Abstract
BackgroundThe diagnosis of graft rejection in kidney transplantation (KT) patients is made by evaluating the histological characteristics of biopsy samples. The evolution of omics sciences and bioinformatics techniques has contributed to the advancement in searching and predicting biomarkers, pathways, and new target drugs that allow a more precise and less invasive diagnosis. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis.Material and MethodsFour GEO databases of kidney biopsies of kidney transplantation with/without AMR were analyzed. The infiltrating leukocyte populations in the graft, new target drugs, protein-protein interactions (PPI), functional and biological analysis were studied by different bioinformatics tools.ResultsOur results show DEGs and the infiltrating leukocyte populations in the graft. There is an increase in the expression of genes related to different stages of the activation of the immune system, antigenic presentation such as antibody-mediated cytotoxicity, or leukocyte migration during AMR. The importance of the IRF/STAT1 pathways of response to IFN in controlling the expression of genes related to humoral rejection. The genes of this biological pathway were postulated as potential therapeutic targets and biomarkers of AMR. These biological processes correlated showed the infiltration of NK cells and monocytes towards the allograft. Besides the increase in dendritic cell maturation, it plays a central role in mediating the damage suffered by the graft during AMR. Computational approaches to the search for new therapeutic uses of approved target drugs also showed that imatinib might theoretically be helpful in KT for the prevention and/or treatment of AMR.ConclusionOur results suggest the importance of the IRF/STAT1 pathways in humoral kidney rejection. NK cells and monocytes in graft damage have an essential role during rejection, and imatinib improves KT outcomes. Our results will have to be validated for the potential use of overexpressed genes as rejection biomarkers that can be used as diagnostic and prognostic markers and as therapeutic targets to avoid graft rejection in patients undergoing kidney transplantation.
Highlights
The severity and occurrence of rejection in kidney transplant (KT) patients depend on numerous variables that can affect the magnitude and nature of immune responses
The aim was to search for differentially expressed genes (DEGs) in antibody-mediated rejection (AMR) patients and to analyze the types of populations of leukocytes infiltrated in the graft developing diagnostic models using computational predictions in order to find diagnostic and prognostic markers and as a therapeutic target that allows avoiding graft rejection in patients undergoing kidney transplantation
A search was conducted in the Gene Expression Omnibus (GEO) database for studies performed with kidney graft biopsy samples from transplant recipients with AMR or without acute rejection (NR) (Table 1)
Summary
The severity and occurrence of rejection in kidney transplant (KT) patients depend on numerous variables that can affect the magnitude and nature of immune responses. The development of genomic and protein databases has led to many bioinformatics tools to predict the Abbreviations: ACR, Acute Cellular Rejection; ADCC, Antibody-Dependent Cellular Cytotoxicity; AMR, Antibody-Mediated Rejection; APC, Antigen Presenting Cell; AT1R, angiotensin II type 1 receptor; Betweenness Centrality (BC); cPRA, calculated Panel Reactive Antibody; CTLA4, Cytotoxic TLymphocyte-Associated Protein 4; CYT, Cytolytic Index; DC, Dendritic Cell; Degree Centrality (DCy); DEGs, Differentially Expressed Genes; DSA, Donor Specific Antibodies; DV, Decision Values; EMA, European Medicines Agency; ES, Enrichment Score; FDA, Food and Drug Administration; GEO, Gene Expression Omnibus; GO, Gene Ontology; GVHD, Graft-versus-host disease; HLA, Human Leukocyte Antigen; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, Protein-Protein Interaction; KT, kidney Transplant; MFI, Mean Fluorescence Intensity; MHC, Mayor Histocompatibility Complex; NGS, Next-Generation Sequencing; NR, Not Rejection; PRA, Panel Reactive Antibody; TCR, Tcell Receptor. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis
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