Dataset Information

Multi-Omics Analysis of the Immunological State at Baseline and Following SARS-CoV-2 mRNA Vaccination in Lung Transplant Recipients

ABSTRACT: Despite their remarkable success, the effectiveness of COVID-19 mRNA vaccines is notably diminished in organ transplant patients. Here, we employed a multi-omics approach to elucidate the immunological state at baseline and following SARS-CoV-2 mRNA vaccination of lung transplant (LTX) patients compared to healthy controls (HC). Our analysis revealed a baseline immune profile in LTX patients that mirrors the immune alterations observed in severe COVID-19 cases and sepsis. This profile is characterized by: (i) elevated pro-inflammatory cytokines in plasma, notably high levels of EN-RAGE and IL-6; (ii) reduced expression of HLA-DR on blood monocytes and dendritic cells (DCs); (iii) diminished cytokine production by blood monocytes and DCs in response to toll-like receptor (TLR) activation; (iv) increased plasma concentrations of microbial products. In addition to these alterations, single-cell RNA-seq analysis revealed 4 transcriptionally distinct clusters of classical monocytes in HC, with a striking enrichment of a unique classical monocyte cluster in LTX patients, differing from the predominant classical monocytes in HC, marked by heightened expression of the S100A family and reduced expression of genes related to cytokine production and antigen presentation. Following vaccination, LTX patients displayed a reduced magnitude and breadth of binding and neutralizing antibody responses, and impaired memory B and T cell responses. Furthermore, there was a blunted innate immune response to vaccination, evidenced by decreased transcriptional signatures linked to antigen presentation, dendritic cell activation, interferon and monocytes at the single-cell level. Integrative multiscale, multiresponse network (MMRN) analysis revealed an inverse correlation between the distinctive baseline immunological state observed in LTX patients and the adaptive immune responses to vaccines. These findings underscore the distinct immunological profile of lung transplant recipients, providing insights into their immunosuppressed condition and reduced immune responses to vaccines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288562 | GEO | 2025/02/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Despite their remarkable success, the effectiveness of COVID-19 mRNA vaccines is notably diminished in organ transplant patients. Here, we employed a multi-omics approach to elucidate the immunological state at baseline and following SARS-CoV-2 mRNA vaccination of lung transplant (LTX) patients compared to healthy controls (HC). Our analysis revealed a baseline immune profile in LTX patients that mirrors the immune alterations observed in severe COVID-19 cases and sepsis. This profile is characterized by: (i) elevated pro-inflammatory cytokines in plasma, notably high levels of EN-RAGE and IL-6; (ii) reduced expression of HLA-DR on blood monocytes and dendritic cells (DCs); (iii) diminished cytokine production by blood monocytes and DCs in response to toll-like receptor (TLR) activation; (iv) increased plasma concentrations of microbial products. In addition to these alterations, single-cell RNA-seq analysis revealed 4 transcriptionally distinct clusters of classical monocytes in HC, with a striking enrichment of a unique classical monocyte cluster in LTX patients, differing from the predominant classical monocytes in HC, marked by heightened expression of the S100A family and reduced expression of genes related to cytokine production and antigen presentation. Following vaccination, LTX patients displayed a reduced magnitude and breadth of binding and neutralizing antibody responses, and impaired memory B and T cell responses. Furthermore, there was a blunted innate immune response to vaccination, evidenced by decreased transcriptional signatures linked to antigen presentation, dendritic cell activation, interferon and monocytes at the single-cell level. Integrative multiscale, multiresponse network (MMRN) analysis revealed an inverse correlation between the distinctive baseline immunological state observed in LTX patients and the adaptive immune responses to vaccines. These findings underscore the distinct immunological profile of lung transplant recipients, providing insights into their immunosuppressed condition and reduced immune responses to vaccines.

Project description:Background: A 58-year-old male with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) underwent bilateral lung transplantation (LTx) but experienced ILD progression and myositis worsening 38 weeks post-transplant, despite glucocorticoids, tacrolimus, and mycophenolic acid treatment. High-dose glucocorticoids led to adverse effects and ILD exacerbation upon tapering. Objective: To identify persistent inflammatory pathways despite anti-rejection therapy. Methods: Two sets of single-cell RNA-seq (scRNA-seq) analyses were conducted on peripheral blood mononuclear cells (PBMCs) from our patient who experienced recurrent ASS-ILD following bilateral LTx: one before regimen adjustment and one after. The goal these analyses is to investigate systemic inflammatory profiles. Results: In comparison to five ASS-ILD patients without LTx, our patient following bilateral LTx (before regimen adjustment) displayed a higher proportion of CD14⁺ and CD16⁺ monocytes, alongside reduced T, B, and NK cells. Notably, interferon- and JAK-STAT–associated pathways were significantly enriched, as evidenced by marked up-regulation of key genes (e.g. JAK1, JAK2, STAT1, STAT2, STAT3, IL4R, IL6R) in the patient’s monocytes. Elevated serum ferritin levels and the enrichment of macrophage and neutrophil activation pathways further underscored hyperactivation of the mononuclear phagocyte system. Due to poor tolerance of high-dose steroids, limited efficacy of tacrolimus and MPA, and the need to manage post-transplant rejection while controlling ASS, the patient’s regimen was modified. Considering the activation of the mononuclear phagocyte system in the patient, tacrolimus was replaced with cyclosporine A, which is more widely used in macrophage activation syndrome (target trough concentration 120-150 ng/ml). Given the significant activation of the interferon and JAK-STAT pathways in the patient’s activated monocytes, we replaced EC-MPS with the Janus kinase inhibitor (JAKi) tofacitinib at 5 mg twice daily. Short-term high-dose glucocorticoids (methylprednisolone 120 mg/d for 3 days) were also administered before rapid tapering. After regimen adjustment, scRNA-seq was conducted again, which indicated a reduction in CD14⁺ and CD16⁺ monocytes, with T, B, and NK cells rebounding. Neutrophils, characterized by high S100A8, S100A9, and DEFA3 expression, became more prominent. Interferon-related gene expression decreased in monocytes and neutrophils, indicating successful suppression of the interferon pathway. Conclusions: We presented a complicated case of a patient with early recurrence of underlying ASS-ILD after bilateral lung transplantation. We used two sets of scRNA-seq analyses to investigate the systemic inflammatory responses.

Project description:Being able to identify patients in whom immunological tolerance has been established or is developing would allow an individually tailored approach to post-transplant management of kidney allograft recipients. Ex vivo immunological monitoring was performed on samples from five groups of European renal transplant recipients (“IOT samples”): ten drug-free tolerant recipients who were functionally stable despite remaining immunosuppression-free for more than one year (Tol-DF); also functionally stable patients on minimal immunosuppression (<10 mg/day prednisone, s-LP); stable patients maintained with calcineurin inhibitors (s-CNI); stable patients maintained on CNI-free immunosuppression regimen (s-nCNI); patients showing signs of chronic rejection (CR) and healthy controls (HC). Among the investigation of other biomarkers and bioassays, gene expression profiles were generated on custom Agilent 8x15K 60mer oligonucleotide microarrays (“RISET 2.0”) on the IOT cohort (training set) and on an independent cohort of patients from the ITN (USA) that contained similar groups of patients and included 23 tolerant recipients (“ITN samples”, test set). Set of genes were identified, whose expression on whole blood allowed the identification of 100% of the tolerant recipients in the training set and 84% in the test set. Keywords: classification of clinical samples, tolerance prediction IOT samples: 13 samples from 10 Tol-DF patients, 16 samples from 11 s-LP patients, 8 samples from 8 s-nCNI patients, 40 samples from 28 s-CNI patients, 10 samples from 9 CR patients, and 8 samples from 8 HC donors were analysed on a custom Agilent 8x15K 60mer oligonucleotide microarray encomprising 5069 probes in triplicates. The microarray is dedicated to transplantation research and was designed based on current literature and published and unpublished data provided by the RISET consortium. For the probe selection procedure we specially focused on the detection of multiple transcript variants of a gene, on optimized hybridization properties of the probes, and on the avoidance of crosshybridization. The sampling dates of replicate samples from the same patient range from one day to 1.5 years. ITN samples: 31 samples from 23 Tol-DF patients, 14 samples from 11 s-LP patients, 52 samples from 34 s-CNI patients, 25 samples from 18 CR patients, and 20 samples from 20 HC donors were analysed on the same microarray platform and served as test set. The samples of the two cohorts differ in the protocol of RNA preparation.

Dataset Information

Multi-Omics Analysis of the Immunological State at Baseline and Following SARS-CoV-2 mRNA Vaccination in Lung Transplant Recipients

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets