Identification of peripheral CD154+ T cells and HLA-DRB1 as biomarkers of acute cellular rejection in adult liver transplant recipients

Abstract

Summary Decreasing graft rejection and increasing graft and patient survival are great challenges facing liver transplantation (LT). Different T cell subsets participate in the acute cellular rejection (ACR) of the allograft. Cell-mediated immunity markers of the recipient could help to understand the mechanisms underlying acute rejection. This study aimed to analyse different surface antigens on T cells in a cohort of adult liver patients undergoing LT to determine the influence on ACR using multi-parametric flow cytometry functional assay. Thirty patients were monitored at baseline and during 1 year post-transplant. Two groups were established, with (ACR) and without (NACR) acute cellular rejection. Leukocyte, total lymphocyte, percentages of CD4+CD154+ and CD8+CD154+ T cells, human leukocyte antigen (HLA) mismatch between recipient–donor and their relation with ACR as well as the acute rejection frequencies were analysed. T cells were stimulated with concanavalin A (Con-A) and surface antigens were analysed by fluorescence activated cell sorter (FACS) analysis. A high percentage of CD4+CD154+ T cells (P = 0·001) and a low percentage of CD8+CD154+ T cells (P = 0·002) at baseline were statistically significant in ACR. A receiver operating characteristic analysis determined the cut-off values capable to stratify patients at high risk of ACR with high sensitivity and specificity for CD4+CD154+ (P = 0·001) and CD8+CD154+ T cells (P = 0·002). In logistic regression analysis, CD4+CD154+, CD8+CD154+ and HLA mismatch were confirmed as independent risk factors to ACR. Post-transplant percentages of both T cell subsets were significantly higher in ACR, despite variations compared to pretransplant. These findings support the selection of candidates for LT based on the pretransplant percentages of CD4+CD154+ and CD8+CD154+ T cells in parallel with other transplant factors.

Computational Prediction of Biomarkers, Pathways, and New Target Drugs in the Pathogenesis of Immune-Based Diseases Regarding Kidney Transplantation Rejection

“…On the other hand, only samples taken at the time of rejection have been studied. In the future, therefore, it would be interesting to carry out longitudinal studies that make it possible to correlate gene expression profiles in the early stages of transplantation with chronic damage, as other previous own studies ( 94 , 95 ), which allow us to develop prognostic models for the better classification of patients and thereby improve their clinical management. Finally, the results obtained in silico must be confirmed by in vivo and in vitro analysis in the future.…”

Monitoring of Serological, Cellular and Genomic Biomarkers in Transplantation, Computational Prediction Models and Role of Cell-Free DNA in Transplant Outcome

“…Neutrophils secrete NGAL during an inflammatory response and it functions as an acute-phase protein. NGAL levels in urine (uNGAL) can also be measured; siderophores and metalloproteinase 9 are its primary ligands and markers of acute tubular cell injury [ 24 ]. NGAL can also be used to detect kidney damage [ 25 ].…”

“…A decrease in these protein levels on day three was also a good predictor of renal function one month later. Another study [ 24 ] concludes that uNGAL may be more helpful in assessing renal function in the first week after KT when combined with other markers. Another study found that NGAL levels in urine and serum could be used to predict kidney damage and as a biomarker of acute kidney injury after transplantation [ 28 ].…”

“…In this way, Tregs lymphocytes, Bregs cells, follicular Th cells (meaningful in the production of antibodies) and myeloid suppressor cells have dominated the transplantation publications in this cellular section in recent years [ 8 , 9 , 24 , 26 , 65 ].…”

The Model for End-Stage Liver Disease Score and the Follow-Up Period Can Cause the Shift of Circulating Lymphocyte Subsets in Liver Transplant Recipients

“…Zhu et al noted a group of LTR that showed acute rejection at a mean follow-up of nearly 2 months, whose interferon-γ + (IFN-γ + ) CD4 + T cells and interleukin-2 (IL-2 + ) CD4 + T cells and transforming growth factor-β (TGF-β + ) CD19 + B cell and granzyme B + CD19 + B cell rose significantly compared with LTR without rejection (9). Boix et al found that LTR, who rejected the allograft, had a statistically significant higher ratio of CD4 + CD154 + T cells and CD8 + CD154 + T cells on the 7th and 15th postoperative days (18). Nevertheless, the recommended tacrolimus trough concentrations used in immunosuppressive schemes taper during the first 6 months (19)(20)(21).…”