Hepatic injury due to cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4 T cell TIM-1 signaling co-stimulates a variety of immune responses in allograft recipients. This study analyzes mechanisms by which TIM-1 affects liver ischemia-reperfusion injury (IRI) in a murine model of prolonged cold storage followed by OLT. Livers from C57BL/6 mice, preserved at 4°C in UW solution for 20h, were transplanted to syngeneic recipients. There was an early (1h) increased accumulation of TIM-1+ activated CD4 T cells in the ischemic OLTs. Disruption of TIM-1 signaling with a blocking mAb (RMT1-10) ameliorated liver damage, evidenced by reduced sALT levels and well-preserved architecture. Unlike in controls, TIM-1 blockade diminished OLT expression of Tbet/IFN-γ, but amplified IL-4/IL-10/IL-22; abolished neutrophil and macrophage infiltration/activation; and inhibited NF-κB while enhancing Bcl-2/Bcl-xl. Although adoptive transfer of CD4 T cells triggered liver damage in otherwise IR-resistant RAG−/− mice, adjunctive TIM-1 blockade reduced Tbet transcription, and abolished macrophage activation, restoring homeostasis in IR-stressed livers. Further, transfer of TIM-1HiCD4+, but not TIM-1LoCD4+ T cells, recreated liver IRI in RAG−/− mice. Thus, TIM-1 expressing CD4 T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLTs.
Background: Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis.Methods: The training set (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) based on the prognosis-related genes associated with ferroptosis and pyroptosis. The intersecting differentially expressed genes (DEGs) among C1, C2, and C3 were used in univariate Cox and LASSO penalized Cox regression analysis for the construction of the risk score. The median risk score served as the unified cutoff to divide patients into high- and low-risk groups.Results: Internal (TCGA, n = 370; GSE14520, n = 239) and external validation (ICGC, n = 231) suggested that the 12-gene risk score had high accuracy in predicting the OS, DSS, DFS, PFS, and RFS of HCC. As an independent prognostic indicator, the risk score could be applicable for patients with different clinical features tested by subgroup (n = 26) survival analysis. In the high-risk patients with a lower infiltration abundance of activated B cells, activated CD8 T cells, eosinophils, and type I T helper cells and a higher infiltration abundance of immature dendritic cells, the cytolytic activity, HLA, inflammation promotion, and type I IFN response in the high-risk group were weaker. The TP53 mutation rate, TMB, and CSC characteristics in the high-risk group were significantly higher than those in the low-risk group. Low-risk patients have active metabolic activity and a more robust immune response. The high- and low-risk groups differed significantly in histology grade, vascular tumor cell type, AFP, new tumor event after initial treatment, main tumor size, cirrhosis, TNM stage, BCLC stage, and CLIP score.Conclusion: The ferroptosis and pyroptosis molecular subtype-related signature identified and validated in this work is applicable for prognosis prediction, immune microenvironment estimation, stem cell characteristics, and clinical feature assessment in HCC.
Macrophage polarization serves an important role in immune regulation that is regulated by T-cell immunoglobulin-mucin-3 (Tim-3). The objective of the present study was to explore the role of 1,25-dihydroxy-vitamin D3 [1,25(OH) 2 D3] in macrophage polarization. Plasmid transfection techniques were applied to prepare RAW264.7 cells with silenced or overexpressed Tim-3 gene. ELISAs were used to examine the level of inflammatory factors secreted by macrophages. Proteins levels were determined by western blot analysis. mRNAs expression levels were assessed using reverse transcription quantitative polymerase chain reaction. It was identified that 1,25(OH) 2 D3 upregulated Tim-3 levels and promoted the secretion of interleukin (IL)-10. 1,25(OH) 2 D3 was also observed to increase the level of transforming growth factor-β and to inhibit tumor necrosis factor-α and IL-6. The results also suggested that Tim-3 gene silencing induced macrophages polarization to classically activated macrophages (M1), and that overexpression of the Tim-3 gene induced macrophage polarization to alternatively activated macrophages (M2). 1,25(OH) 2 D3 treatment upregulated the expression level of Tim-3 in macrophages, which promoted cell polarization to M2 and inhibited polarization to M1. The data from the present study indicated that Tim-3 may induce macrophage polarization to M2, and that 1,25(OH) 2 D3 produced immunosuppressive effects by upregulating Tim-3.
We retrospectively analyzed 252 patients with end-stage liver disease who had undergone LDLT from January 2009 to September 2015. Of these, 25 had a GRWR of <2.0% (Group A), 204 had a GRWR of ≥2.0% or <4.0% (Group B), and 23 had a GRWR ≥4.0% (Group C). The three GRWR groups demonstrated similar characteristics, except for recipient age and recipient BMI. The overall 1-, 2-, and 3-year graft survival rates were 95.1%, 93.5%, and 93.5%, respectively. However, among the three groups, graft survival rates at 1 year, 2 years, and 3 years were significantly different (P = .0009). Hepatic artery stenosis/thrombosis was more frequently observed in Group C than in Groups A and B (P = .001). Wound infection was also more frequently observed in Group C than in Group A and B (P = .002). However, intestinal fistula/bile leakage/biliary-enteric anastomotic fistula was more frequently observed in Group A than in Groups B and C (P = .001). In addition, reoperation more frequently occurred in Group A and C than in Group B (P = .001). Recipients with a GRWR between 2.0% and 4.0% had significantly better graft survival rates. K E Y W O R D Sgraft-to-recipient weight ratio, living-donor liver transplantation, patient and graft survival rates, pediatric
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