Diagnostic Biomarkers and Immune Infiltration in Patients With T Cell-Mediated Rejection After Kidney Transplantation.
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ABSTRACT:
SUBMITTER: Zhou H
PROVIDER: S-EPMC8764245 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite the advances in immunosuppressive medications, antibody-mediated rejection (AMR) continues to be a major cause of kidney allograft failure and remains a barrier to improving long-term allograft survival. Recently, there have been significant advances in the understanding of the pathophysiological process of AMR, along with the development of new therapeutic options. Additionally, surveillance protocols with donor-derived cell-free DNA and gene profile testing have been established, leading to the early detection of AMR. A multitude of clinical trials are ongoing, opening numerous opportunities for improving outcome in kidney transplant recipients. In this brief review, we discuss the emerging therapies for managing both active and chronic active AMR and highlight the ongoing clinical trials.
| S-EPMC10419906 | biostudies-literature
Project description:The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.
| S-EPMC6309659 | biostudies-literature
Project description:BackgroundImmune infiltrates in the tumor microenvironment have established roles in tumor growth, invasion, and metastasis. However, the diagnostic and prognostic potential of immune cell signature in esophageal squamous cell carcinoma (ESCC) remains unclear.ResultsThe proportions of 22 subsets of immune cells from 331 samples including 205 ESCC and 126 normal esophageal mucosa retrieved from TCGA, GEO, and GTEx databases were deciphered by CIBERSORT. Nine overlapping subsets of immune cells were identified as important features for discrimination of ESCC from normal tissue in the training cohort by LASSO and Boruta algorithms. A diagnostic immune score (DIS) developed by XGBoost showed high specificities and sensitivities in the training cohort, the internal validation cohort, and the external validation cohort (AUC: 0.999, 0.813, and 0.966, respectively). Furthermore, the prognostic immune score (PIS) was developed based on naive B cells and plasma cells using Cox proportional hazards model. The PIS, an independent prognostic predictor, classified patients with ESCC into low- and high-risk subgroups in the internal validation cohort (P = 0.038) and the external validation cohort (P = 0.022). In addition, a nomogram model comprising age, N stage, TNM stage, and PIS was constructed and performed excellent (HR = 4.17, 95% CI: 2.22-7.69, P < 0.0001) in all ESCC patients, with a time-dependent 5-year AUC of 0.745 (95% CI: 0.644 to 0.845), compared with PIS or TNM stage as a prognostic model alone.ConclusionOur DIS, PIS, and nomogram models based on infiltrated immune features may aid diagnosis and survival prediction for patients with ESCC.
| S-EPMC9251101 | biostudies-literature
Project description:An increased frequency of kidney rejection has been reported in diabetic patients who have simultaneous pancreas and kidney transplantation compared with patients who have a kidney transplant alone. Kidney graft outcome is similar in the two groups. The mechanism for increased kidney graft rejection with a simultaneous pancreas graft is not clear. It is ascribed to the immunogenicity of the exocrine pancreas that initiates migration of activated cells from the peripheral blood that are entrapped in the kidney. Since the volume of the transplanted tissue is less in islet transplantation (usually < 2 ml) than in pancreas transplantation, one might not expect an increased frequency of kidney rejection in islet cell recipients. We looked at biopsy-proven kidney rejection episodes in patients who had combined kidney and islet transplants and compared this with the frequency of rejection in diabetic and nondiabetic patients who underwent a kidney transplant alone under the same immunosuppression. Diabetic patients who had kidney islet transplants (n = 9) had a higher frequency of rejection (100%) compared with diabetic patients (n = 107, 55.1%) and nondiabetic patients (n = 327, 65%) who had a kidney transplant alone. The 1-year graft and patient survival rates were not different among the groups. Although the number of patients is small, it would appear that transplantation of a low volume of islet cells with high purity can lead to an increased frequency of kidney rejection. This is unlikely to be explained solely on the basis of fewer antigen matches in these recipients but may reflect the inherent immunogenicity of the purified islet preparations. Alternatively, there may be an effect of their direct infusion into the portal vein.
| S-EPMC2952505 | biostudies-literature
Project description:Objective: The present study was designed to identify potential diagnostic markers for acute myocardial infarction (AMI) and determine the significance of immune cell infiltration in this pathology. Methods: Two publicly available gene expression profiles (GSE66360 and GSE48060 datasets) from human AMI and control samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were screened between 80 AMI and 71 control samples. The LASSO regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were performed to identify candidate biomarkers. The area under the receiver operating characteristic curve (AUC) value was obtained and used to evaluate discriminatory ability. The expression level and diagnostic value of the biomarkers in AMI were further validated in the GSE60993 dataset (17 AMI patients and 7 controls). The compositional patterns of the 22 types of immune cell fraction in AMI were estimated based on the merged cohorts using CIBERSORT. Results: A total of 27 genes were identified. The identified DEGs were mainly involved in carbohydrate binding, Kawasaki disease, atherosclerosis, and arteriosclerotic cardiovascular disease. Gene sets related to atherosclerosis signaling, primary immunodeficiency, IL-17, and TNF signaling pathways were differentially activated in AMI compared with the control. IL1R2, IRAK3, and THBD were identified as diagnostic markers of AMI (AUC = 0.877) and validated in the GSE60993 dataset (AUC = 0.941). Immune cell infiltration analysis revealed that IL1R2, IRAK3, and THBD were correlated with M2 macrophages, neutrophils, monocytes, CD4+ resting memory T cells, activated natural killer (NK) cells, and gamma delta T cells. Conclusion: IL1R2, IRAK3, and THBD can be used as diagnostic markers of AMI, and can provide new insights for future studies on the occurrence and the molecular mechanisms of AMI.
| S-EPMC7644926 | biostudies-literature
Project description:BackgroundRheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by inflammatory cell infiltration, leading to persistent synovitis and joint destruction. The pathogenesis of RA remains unclear. This study aims to explore the immune molecular mechanism of RA through bioinformatics analysis.MethodsFive microarray datasets and a high throughput sequencing dataset were downloaded. CIBERSORT algorithm was performed to evaluate immune cell infiltration in synovial tissues between RA and healthy control (HC). Wilcoxon test and Least Absolute Shrinkage and Selection Operator (LASSO) regression were conducted to identify the significantly different infiltrates of immune cells. Differentially expressed genes (DEGs) were screened by "Batch correction" and "RobustRankAggreg" methods. Functional correlation of DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Candidate biomarkers were identified by cytoHubba of Cytoscape, and their diagnostic effectiveness was predicted by Receiver Operator Characteristic Curve (ROC) analysis. The association of the identified biomarkers with infiltrating immune cells was explored using Spearman's rank correlation analysis in R software.ResultsTen significantly different types of immune cells between RA and HC were identified. A total of 202 DEGs were obtained by intersection of DEGs screened by two methods. The function of DEGs were significantly associated with immune cells. Five hub genes (CXCR4, CCL5, CD8A, CD247, and GZMA) were screened by R package "UpSet". CCL5+CXCR4 and GZMA+CD8A were verified to have the capability to diagnose RA and early RA with the most excellent specificity and sensitivity, respectively. The correlation between immune cells and biomarkers showed that CCL5 was positively correlated with M1 macrophages, CXCR4 was positively correlated with memory activated CD4+ T cells and follicular helper T (Tfh) cells, and GZMA was positively correlated with Tfh cells.ConclusionsCCL5, CXCR4, GZMA, and CD8A can be used as diagnostic biomarker for RA. GZMA-Tfh cells, CCL5-M1 macrophages, and CXCR4- memory activated CD4+ T cells/Tfh cells may participate in the occurrence and development of RA, especially GZMA-Tfh cells for the early pathogenesis of RA.
| S-EPMC8411707 | biostudies-literature
Project description:Kawasaki disease (KD) is characterized by disorder of immune response with unknown etiology. Immune cells may be closely related to the onset of KD. The focus of this research was to evaluate the significance of the infiltration of immune cells for this disease and find possible diagnostic biomarkers for KD. The Gene Expression Omnibus database was utilized to retrieve two freely accessible gene expression patterns (GSE68004 and GSE18606 datasets) from human KD and control specimens. 114 KD, as well as 46 control specimens, were searched for obtaining differentially expressed genes (DEGs). Candidate biological markers were determined utilizing the support vector machine recursive feature elimination and the least absolute shrinkage and selection operator regression model analysis. To assess discriminating capacity, the area under the receiver operating characteristic curve (AUC) was computed. The GSE73461 dataset was utilized to observe the biomarkers' expression levels and diagnostic significance in KD (78 KD patients and 55 controls). CIBERSORT was employed to assess the composition profiles of the 22 subtypes of immune cell fraction in KD on the basis of combined cohorts. 37 genes were discovered. The DEGs identified were predominantly involved in arteriosclerotic cardiovascular disease, atherosclerosis, autoimmune disease of the urogenital tract, and bacterial infectious disease. Gene sets related to complement and coagulation cascades, Toll-like receptor signaling pathway, Fc gamma R-mediated phagocytosis, NOD-like receptor signaling pathway, and regulation of actin cytoskeleton underwent differential activation in KD as opposed to the controls. KD diagnostic biomarkers, including the alkaline phosphatase (ALPL), endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2), and histone cluster 2 (HIST2H2BE), were discovered (AUC = 1.000) and verified utilizing the GSE73461 dataset (AUC = 1.000). Analyses of immune cell infiltration demonstrated that ALPL, EDEM2, and HIST2H2BE were linked to CD4 memory resting T cells, monocytes, M0 macrophages, CD8 T cells, neutrophils, and memory CD4 T cells. ALPL, EDEM2, and HIST2H2BE could be utilized as KD diagnostic indicators, and they can also deliver useful information for future research on the disease's incidence and molecular processes.
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Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 5 patients included into the control-group and 4 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.
2015-12-10 | E-GEOD-51676 | biostudies-arrayexpress
Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling was a specific hallmark of CAMR. In addition, in CAMR patients we detected a reduction of circulating BDCA2+ dendritic cells, the natural type I interferon- producing cells and their recruitment into the graft along with an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 8 patients included into the control-group and 10 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.
2015-12-10 | E-GEOD-51675 | biostudies-arrayexpress
Project description:Heart failure (HF) and osteoarthritis (OA) are medical conditions that can significantly impact daily activities. Evidence has shown that HF and OA may share some pathogenic mechanisms. However, the underlying genomic mechanisms remain unclear. This study aimed to explore the underlying molecular mechanism and identify diagnostic biomarkers for HF and OA. With the cutoff criteria of fold change (FC) > 1.3 and P < .05, 920, 1500, 2195, and 2164 differentially expressed genes (DEGs) were identified in GSE57338, GSE116250, GSE114007, and GSE169077, respectively. After making the intersection of DEGs, we obtained 90 upregulated DEGs and 51 downregulated DEGs in HF datasets and 115 upregulated DEGs and 75 downregulated DEGs in OA datasets. Afterward, we conducted genome ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, protein-protein interaction (PPI) networks, and hub genes screening based on DEGs. Then, 4 common DEGs (fibroblast activation protein alpha [FAP], secreted frizzled-related protein 4 (SFRP4), Thy-1 cell surface antigen (THY1), matrix remodeling associated 5 [MXRA5]) between HF and OA were screened and validated in GSE5406 and GSE113825 datasets, based on which we established the support vector machine (SVM) models. The combined area under the receiver operating characteristic curve (AUC) of THY1, FAP, SFRP4, and MXRA5 in the HF training and test sets reached 0.949 and 0.928. While in the OA training set and test set, the combined AUC of THY1, FAP, SFRP4, and MXRA5 reached 1 and 1, respectively. The analysis of immune cells in HF revealed high levels of dendritic cell (DC), B cells, natural killer T cell (NKT), Type 1 regulatory T cell (Tr1), cytotoxic T cell (Tc), exhausted T cell (Tex), and mucosal-associated invariant T cell (MAIT), while displaying lower levels of monocytes, macrophages, NK, CD4 + T, gamma delta T (γδ T), T helper type 1 (Th1), T helper type 2 (Th2), and effector memory T cell (Tem). Moreover, the 4 common DEGs were positively correlated with DCs and B cells and negatively correlated with γδ T. In OA patients, the abundance of monocyte, macrophage, CD4 + naïve, and natural T regulatory cell (nTreg) was higher, while the infiltration of CD8 + T, γδ T, CD8 + naïve, and MAIT was lower. The expression of THY1 and FAP was significantly correlated with macrophage, CD8 + T, nTreg, and CD8 + naïve. SFRP4 was correlated with monocyte, CD8 + T, γδ T, CD4 + naïve, nTreg, CD8 + naïve and MAIT. MXRA5 was correlated with macrophage, CD8 + T, nTreg and CD8 + naïve. FAP, THY1, MXRA5, and SFRP4 may be diagnostic biomarkers for both HF and OA, and their correlation with immune cell infiltrations suggests shared immune pathogenesis.
| S-EPMC10313258 | biostudies-literature