Novel Soluble Mediators of Innate Immune System Activation in Solid Allograft Rejection

Usuelli, Vera; Loretelli, Cristian; Seelam, Andy Joe; Pastore, Ida; D’Addio, Francesca; Nasr, Moufida Ben; Fiorina, Paolo

doi:10.1097/tp.0000000000003834

Cited by 9 publications

(7 citation statements)

References 85 publications

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“…All our results collectively point to monocytes, which have recently emerged at the forefront of research in transplantation, 28-31 as main miRNA source. This major finding is thus extensively discussed in Supplemental Discussion ( SDC , http://links.lww.com/TP/C605).…”

Section: Discussionsupporting

confidence: 61%

“…25 Moreover, RORA may regulate the activity of signaling receptors and transmembrane transporters in human monocytic THP-1 cell line and endothelial cell lines. 26,27 All our results collectively point to monocytes, which have recently emerged at the forefront of research in transplantation, [28][29][30][31] as main miRNA source. This major finding is thus extensively discussed in Supplemental Discussion (SDC, http://links.lww.com/TP/C605).…”

Section: Discussionsupporting

confidence: 59%

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Modulation of Monocyte Response by MicroRNA-15b/106a/374a During Antibody-mediated Rejection in Kidney Transplantation

et al. 2023

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Background. Increasing evidence suggest that microRNAs are involved in the physiopathology of acute or chronic renal disease. In kidney transplantation, as key regulators of cellular homeostasis, microRNAs may be involved in the regulation of immune cell function and the allograft response. Here, we investigated the change in circulating microRNA expression profile and their involvement in the profound transcriptional changes associated with antibody-mediated rejection (AMR). Methods. Blood samples were collected at the time of the 710 kidney allograft biopsies at 4 European transplant centers. Messenger RNA and microRNA profiling analyses were performed in a discovery-to-validation study within 3 independent cohorts encompassing N = 126, N = 135, and N = 416 patients, respectively. Results. Compared with samples with no AMR, 14 microRNAs were significantly decreased in AMR samples. Among them, expression levels of microRNA-15b, microRNA-106a, and microRNA-374a gradually decreased with the severity of AMR lesions. From their in silico–predicted target genes, a high proportion proved to be significantly upregulated in the paired transcriptomic analysis. Gene ontology analyses of microRNA-15b/-106a/-374a suggested enrichment in myeloid-related pathways, which was further refined by in silico and ex vivo transcriptomic analyses, showing a specific origin from classical CD14+ monocytes. Finally, human CD14+ monocytes were subjected to transduction by antago-microRNAs to mimic AMR pathology. MicroRNA-15b/-106a/-374a impairment resulted in cellular activation with an increased expression of CD69, CRIM1, IPO7, and CAAP1, direct and common targets of the 3 microRNAs. Conclusions. Together, our data provide new insights into circulating microRNAs as markers and key players in AMR, and they suggest monocyte involvement in this process.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionsupporting

confidence: 59%

Modulation of Monocyte Response by MicroRNA-15b/106a/374a During Antibody-mediated Rejection in Kidney Transplantation

et al. 2023

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“… 25 Notably, the KEGG pathway of DEGs was enriched in allograft rejection, which is a part of the adaptive immune response. 26 Previous studies have also revealed a key role for immune cells in the initiation, metastasis, and recurrence of HCC. 27 , 28 Therefore, it is necessary to reveal the potential mechanism of HCC relapse and identify potential predictive targets, with emphasis on immune repertoire profiling.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq and Immune Repertoire Analysis of Normal and Hepatocellular Carcinoma Relapse After Liver Transplantation

Guo,

Yuan,

Cao

et al. 2023

IJGM

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Background: Hepatocellular carcinoma (HCC) relapse is the main reason for the poor prognosis of HCC after Liver transplantation (LT). This study aimed to explore the molecular mechanisms and immune repertoire profiles of HCC relapse. Material and Methods: RNA-seq of blood samples from patients with normal (n=12) and HCC relapse (n=6) after LT was performed to identify differentially expressed genes (DEGs) and key signalling pathways. The DEGs and immune genes were further analyzed by bioinformatics. TRUST4 was used to analyze the differences in the immune repertoire between the two groups. Another 11 blood samples from patients with HCC who had received LT were collected for RT-qPCR verification of key genes. Results: A total of 131 upregulated and 157 downregulated genes were identified using RNA-seq, and GO enrichment analysis revealed that the top 15 pathways were immune-related. The PPI network identified 10 key genes. Immune infiltration analysis revealed a significant difference in the five immune cell types between the two groups. A total of 83 intersecting genes were obtained by intersecting DEGs and immune genes. 6 key genes, including MX1, ISG15, OAS1, PRF1, SPP1, and THBS1 were obtained according to the intersection of DEGs, PPI network top 10 genes and immune intersecting genes. Immune repertoire analysis showed that the usage frequency of variable (V) and joining (J) genes in the normal group was higher than that in the relapse group. RT-qPCR validation showed that the expression levels of key genes were consistent with the RNA-seq results. Conclusion: Our study identified key pathways and genes that could help determine whether transplant recipients are more prone to HCC relapse. Immune repertoire analysis revealed a difference in the usage frequency of VJ genes between the normal and relapse groups, providing a research direction for immunotherapy in patients with HCC relapse after liver transplantation.

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“…Finally, recent studies suggest that innate immune cells may be targeted in vivo to promote transplant tolerance by stimulating or inhibiting various signaling pathways, including microRNA (miRNA) and purinergic signaling ( 262 – 265 ). Usuelli et al found that suppression of miRNA-21 prevented allograft rejection and chronic allograft vasculopathy in a murine model of cardiac transplantation by promoting M2 polarization in infiltrating macrophages ( 262 ).…”

Section: Discussionmentioning

confidence: 99%

Innate immune cellular therapeutics in transplantation

Ott

Cuenca

2023

Front. Transplant.

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Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed “trained immunity.” Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.

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Novel Soluble Mediators of Innate Immune System Activation in Solid Allograft Rejection

Cited by 9 publications

References 85 publications

Modulation of Monocyte Response by MicroRNA-15b/106a/374a During Antibody-mediated Rejection in Kidney Transplantation

Modulation of Monocyte Response by MicroRNA-15b/106a/374a During Antibody-mediated Rejection in Kidney Transplantation

RNA-Seq and Immune Repertoire Analysis of Normal and Hepatocellular Carcinoma Relapse After Liver Transplantation

Innate immune cellular therapeutics in transplantation

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