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Defining an NK cell-enriched rejection-like phenotype in liver transplant biopsies from the INTERLIVER study

ABSTRACT: Background: Initial analysis of liver transplant biopsies in the INTERLIVER study (#NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (i.e. rich in NK cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like state (NKRL) that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population. Results: The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: No-rejection (NR) 54%; TCMR 16%; NKRL 13%; and Injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased IFNG-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities. Conclusions: Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well-tolerated in the short-term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277334 | GEO | 2025/07/03

REPOSITORIES: GEO

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The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study

Project description:Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. Groups differed in median time post-transplant e.g. R3injury 99 days vs. R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts e.g. intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (e.g. hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR, R3injury, and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical ABMR were present in the population, and strategies that previously revealed antibody-mediated rejection (ABMR) in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.

2020-05-06 | GSE145780 | GEO

Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.

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Project description:Background. Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart (ClinicalTrials.gov #NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with the gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study (ClinicalTrials.gov #NCT04239703). Results. Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as IFNG-inducible genes (e.g., HLA-DMA), but also with genes induced by injury and expressed in macrophages (e.g., SERPINA1, HMOX1). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts. Conclusions: In heart transplants in the Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in the clinical management of heart transplant recipients.

2024-07-19 | GSE272655 | GEO

Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes

Project description:Previous studies of rejection-associated transcript expression in heart transplant biopsies identified not only rejection but a group of early biopsies with injury but no rejection. The present analysis used an expanded population of biopsies to explore parenchymal injury in all biopsies, with or without rejection, and its relationship to function, and outcome. Archetypal analysis defined five injury clusters: no-injury (N=376); mild (N=526); moderate (N=110); severe (N=87); and late (N=221). The late group, 62% of which had no rejection, had molecular characteristics associated with atrophy-fibrosis, depressed LVEF, and increased graft loss independent of rejection status. In random forest analysis, low LVEF was more strongly associated with injury scores than with rejection scores. Three-year graft failure was best predicted using a combination of injury and rejection scores. In heart transplant biopsies, injury-related molecular scores correlate with dysfunction and risk of failure and identify an important new group of late heart transplants, many with no rejection, that have impaired function and a high risk of graft loss. (ClinicalTrials.gov #NCT02670408).

2021-12-28 | GSE150059 | GEO

Molecular Assessment of Rejection and Injury in Lung Transplant Biopsies

Project description:Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified four idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal, T cell-mediated rejection (TCMR; T cell transcripts), antibody-mediated rejection (ABMR)-like (endothelial transcripts), and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or three pieces for each TBB will probably be needed to offset sampling variance.

2019-08-16 | GSE125478 | GEO

Potential impact of microarray diagnosis of T cell-mediated rejection in kidney transplants: the INTERCOM study

Project description:The authors report that in INTERCOM, a prospective international study of 300 kidney transplant biopsies, a microarray-based molecular score for T cell-mediated rejection changed the assessment of 26% of all biopsies, illustrating the potential of precision diagnostics to impact practice. Microarray analysis of 300 kidney transplant biopsies (non-TCMR, TCMR) and 6 nephrectomies.

2013-09-15 | E-GEOD-48581 | biostudies-arrayexpress

The Trifecta study: comparing plasma donor-derived cell-free DNA levels with the molecular phenotype of kidney transplant biopsies

Project description:Background. The Trifecta study (ClinicalTrials.gov #NCT04239703) is a prospective investigator-initiated trial to evaluate the relationship between plasma %dd-cfDNA at the time of indication biopsy and the molecular phenotype of the biopsy. Results. Median time of biopsy post-transplant was 455 days (5 days - 32 years), with case-mix similar to previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probesets correlating with %dd-cfDNA were previously annotated for association with ABMR and all rejection, either NK cell-expressed (e.g. GNLY, CCL4, TRDC, and S1PR5) or IFNG-inducible (e.g. PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, %dd-cfDNA correlated very strongly with ABMR and all rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury and atrophy-fibrosis. %dd-cfDNA was highest in active ABMR, mixed, and active TCMR but lower in late-stage ABMR and less active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted %dd-cfDNA better than histologic variables. Conclusions. %dd-cfDNA at time of indication biopsy strongly correlates with active molecular rejection and has potential to reduce unnecessary biopsies.

2021-12-23 | GSE192444 | GEO

Transcriptomics of Chronic Active Antibody-Mediated Rejection of Human Kidney Allografts and Identification of Intragraft Overexpression of Natural Kill Cell Cytotoxicity Gene Set

Project description:The enigmatic natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity via cell surface Fc receptors. The dual functionality of NK cells may enable their participation in chronic active antibody-mediated rejection (CA-ABMR), wherein evidence for complement activation is inconsistent. We RNA sequenced 57 human kidney allograft biopsies to determine whether NK cell cytotoxicity pathway gene set enrichment is an attribute of CA-ABMR. Among the 15,910 intragraft-expressed genes, 60 were uniquely overexpressed in CA-ABMR compared to active antibody-mediated rejection (active-ABMR) or acute T cell-mediated rejection (TCMR), versus no rejection (NR) biopsies. Cell type annotation showed enrichment for T cells and NK cells, and molecular pathways related to T cells and NK cells in CA-ABMR versus active-ABMR biopsies. NK cell cytotoxicity gene set enrichment in CA-ABMR than in ABMR biopsies, but not in TCMR, was confirmed by gene set variation analysis. Cellular deconvolution analysis divulged a higher proportion of NK cells in CA-ABMR compared to active-ABMR, but not in TCMR; immunohistochemistry of 138 consecutive clinically indicated allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR. Principal component analysis of deconvolved immune cell transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR biopsies. NK cell cytotoxicity pathway gene set was found to be enriched in rejection compared to no rejection biopsies in two publicly available kidney allograft microarray datasets. Altogether, CA-ABMR is exemplified by the overexpression of the NK cell pathway, and, surprisingly, compared to active-ABMR, is exemplified by key gene sets that are similar to TCMR.

2024-02-14 | GSE232825 | GEO

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