RESUMO
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.
RESUMO
Intense monocyte activation and infiltration into the target tissues is the main mechanism of lung injury in SARS CoV2 infection. A reduction in the degree and nature of such cellular responses is expected following recovery. We aimed to investigate the immune responses in severe Covid-19 patients and recovered patients. MethodsSevere COVID-19 patients (n=34) at Lok Nayak Hospital, New Delhi and COVID-19 recovered patients (n=15) from mild disease and considered for convalescent plasma (COPLA) donation at Institute of Liver and Biliary Sciences (ILBS), New Delhi were recruited. We performed a multiplex cytokine bead assay in plasma and detailed multicolour flow cytometric analysis in peripheral blood of both groups and outcomes were compared in both groups and with healthy controls (n=10). ResultsA significant increase in inflammatory markers [MIP1-a, MIP3a, MCP1, MIF, MMP12, ITAC, VEGF-A, and leptin] was observed in severe patients. Non-survivors additionally showed increased IL-6 levels. Despite the sustained expression of MIPs, the recovered patients showed a surge in MCSF and IL-18 levels. Both the groups had increased CCR2, CX3CR1 positive monocytes, low CD8 T cells, APRIL and BAFFR+ve B cells compared with healthy subjects. In conclusion, patients who have recovered and considered for COPLA donations still have compromised immunity with sustained expression of inflammatory monocytes and activated T cells.
