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Discovering Molecular Signatures in ATMR: Single-cell RNA Sequencing Analysis of Human Blood and Tissue Spatial Transcriptomics [Spatial Transcriptomics]

ABSTRACT: Background. Acute T cell-mediated rejection (ATMR) is a significant challenge in kidney allograft. Despite this, high-resolution transcriptomic analysis of both the targeted tissue and systemic blood is lacking. To address this void, we embarked on a study employing single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs), coupled with spatial transcriptomics analysis on graft biopsy specimens, to unveil the intricacies of ATMR. Methods. We collected paired pre- and post-operative blood samples from six kidney transplant patients. Among these, two patients exhibited a lack of rejection, while four patients bore biopsy-proven ATMR. By scrutinizing tissue samples from protocol biopsies taken two weeks post-operation in comparison to zero-time biopsies. Moreover, our investigation delved into peripheral blood samples, where we detected an expanded cell population within PBMCs, presumed to harbor numerous alloreactive T cells. This CD8+ effector memory (CD8 Tem) cell population was subsequently examined for DEGs between the two patient groups. Results. Our comprehensive approach, which combined scRNA-seq and spatial transcriptomics results, unveiled specific genes such as LTB, GZMK, STAT1, PSME2, UBE2L6, and GBP5, which showcased heightened expression levels among ATMR patients. Network analysis underscored the interconnection of STAT1 with the other identified genes, suggesting its plausible role in the rejection process. Conclusions. Our findings demonstrate CD8+ STAT1+ hold notable significance in the context of ATMR. This subpopulation undergoes clonal expansion and retains a memory phenotype, there by contributing to a heightened and swifter inflammatory response within the graft.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248787 | GEO | 2023/12/03

REPOSITORIES: GEO

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Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection. All clinically indicated kidney transplant biopsies performed at our institution after January 2009 were reviewed and 263 patients with anti-HLA antibody testing at the time of biopsy were identified. There were 71 DSA+ and 192 DSA- patients (Figure 1). Of the 71 DSA+ patients, 46 had biopsy diagnosis of acute AMR (n=9) or chronic AMR (n=37), and 25 had normal histopathology or minimal non-specific interstitial fibrosis/tubular atrophy (IFTA). Of the 192 DSA- patients, 50 patients with normal histology and/or mild non-specific IFTA were used as a control group. Clinical and histopathological findings of these 3 groups (DSA+/AMR+, DSA+/AMR- and DSA-) were analyzed. A subgroup of patients who were enrolled in the Institutional Review Board-approved âImmune Monitoring Studyâ who had clinically indicated biopsy (n=61) and whole blood samples (n=54) stored were used for genomic analysis. Twenty-eight biopsy and blood samples from DSA+/AMR+ patients, 13 biopsy and 14 blood samples from DSA+/AMR- patients, and 20 biopsy and 12 blood samples from DSA- patients, were available for microarray analysis.

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Discovering Molecular Signatures in ATMR: Single-cell RNA Sequencing Analysis of Human Blood and Tissue Spatial Transcriptomics [Spatial Transcriptomics]

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