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Cells
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Immuno-Pathology in Organ and Cell Transplantation
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Immuno-Pathology in Organ and Cell Transplantation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 15672

Special Issue Editors

Dr. Valentina Vaira

E-Mail Website
Guest Editor
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Interests: molecular pathology; non-coding RNAs; transcriptomic; cell signaling
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Daria Lucia Trabattoni

E-Mail Website
Guest Editor
Department of Biomedical and Clinical Sciences-L. Sacco, University of Milan, 20157 Milan, Italy
Interests: innate and acquired immune responses; antiviral immune responses; immune correlates of protection; immunomodulators; vaccines; transplantation rejection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent years have witnessed vast improvements in our understanding of the functioning and the therapeutic modulation of the immune system. Organ and cellular transplantation to cure end-stage chronic diseases has also undergone a number of positive changes, resulting in improved graft function and survival in transplant patients. Thus, the last 10 years have seen increased survival of patients who undergo allograft transplantation. This is mainly due to the availability of improved immunosuppression regimens, full HLA sequencing and matching strategies, improvements in early graft dysfunction detection, and better understanding of the immune mechanisms underlying graft rejection. At the same time, the identification of biomarkers as non-invasive indicators of the pathologic processes leading to rejection would allow for more precise and timely monitoring of early, acute, or chronic graft dysfunction.

Similarly, the world of cell transplantation has exploded both in terms of cell types available for transplantation and medical applications. In this scenario, adoptive cell therapy (also known as cellular immunotherapies) has offered curative opportunities for cancer patients for whom chemotherapy has failed. Finally, advances in genetic engineering and stem cell technology have contributed to rapid developments of functional organs from induced pluripotent stem (IPS) cells.

All these advances notwithstanding, immune-mediated pathological mechanisms of graft rejection, graft-versus-host disease, infections, and, finally, increased susceptibility to the development of tumors hinder the long-term survival of transplant recipients and of patients undergoing cellular immunotherapies. Many questions still require answers in order to maximize successful graft outcomes and use of these therapies.

This Special Issue offers an open access forum that aims to bring together translational research and medical advances (both in the form of reviews and original research) to improve our understanding of the immunopathogenesis of organ or cellular transplant. Suggested potential topics may include immune-based or genomic biomarkers, molecular or proteomic signatures, signaling pathways involved in transplant outcome, and novel therapeutic approaches.

Dr. Valentina Vaira
Prof. Dr. Daria Lucia Trabattoni
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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.

Published Papers (5 papers)

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Research

13 pages, 2747 KiB  
Article
miRNAs Potentially Involved in Post Lung Transplant-Obliterative Bronchiolitis: The Role of miR-21-5p
by Sara Bozzini, Laura Pandolfi, Elena Rossi, Simona Inghilleri, Michele Zorzetto, Giuseppina Ferrario, Stefano Di Carlo, Gianfranco Politano, Annalisa De Silvestri, Vanessa Frangipane, Michele Porzio, Romain Kessler, Fiorella Calabrese, Federica Meloni and Patrizia Morbini
Cells 2021, 10(3), 688; https://doi.org/10.3390/cells10030688 - 20 Mar 2021
Cited by 3 | Viewed by 2141
Abstract
Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate [...] Read more.
Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate miRNAs, previously indicated as possibly being associated with OB, were analyzed by combining the quantitative real time-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) of lung tissues of OB affected patients. Disease and OB-lesion-specific expression of miR-21-5p was confirmed and by computational analysis we were able to identify the network of genes most probably associated miR-21-5p in the context of OB fibrogenesis. Among all potentially associated genes, STAT3 had a very high probability score. Immunohistochemistry showed that STAT3/miR-21-5p were co-over expressed in OB lesions, thus, suggesting miR-21-5p could regulate STAT3 expression. However, miR-21-5p inhibition in cultures of bronchiolitis obliterans syndrome (BOS) derived myofibroblasts did not significantly affect STAT3 mRNA and protein expression levels. This study demonstrates the specificity of miR-21-5p over-expression in OB lesions and contributes to existing knowledge on the miR-21-5p downstream pathway. Activation of STAT3 is associated with miR-21-5p upregulation, however, STAT-3 network activation is most likely complex and miR-21-5p is not the sole regulator of STAT3. Full article
(This article belongs to the Special Issue Immuno-Pathology in Organ and Cell Transplantation)
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13 pages, 4852 KiB  
Article
Emergency Lung Transplantation after COVID-19: Immunopathological Insights on Two Affected Patients
by Giorgio A. Croci, Valentina Vaira, Daria Trabattoni, Mara Biasin, Luca Valenti, Guido Baselli, Massimo Barberis, Elena Guerini Rocco, Giuliana Gregato, Mara Scandroglio, Evgeny Fominskiy, Alessandro Palleschi, Lorenzo Rosso, Mario Nosotti, Mario Clerici and Stefano Ferrero
Cells 2021, 10(3), 611; https://doi.org/10.3390/cells10030611 - 10 Mar 2021
Cited by 9 | Viewed by 3273
Abstract
We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels [...] Read more.
We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs’ GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression. Full article
(This article belongs to the Special Issue Immuno-Pathology in Organ and Cell Transplantation)
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12 pages, 1274 KiB  
Article
Peripheral Blood Eosinophilia Is Associated with Poor Outcome Post-Lung Transplantation
by Janne Kaes, Elise Van der Borght, Arno Vanstapel, Anke Van Herck, Annelore Sacreas, Tobias Heigl, Bart M. Vanaudenaerde, Laurent Godinas, Dirk E. Van Raemdonck, Laurens J. Ceulemans, Arne P. Neyrinck, Robin Vos, Geert M. Verleden, Stijn E. Verleden and Group the Leuven Lung Transplant
Cells 2020, 9(11), 2516; https://doi.org/10.3390/cells9112516 - 20 Nov 2020
Cited by 13 | Viewed by 3027
Abstract
Eosinophils play a role in many chronic lung diseases. In lung transplantation (LTx), increased eosinophils in bronchoalveolar lavage (BAL) was associated with worse outcomes. However, the effect of peripheral blood eosinophilia after LTx has not been investigated thoroughly. A retrospective study was performed [...] Read more.
Eosinophils play a role in many chronic lung diseases. In lung transplantation (LTx), increased eosinophils in bronchoalveolar lavage (BAL) was associated with worse outcomes. However, the effect of peripheral blood eosinophilia after LTx has not been investigated thoroughly. A retrospective study was performed including all LTx patients between 2011–2016. Chronic lung allograft dysfunction (CLAD)-free and graft survival were compared between patients with high and low blood eosinophils using an 8% threshold ever during follow-up. A total of 102 patients (27.1%) had high blood eosinophils (≥8%) (45 before CLAD and 17 after, 40 had no CLAD) and 274 (72.9%) had low eosinophils (<8%). Patients with high blood eosinophils demonstrated worse graft survival (p = 0.0001) and CLAD-free survival (p = 0.003) compared to low eosinophils. Patients with both high blood and high BAL (≥2%) eosinophils ever during follow-up had the worst outcomes. Within the high blood eosinophil group, 23.5% had RAS compared to 3% in the group with low eosinophils (p < 0.0001). After multivariate analysis, the association between high blood eosinophils and graft and CLAD-free survival remained significant (p = 0.036, p = 0.013) independent of high BAL eosinophils and infection at peak blood eosinophilia, among others. LTx recipients with ever ≥8% blood eosinophils demonstrate inferior graft and CLAD-free survival, specifically RAS, which requires further prospective research. Full article
(This article belongs to the Special Issue Immuno-Pathology in Organ and Cell Transplantation)
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21 pages, 3774 KiB  
Article
Functional, Metabolic and Morphologic Results of Ex Vivo Donor Lung Perfusion with a Perfluorocarbon-Based Oxygen Carrier Nanoemulsion in a Large Animal Transplantation Model
by Ilhan Inci, Stephan Arni, Ilker Iskender, Necati Citak, Josep Monné Rodriguez, Miriam Weisskopf, Isabelle Opitz, Walter Weder, Thomas Frauenfelder, Marie Pierre Krafft and Donat R. Spahn
Cells 2020, 9(11), 2501; https://doi.org/10.3390/cells9112501 - 18 Nov 2020
Cited by 9 | Viewed by 3018
Abstract
Background: Ex vivo lung perfusion (EVLP) is a technology that allows the re-evaluation of questionable donor lung before implantation and it has the potential to repair injured donor lungs that are otherwise unsuitable for transplantation. We hypothesized that perfluorocarbon-based oxygen carrier, a novel [...] Read more.
Background: Ex vivo lung perfusion (EVLP) is a technology that allows the re-evaluation of questionable donor lung before implantation and it has the potential to repair injured donor lungs that are otherwise unsuitable for transplantation. We hypothesized that perfluorocarbon-based oxygen carrier, a novel reconditioning strategy instilled during EVLP would improve graft function. Methods: We utilized perfluorocarbon-based oxygen carrier (PFCOC) during EVLP to recondition and improve lung graft function in a pig model of EVLP and lung transplantation. Lungs were retrieved and stored for 24 h at 4 °C. EVLP was done for 6 h with or without PFCOC. In the transplantation groups, left lung transplantation was done after EVLP with or without PFCOC. Allograft function was assessed by means of pulmonary gas exchange, lung mechanics and vascular pressures, histology and transmission electron microscopy (TEM). Results: In the EVLP only groups, physiological and biochemical markers during the 6-h perfusion period were comparable. However, perfusate lactate potassium levels were lower and ATP levels were higher in the PFCOC group. Radiologic assessment revealed significantly more lung infiltrates in the controls than in the PFCOC group (p = 0.04). In transplantation groups, perfusate glucose consumption was higher in the control group. Lactate levels were significantly lower in the PFCOC group (p = 0.02). Perfusate flavin mononucleotide (FMN) was significantly higher in the controls (p = 0.008). Post-transplant gas exchange was significantly better during the 4-h reperfusion period in the PFCOC group (p = 0.01). Plasma IL-8 and IL-12 levels were significantly lower in the PFCOC group (p = 0.01, p = 0.03, respectively). ATP lung tissue levels at the end of the transplantation were higher and myeloperoxidase (MPO) levels in lung tissue were lower in the PFCOC group compared to the control group. In the PFCOC group, TEM showed better tissue preservation and cellular viability. Conclusion: PFCOC application is safe during EVLP in lungs preserved 24 h at 4 °C. Although this strategy did not significantly affect the EVLP physiology, metabolic markers of the donor quality such as lactate production, glucose consumption, neutrophil infiltration and preservation of mitochondrial function were better in the PFCOC group. Following transplantation, PFCOC resulted in better graft function and TEM showed better tissue preservation, cellular viability and improved gas transport. Full article
(This article belongs to the Special Issue Immuno-Pathology in Organ and Cell Transplantation)
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15 pages, 2034 KiB  
Article
Human Amnion Epithelial Cells Impair T Cell Proliferation: The Role of HLA-G and HLA-E Molecules
by Fabio Morandi, Danilo Marimpietri, Andre Görgens, Alessia Gallo, Raghuraman Chittor Srinivasan, Samir El-Andaloussi and Roberto Gramignoli
Cells 2020, 9(9), 2123; https://doi.org/10.3390/cells9092123 - 19 Sep 2020
Cited by 19 | Viewed by 3619
Abstract
The immunoprivilege status characteristic of human amnion epithelial cells (hAECs) has been recently highlighted in the context of xenogenic transplantation. However, the mechanism(s) involved in such regulatory functions have been so far only partially been clarified. Here, we have analyzed the expression of [...] Read more.
The immunoprivilege status characteristic of human amnion epithelial cells (hAECs) has been recently highlighted in the context of xenogenic transplantation. However, the mechanism(s) involved in such regulatory functions have been so far only partially been clarified. Here, we have analyzed the expression of HLA-Ib molecules in isolated hAEC obtained from full term placentae. Moreover, we asked whether these molecules are involved in the immunoregulatory functions of hAEC. Human amnion-derived cells expressed surface HLA-G and HLA-F at high levels, whereas the commonly expressed HLA-E molecule has been measured at a very low level or null on freshly isolated cells. HLA-Ib molecules can be expressed as membrane-bound and soluble forms, and in all hAEC batches analyzed we measured high levels of sHLA-G and sHLA-E when hAEC were maintained in culture, and such a release was time-dependent. Moreover, HLA-G was present in extracellular vesicles (EVs) released by hAEC. hAEC suppressed T cell proliferation in vitro at different hAEC:T cell ratios, as previously reported. Moreover, inhibition of T cell proliferation was partially reverted by pretreating hAEC with anti-HLA-G, anti-HLA-E and anti-β2 microglobulin, thus suggesting that HLA-G and -E molecules are involved in hAEC-mediated suppression of T cell proliferation. Finally, either large-size EV (lsEV) or small-size EV (ssEV) derived from hAEC significantly modulated T-cell proliferation. In conclusion, we have here characterized one of the mechanism(s) underlying immunomodulatory functions of hAEC, related to the expression and release of HLA-Ib molecules. Full article
(This article belongs to the Special Issue Immuno-Pathology in Organ and Cell Transplantation)
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