.004

Biliary Epithelial Senescence in Cellular Rejection Following Live Donor Liver Transplantation

J Clin Exp Hepatol. 2022 Nov-Dec;12(6):1420-1427. doi: 10.1016/j.jceh.2022.08.004. Epub 2022 Aug 28.

Authors

Archana Rastogi¹, Neha Nigam², Ramakrishna Gayatri³, Chhagan Bihari¹, Viniyendra Pamecha⁴

Affiliations

¹ Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India.
² Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
³ Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
⁴ Department of Hepato-Pancreato-Biliary Surgery, Institute of Liver and Biliary Sciences, New Delhi, India.

Abstract

Background: As with the hepatocytes, cholangiocyte senescence can also easily be detected in damaged small bile ducts and bile ductules during liver disease affecting the biliary system and cholangiocytes. Despite cellular senescence being a feature of chronic progressive cholangiopathies in adults, only a few studies have investigated its role in liver transplant rejection.

Method: Transplant biopsies displaying features of rejection were reviewed and classified based on the type of rejection and the time since transplantation. An immunohistochemistry panel has been applied for 3 senescent cell markers (p53, p21, p16).

Results: Immunohistochemical expression analysis for the biliary senescence markers (53 biopsies) was done in the post-transplantation periods (Group 1-4) for the cases with the histologically proven diagnosis of rejection. In post-transplant group 1 (<3 months), group 2 (3-6 months), group 3 (6-12 months) and group 4 (>12 months), any 2 senescent markers' positivity was noted in 5/14 (35.7%), 8/13 (61.5%), 16/17 (94.1%) and 9/9 (100%) biopsies respectively and were comparable in all four groups (P = 0.001). A comparison of early biopsies (Group1; 3 months) and late biopsies (Group 2,3&4; >3 months) revealed significantly higher expression in late biopsies (>3 months) (P = 0.001 for any two markers). In ACR, LAR, ECR, and CR/DR any two senescent markers were positive in 14/28 (50%), 12/13 (92.3%) cases, 9/9 (100%), and 3/3cases (100%). Senescent markers (any two) were comparable in all four histological groups (P < 0.001).LAR group had increased expression (P = 0.009 for any two markers and 0.001 for all three markers) and has increased progression to CR (P = 0.019) as compared to ACR.

Conclusion: This study on a large number of LDLT allograft biopsies demonstrates the role of biliary senescence in rejection and suggests a pathobiological role for senescence in the poor prognosis seen in late acute cellular rejection and chronic rejection.

Keywords: ACR, Acute cellular rejection; BEC, Biliary epithelial cells; CR/DR, Chronic Rejection/Ductopenic Rejection; ECR, Early chronic rejection; LAR, Late acute cellular rejection; LDLT, Live donor liver transplantation; MELD, Model for end-stage liver disease; RAI, Rejection activity index; liver; rejection; senescence; transplant.