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Molecular Aspects of Renal Immunology: Current Status and Future Perspectives
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Molecular Aspects of Renal Immunology: Current Status and Future Perspectives

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 17186

Special Issue Editors

Prof. Theodoros Eleftheriadis

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Guest Editor
Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece
Interests: nephrology; immunology; kidney transplantation; immunosuppression; immunoregulation; autoimmunity; hypoxia; hypoglycemia
Prof. Marta Crespo Barrio

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Guest Editor
Nephrology Department and Renal Transplant Unit, Hospital del Mar, Parc de Salut Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
Interests: nephrology; immunology; kidney transplantation; immunosuppression; immunoregulation; cellular and humoral rejection; donor evaluation; transplantation complications

Special Issue Information

Dear Colleagues,

Kidney transplantation is the best therapeutic option for patients with end-stage renal disease, since it enhances both quantity and quality of life. Progression in understanding kidney transplantation immunology has led to the development of diagnostic tests and immunosuppressive drugs that extend graft survival. However, excluding the first year, long-term graft survival remains unchanged, mainly but not exclusively due to chronic humoral rejection.

This Special Issue aims to collect original and review articles about the molecular mechanisms that govern various types of kidney rejection. In addition, articles on the molecular targets and actions of the currently available immunosuppressive drugs (or those under evaluation) as well as the limitations of their administration owing to their primary molecular mechanism of action, parallel pathways, or metabolism, are welcome. Finally, it would be an omission not to include articles related to molecular diagnostic tests. Before transplantation, molecular tests may prevent an adverse outcome or identify patients high at immunological risk that may require specific therapeutic maneuvers. Efforts are ongoing to discover molecular markers for the early detection of immune responses against the graft and/or the related graft injury after transplantation, to make treatment less challenging.

We strongly believe that with your contribution, this Special Issue will provide a current and comprehensive overview of the molecular aspects of kidney transplant immunology, diagnostics, and treatment.

Prof. Theodoros Eleftheriadis
Prof. Marta Crespo Barrio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • kidney transplantation
  • transplant immunology
  • cellular rejection
  • humoral rejection
  • immunosuppressive drugs
  • rejection treatment
  • immunologic risk stratification
  • rejection markers
  • T cells
  • B cells
  • NK cells
  • macrophages
  • renal endothelial cells
  • anti-HLA
  • complement
  • xenotransplantation

Published Papers (6 papers)

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Editorial

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4 pages, 188 KiB  
Editorial
Molecular Aspects of Renal Immunology: Current Status and Future Perspectives
by Theodoros Eleftheriadis and Marta Crespo
Int. J. Mol. Sci. 2022, 23(7), 4040; https://doi.org/10.3390/ijms23074040 - 06 Apr 2022
Viewed by 1369
Abstract
Kidney transplantation is the most promising treatment available for patients with end-stage kidney disease [...] Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)

Research

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14 pages, 1345 KiB  
Article
A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion
by Theodoros Eleftheriadis, Georgios Pissas, Marta Crespo, Evdokia Nikolaou, Vassilios Liakopoulos and Ioannis Stefanidis
Int. J. Mol. Sci. 2021, 22(4), 1733; https://doi.org/10.3390/ijms22041733 - 09 Feb 2021
Cited by 6 | Viewed by 2286
Abstract
Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated [...] Read more.
Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated the possible role of primary human proximal renal tubular epithelial cells (RPTECs) in direct allorecognition by CD4+ T-cells and the effect of anoxia-reoxygenation. In cell culture, we detected that RPTECs express all the required molecules for CD4+ T-cell activation (HLA-DR, CD80, and ICAM-1). Anoxia-reoxygenation decreased HLA-DR and CD80 but increased ICAM-1. Following this, RPTECs were co-cultured with alloreactive CD4+ T-cells. In T-cells, zeta chain phosphorylation and c-Myc increased, indicating activation of T-cell receptor and co-stimulation signal transduction pathways, respectively. T-cell proliferation assessed with bromodeoxyuridine assay and with the marker Ki-67 increased. Previous culture of RPTECs under anoxia raised all the above parameters in T-cells. FOXP3 remained unaffected in all cases, signifying that proliferating T-cells were not differentiated towards a regulatory phenotype. Our results support that direct allorecognition may be mediated by RPTECs even in the absence of donor-derived professional APCs. Also, ischemia-reperfusion injury of the graft may enhance the above capacity of RPTECs, increasing the possibility of acute rejection. Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)
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15 pages, 7599 KiB  
Article
Immunomodulatory Properties of Mesenchymal Stromal Cells Can Vary in Genetically Modified Rats
by Natalie Vallant, Bynvant Sandhu, Karim Hamaoui, Maria Prendecki, Charles Pusey and Vassilios Papalois
Int. J. Mol. Sci. 2021, 22(3), 1181; https://doi.org/10.3390/ijms22031181 - 25 Jan 2021
Cited by 2 | Viewed by 2103
Abstract
Mesenchymal Stromal Cells (MSC) have been shown to exhibit immuno-modulatory and regenerative properties at sites of inflammation. In solid organ transplantation (SOT), administration of MSCs might lead to an alleviation of ischemia-reperfusion injury and a reduction of rejection episodes. Previous reports have suggested [...] Read more.
Mesenchymal Stromal Cells (MSC) have been shown to exhibit immuno-modulatory and regenerative properties at sites of inflammation. In solid organ transplantation (SOT), administration of MSCs might lead to an alleviation of ischemia-reperfusion injury and a reduction of rejection episodes. Previous reports have suggested ‘MSC-preconditioning’ of macrophages to be partly responsible for the beneficial effects. Whether this results from direct cell-cell interactions (e.g., MSC trans-differentiation at sites of damage), or from paracrine mechanisms, remains unclear. Immunosuppressive capacities of MSCs from donors of different age and from genetically modified donor animals, often used for in-vivo experiments, have so far not been investigated. We conducted an in vitro study to compare paracrine effects of supernatants from MSCs extracted from young and old wild-type Wystar-Kyoto rats (WKY-wt), as well as young and old WKY donor rats positive for the expression of green fluorescent protein (WKY-GFP), on bone marrow derived macrophages (BMDM). Expression levels of Mannose receptor 1 (Mrc-1), Tumor necrosis factor α (TNFα), inducible NO synthase (iNos) and Interleukin-10 (IL-10) in BMDMs after treatment with different MSC supernatants were compared by performance of quantitative PCR. We observed different expression patterns of inflammatory markers within BMDMs, depending on age and genotype of origin for MSC supernatants. This must be taken into consideration for preclinical and clinical studies, for which MSCs will be used to treat transplant patients, aiming to mitigate inflammatory and allo-responses. Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)
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14 pages, 775 KiB  
Article
A Rejection Gene Expression Score in Indication and Surveillance Biopsies Is Associated with Graft Outcome
by Betty Chamoun, Anna Caraben, Irina B. Torres, Joana Sellares, Raquel Jiménez, Néstor Toapanta, Ignacio Cidraque, Alejandra Gabaldon, Manel Perelló, Ricardo Gonzalo, Francisco O’Valle, Francesc Moreso and Daniel Serón
Int. J. Mol. Sci. 2020, 21(21), 8237; https://doi.org/10.3390/ijms21218237 - 03 Nov 2020
Cited by 1 | Viewed by 1876
Abstract
Rejection-associated gene expression has been characterized in renal allograft biopsies for cause. The aim is to evaluate rejection gene expression in subclinical rejection and in biopsies with borderline changes or interstitial fibrosis and tubular atrophy (IFTA). We included 96 biopsies. Most differentially expressed [...] Read more.
Rejection-associated gene expression has been characterized in renal allograft biopsies for cause. The aim is to evaluate rejection gene expression in subclinical rejection and in biopsies with borderline changes or interstitial fibrosis and tubular atrophy (IFTA). We included 96 biopsies. Most differentially expressed genes between normal surveillance biopsies (n = 17) and clinical rejection (n = 12) were obtained. A rejection-associated gene (RAG) score was defined as its geometric mean. The following groups were considered: (a) subclinical rejection (REJ-S, n = 6); (b) borderline changes in biopsies for cause (BL-C, n = 13); (c) borderline changes in surveillance biopsies (BL-S, n = 12); (d) IFTA in biopsies for cause (IFTA-C, n = 20); and (e) IFTA in surveillance biopsies (IFTA-S, n = 16). The outcome variable was death-censored graft loss or glomerular filtration rate decline ≥ 30 % at 2 years. A RAG score containing 109 genes derived from normal and clinical rejection (area under the curve, AUC = 1) was employed to classify the study groups. A positive RAG score was observed in 83% REJ-S, 38% BL-C, 17% BL-S, 25% IFTA-C, and 5% IFTA-S. A positive RAG score was an independent predictor of graft outcome from histological diagnosis (hazard ratio: 3.5 and 95% confidence interval: 1.1–10.9; p = 0.031). A positive RAG score predicts graft outcome in surveillance and for cause biopsies with a less severe phenotype than clinical rejection. Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)
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Review

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18 pages, 726 KiB  
Review
The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?
by Anila Duni, Vassilios Liakopoulos, Vasileios Koutlas, Charalampos Pappas, Michalis Mitsis and Evangelia Dounousi
Int. J. Mol. Sci. 2021, 22(4), 2157; https://doi.org/10.3390/ijms22042157 - 22 Feb 2021
Cited by 18 | Viewed by 3146
Abstract
The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration [...] Read more.
The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration of the endothelial glycocalyx induced by IRI is the crucial event which exposes the denuded endothelial cells to further inflammatory and oxidative damage. The aim of our review is to present the currently available data regarding complex links between shedding of the glycocalyx components, like syndecan-1, hyaluronan, heparan sulphate, and CD44 with the activation of intricate immune system responses, including toll-like receptors, cytokines and pro-inflammatory transcription factors. Evidence on modes of protection of the endothelial glycocalyx and subsequently maintenance of endothelial permeability as well as novel nephroprotective molecules such as sphingosine-1 phosphate (S1P), are also depicted. Although advances in technology are making the visualization and the analysis of the endothelial glycocalyx possible, currently available evidence is mostly experimental. Ongoing progress in understanding the complex impact of IRI on the endothelial glycocalyx, opens up a new era of research in the field of organ transplantation and clinical studies are of utmost importance for the future. Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)
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21 pages, 1038 KiB  
Review
Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation
by André Renaldo Fernández, Rodrigo Sánchez-Tarjuelo, Paolo Cravedi, Jordi Ochando and Marcos López-Hoyos
Int. J. Mol. Sci. 2020, 21(22), 8549; https://doi.org/10.3390/ijms21228549 - 13 Nov 2020
Cited by 57 | Viewed by 5721
Abstract
Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over [...] Read more.
Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI. Full article
(This article belongs to the Special Issue Molecular Aspects of Renal Immunology: Current Status and Future Perspectives)
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