Publications by authors named "Emanuele Cozzi"

109 Publications

Machine learning-based analysis of alveolar and vascular injury in SARS-CoV-2 acute respiratory failure.

J Pathol 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padua, Medical School, Padua, Italy.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumopathy is characterized by a complex clinical picture and heterogenous pathological lesions, both involving alveolar and vascular components. The severity and distribution of morphological lesions associated with SARS-CoV-2 and how they relate to clinical, laboratory, and radiological data have not yet been studied systematically. The main goals of the present study were to objectively identify pathological phenotypes and factors, that, in addition to SARS-CoV-2, may influence their occurrence. Lungs from 26 patients who died from SARS-CoV-2 acute respiratory failure were comprehensively analysed. Robust machine learning techniques were implemented to obtain a global pathological score to distinguish phenotypes with prevalent vascular or alveolar injury. The score was then analysed to assess its possible correlation with clinical, laboratory, radiological, and tissue viral data. Furthermore, an exploratory random forest algorithm was developed to identify the most discriminative clinical characteristics at hospital admission that might predict pathological phenotypes of SARS-CoV-2. Vascular injury phenotype was observed in most cases being consistently present as pure form or in combination with alveolar injury. Phenotypes with more severe alveolar injury showed significantly more frequent tracheal intubation, longer invasive mechanical ventilation, illness duration, intensive care unit, hospital stay and lower tissue viral quantity (p<0.001). Furthermore, in this phenotype, superimposed infections, tumours, and aspiration pneumonia were also more frequent (p<0.001). Random forest algorithm identified some clinical features at admission (body mass index, white blood cells, D-dimer, lymphocyte and platelet counts, fever, respiratory rate, and PaCO ) to stratify patients into different clinical clusters and potential pathological phenotypes (a web-app for score assessment has also been developed https://r-ubesp.dctv.unipd.it/shiny/AVI-Score/). In SARS-CoV-2 positive patients, alveolar injury is often associated with other factors in addition to viral infection. Identifying phenotypical patterns at admission may enable a better stratification of patients, ultimately favouring the most appropriate management. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5653DOI Listing
February 2021

High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2.

Eur J Immunol 2021 Feb 12. Epub 2021 Feb 12.

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France.

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID-19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrates, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3-galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate-N-acetylneuraminic acid hydroxylase and α1,3-galactosyl-transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain to produce glyco-humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3-galactose epitopes. Animals rapidly developed a hyperimmune response with anti-SARS-CoV-2 end-titers binding dilutions over one to a million and end-titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV-19, neutralized spike/angiotensin converting enzyme-2 interaction at a concentration <1 μg/mL, and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. We also found that pig GH-pAb Fc domains fail to interact with human Fc receptors, thereby avoiding macrophage-dependent exacerbated inflammatory responses and a possible antibody-dependent enhancement. These data and the accumulating safety advantages of using GH-pAbs in humans warrant clinical assessment of XAV-19 against COVID-19.
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http://dx.doi.org/10.1002/eji.202049072DOI Listing
February 2021

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 Mar;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 2021

Association between Neu5Gc carbohydrate and serum antibodies against it provides the molecular link to cancer: French NutriNet-Santé study.

BMC Med 2020 09 23;18(1):262. Epub 2020 Sep 23.

Department of Cell Research and Immunology, The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.

Background: High consumption of red and processed meat is commonly associated with increased cancer risk, particularly colorectal cancer. Antibodies against the red meat-derived carbohydrate N-glycolylneuraminic acid (Neu5Gc) exacerbate cancer in "human-like" mice. Human anti-Neu5Gc IgG and red meat are both independently proposed to increase cancer risk, yet how diet affects these antibodies is largely unknown.

Methods: We used world global data to demonstrate that colorectal cancer incidence and mortality are associated with increased national meat consumption. In a well-defined large cohort, we used glycomics to measure daily Neu5Gc intake from red meat and dairy, and investigated serum as well as affinity-purified anti-Neu5Gc antibodies. Based on 24-h dietary records, daily Neu5Gc intake was calculated for 19,621 subjects aged ≥ 18 years of the NutriNet-Santé study. Serum and affinity-purified anti-Neu5Gc antibodies were evaluated by ELISA and glycan microarrays in representative 120 individuals, each with at least eighteen 24-h dietary records (aged 45-60, Q1-Q4; aged > 60, Q1 and Q4; 10 men/women per quartile).

Results: We found that high-Neu5Gc diet, gender, and age affect the specificity, levels, and repertoires of anti-Neu5Gc IgG immune responses, but not their affinity. Men consumed more Neu5Gc than women, mostly from red meat (p = 0.0015), and exhibited higher overall serum anti-Neu5Gc IgG levels by ELISA (3.94 ng/μl versus 2.22 ng/μl, respectively; p = 0.039). Detailed glycan microarray analysis against 56 different glycans revealed high Neu5Gc-specificity with increased anti-Neu5Gc IgG and altered repertoires, associated with higher consumption of Neu5Gc from red meat and cow dairy. Affinity purification of serum anti-Neu5Gc antibodies revealed increased levels and biased array repertoire patterns, without an increase in antibody affinity, in individuals consuming higher Neu5Gc levels. Furthermore, in a high-meat diet, antibody diversity patterns on glycan microarrays shifted towards Neu5Gcα3-linked glycans, increasing the α3/α6-glycans ratio score.

Conclusions: We found a clear link between the levels and repertoire of serum anti-Neu5Gc IgG and Neu5Gc intake from red meat and dairy. These precise rational methodologies allowed to develop a Gcemic index to simplify the assessment of Neu5Gc in foods that could potentially be adapted for dietary recommendations to reduce cancer risk.
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http://dx.doi.org/10.1186/s12916-020-01721-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510162PMC
September 2020

IgE-Mediated Immune Response and Antibody-Mediated Rejection.

Clin J Am Soc Nephrol 2020 Oct 9;15(10):1474-1483. Epub 2020 Sep 9.

Department of Translational Medicine and Surgery, Nephrology Unit, Università Cattolica del Sacro Cuore, Rome, Italy.

Background And Objectives: Active antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN- pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN- secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection.

Design, Setting, Participants, & Measurements: This was a cross-sectional study of 56 biopsy-proven antibody-mediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-induced protein, and anti-HLA IgE.

Results: We observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766±79 pixels) and SLE (1495±43 pixels) compared with interstitial fibrosis/tubular atrophy (582±122 pixels) and control (253±50 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibody-mediated rejection compared with control and correlated with the extent of IgE deposition.

Conclusions: Our data suggest that IgE deposition and the subsequent recruitment of basophils and mast cells within the kidney transplant might play a role in antibody-mediated rejection.
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http://dx.doi.org/10.2215/CJN.02870320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536744PMC
October 2020

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Front Cell Neurosci 2020 11;14:250. Epub 2020 Aug 11.

Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.

Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.
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http://dx.doi.org/10.3389/fncel.2020.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433375PMC
August 2020

Kidney exchange strategies: new aspects and applications with a focus on deceased donor-initiated chains.

Transpl Int 2020 Oct 4;33(10):1177-1184. Epub 2020 Sep 4.

Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.

Kidney paired donation (KPD) is a valuable way to overcome immunological incompatibility in the context of living donation, and several strategies have been implemented to boost its development. In this article, we reviewed the current state of the art in this field, with a particular focus on advanced KPD strategies, including the most recent idea of initiating living donor (LD) transplantation chains with a deceased donor (DD) kidney, first applied successfully in 2018. Since then, Italy has been running a national programme in which a chain-initiating kidney is selected from a DD pool and allocated to a recipient with an incompatible LD, and the LD's kidney is transplanted into a patient on the waiting list (WL). At this stage, since the ethical and logistic issues have been managed appropriately, KPD starting with a DD has proved to be a feasible strategy. It enables transplants in recipients of incompatible pairs without the need for desensitizing and also benefits patients on the WL who are allocated chain-ending kidneys from LDs (prioritizing sensitized patients and those on the WL for longer).
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http://dx.doi.org/10.1111/tri.13712DOI Listing
October 2020

Challenging the Role of Diet-Induced Anti-Neu5Gc Antibodies in Human Pathologies.

Front Immunol 2020 9;11:834. Epub 2020 Jun 9.

IECM, Immuno-Endocrinology, USC1383, Oniris, INRAE, Nantes, France.

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http://dx.doi.org/10.3389/fimmu.2020.00834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325919PMC
June 2020

COVID-19 pneumonia in lung transplant recipients: Report of 2 cases.

Am J Transplant 2020 10 14;20(10):2933-2937. Epub 2020 Jun 14.

Thoracic Surgery and Lung Transplant Center, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.

Coronavirus disease 2019 (COVID-19) has been declared pandemic since March 2020. In Europe, Italy was the first nation affected by this infection. We report anamnestic data, clinical features, and therapeutic management of 2 lung transplant recipients with confirmed COVID-19 pneumonia. Both patients were in good clinical condition before the infection and were receiving immunosuppression with calcineurin inhibitors (CNI), mycophenolate mofetil, and corticosteroids. Whereas mycophenolate mofetil was withdrawn in both cases, CNI were suspended only in the second patient. The first patient always maintained excellent oxygen saturation throughout hospitalization with no need for additional oxygen therapy. He was discharged with a satisfactory pulmonary function and a complete resolution of radiological and clinical findings. However, at discharge SARS-CoV-2 RNA could still be detected in the nasopharyngeal swab and in the stools. The second patient required mechanical ventilation, had a progressive deterioration of his clinical conditions, and had a fatal outcome. Further insight into SARS-CoV-2 infection is eagerly awaited to improve the outcome of transplant recipients affected by COVID-19 pneumonia.
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http://dx.doi.org/10.1111/ajt.15993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273094PMC
October 2020

Can we extrapolate from a mouse model a susceptibility for atherosclerosis in humans?

Proc Natl Acad Sci U S A 2020 01 21;117(4):1845-1846. Epub 2020 Jan 21.

Cellular and Molecular Immuno-Endocrinology Research Unit, Oniris, Institut National de la Recherche Agronomique, Université Bretagne Loire, 44307 Nantes, France.

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http://dx.doi.org/10.1073/pnas.1915658117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995011PMC
January 2020

MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates.

Nat Commun 2019 09 25;10(1):4357. Epub 2019 Sep 25.

Inserm U861, I-STEM, AFM, Corbeil-Essonnes, 91100, France.

Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors' and patients' HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington's disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.
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http://dx.doi.org/10.1038/s41467-019-12324-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761126PMC
September 2019

Assessment and prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant and in solid organ transplant: A multidisciplinary consensus conference by the Italian GITMO, SITO, and AMCLI societies.

Clin Transplant 2019 10 6;33(10):e13666. Epub 2019 Aug 6.

Section of Infectious and Tropical Diseases, Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT) recipients. In view of the uncertainties on the assessment and prevention of CMV infection in both transplant procedures, three Italian scientific societies for HSCT and SOT and for Clinical Microbiology appointed a panel of experts to compose a framework of recommendations. Recommendations were derived from a comprehensive analysis of the scientific literature and from a multidisciplinary consensus conference process. The lack of adequate clinical trials focused on certain diagnostic procedures, and antiviral intervention forced the panel to use the methods of consensus for shaping some recommendations. Recommendations concerning the two types of transplant were given for the following issues: assessment of pretransplant CMV serostatus, immunological monitoring after transplant, CMV prophylaxis with antivirals, CMV preemptive strategy, and CMV prophylaxis with immunoglobulin infusion and with adoptive immunotherapy. The questions raised by and the recommendations resulting from this consensus conference project may contribute to the improvement of certain crucial aspects of the management of CMV infections in allo-HSCT and in SOT populations.
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http://dx.doi.org/10.1111/ctr.13666DOI Listing
October 2019

Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome.

Xenotransplantation 2019 11 10;26(6):e12535. Epub 2019 Jul 10.

Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.

Humans cannot synthesize N-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet-induced anti-Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti-Neu5Gc Abs following a challenge with animal-derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity-purified anti-Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc-glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre-existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti-Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre-existing or anti-human T-cell globulin (ATG)-elicited anti-Neu5Gc Abs. Compared with pre-existing anti-Neu5Gc Abs, which are normal component of ECs environment, elicited anti-Neu5Gc Abs down-regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement-containing serum down-regulated most transcripts mobilized by serum alone. Both types of anti-Neu5Gc Abs-induced a dose- and complement-dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre-existing anti-Neu5Gc Abs, ATG-elicited anti-Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.
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http://dx.doi.org/10.1111/xen.12535DOI Listing
November 2019

Generation of cattle knockout for galactose-α1,3-galactose and N-glycolylneuraminic acid antigens.

Xenotransplantation 2019 09 22;26(5):e12524. Epub 2019 May 22.

Avantea, Laboratory of Reproductive Technologies, Cremona, Italy.

Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet.
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http://dx.doi.org/10.1111/xen.12524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852128PMC
September 2019

Deceased Donor-initiated Chains: First Report of a Successful Deliberate Case and Its Ethical Implications.

Transplantation 2019 10;103(10):2196-2200

Department of Economics and Management, University of Padova, Padova, Italy.

Background: It has been suggested that deceased donor kidneys could be used to initiate chains of living donor kidney paired donation, but the potential gains of this practice need to be quantified and the ethical implications must be addressed before it can be implemented.

Methods: The gain of implementing deceased donor-initiated chains was measured with an algorithm, using retrospective data on the pool of incompatible donor/recipient pairs, at a single center. The allocation rules for chain-ending kidneys and the characteristics and quality of the chain-initiating kidney are described.

Results: The benefit quantification process showed that, with a pool of 69 kidneys from deceased donors and 16 pairs enrolled in the kidney paired donation program, it was possible to transplant 8 of 16 recipients (50%) over a period of 3 years. After obtaining the approval of the Veneto Regional Authority's Bioethical Committee and the revision of the Italian National Transplant Center's allocation policies, the first successful case was completed. For the recipient (male, aged 53 y), who entered the program for a chain-initiating kidney with a Kidney Donor Risk Index of 0.61 and a Kidney Donor Profile Index of 3%, the waiting time was 4 days. His willing donor (female, aged 53 y) with a Living Kidney Donor Profile Index of 2, donated 2 days later to a chain-ending recipient (male, aged 47 y) who had been on dialysis for 5 years.

Conclusions: This is the first report of a successfully completed, deliberate deceased donor-initiated chain, which was made possible after a thorough assessment of the ethical issues and the impact of allocation policies. This article includes a preliminary efficacy assessment and describes the development of a dedicated algorithm.
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http://dx.doi.org/10.1097/TP.0000000000002645DOI Listing
October 2019

Alveolar Septal Widening as an "Alert" Signal to Look Into Lung Antibody-mediated Rejection: A Multicenter Pilot Study.

Transplantation 2019 11;103(11):2440-2447

Department of Histopathology, Papworth Hospital NHS Trust, Cambridge, United Kingdom.

Background: Antibody-mediated rejection (AMR) plays an important role in allograft dysfunction. Acute lung injury (ALI), endotheliitis, capillary inflammation, and C4d positivity have been described as morphological features conventionally associated with lung AMR. A multidisciplinary, international task force reviewed AMR cases in the context of four face-to-face meetings. Septal widening was a frequent, striking histological feature recognized first and easily at low-power magnification. This study aimed to evaluate whether septal widening could represent an "alert" signal for AMR.

Methods: Following the face-to-face meetings that enabled the classification of cases as AMR or non-AMR, morphometry was performed on biopsies from 48 recipients with definite, probable or possible AMR, 31 controls (negative for any posttransplant injury) and 10 patients with nonimmune-related ALI.

Results: Mean alveolar septal thickness was greater in AMR patients than in controls (P < 0.001). Septal thickness was not significantly different between AMR-ALI and non-AMR-ALI. Unexpectedly septal widening was the only histological change detected in some cases with probable or possible AMR that lacked the histological lesions conventionally associated with AMR. The thickness in these cases was similar to that observed in AMR cases with more severe histological injury such as ALI or neutrophilic capillaritis.

Conclusions: Our data suggest that, even if unspecific as the other lesions conventionally associated with AMR, septal widening may represent an "alert" signal to look into lung AMR. A larger prospective study is mandatory to confirm the potential value of septal widening in the multidisciplinary approach of AMR.
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http://dx.doi.org/10.1097/TP.0000000000002688DOI Listing
November 2019

Extended criteria donor lung reconditioning with the organ care system lung: a single institution experience.

Transpl Int 2019 02 13;32(2):131-140. Epub 2018 Nov 13.

Thoracic Surgery Division, Department of Cardiac, Thoracic and Vascular Sciences, Padova University Hospital, Padova, Italy.

Lung transplantation is a life-saving procedure limited by donor's availability. Lung reconditioning by ex vivo lung perfusion represents a tool to expand the donor pool. In this study, we describe our experience with the OCS™ Lung to assess and recondition extended criteria lungs. From January 2014 to October 2016, of 86 on-site donors evaluated, eight lungs have been identified as potentially treatable with OCS™ Lung. We analyzed data from these donors and the recipient outcomes after transplantation. All donor lungs improved during OCS perfusion in particular regarding the PaO /FiO ratio (from 340 mmHg in donor to 537 mmHg in OCS) leading to lung transplantation in all cases. Concerning postoperative results, primary graft dysfunction score 3 at 72 h was observed in one patient, while median mechanical ventilation time, ICU, and hospital stay were 60 h, 14 and 36 days respectively. One in-hospital death was recorded (12.5%), while other two patients died during follow-up leading to 1-year survival of 62.5%. The remaining five patients are alive and in good conditions. This case series demonstrates the feasibility and value of lung reconditioning with the OCS™ Lung; a prospective trial is underway to validate its role to safely increase the number of donor lungs.
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http://dx.doi.org/10.1111/tri.13365DOI Listing
February 2019

C1q-binding donor-specific antibody assays help define risk and prognosis in antibody-mediated rejection.

Kidney Int 2018 10;94(4):657-659

Renal Transplantation Unit 'A. Vercellone,' Division of Nephrology Dialysis and Transplantation, AOU Città della Salute e della Scienza di Torino and Department of Medical Sciences, University of Turin, Turin, Italy; Center for Experimental Medical Research (CeRMS), University of Turin, Turin, Italy.

Antibody-mediated rejection represents the first cause of graft loss in renal transplant recipients, and it is imperative to identify appropriate tools to enable risk stratification of such patients. Lately, the usefulness of measuring complement-binding anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) in renal transplantation has been intensely debated. While the jury is still out, recent data suggest that monitoring complement-binding DSAs may help to recognize high-risk patients and possibly trigger more effective interventions in selected patients.
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http://dx.doi.org/10.1016/j.kint.2018.06.032DOI Listing
October 2018

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

Am J Transplant 2019 01 19;19(1):123-131. Epub 2018 Jul 19.

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.
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http://dx.doi.org/10.1111/ajt.14979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309659PMC
January 2019

Xenotransplantation: The Way beyond and Ahead toward Clinical Application.

J Immunol Res 2018;2018:6191359. Epub 2018 Apr 4.

Transplant Immunology Unit, Department of Cardiac, Thoracic and Vascular Sciences, Padua University Hospital, Padua, Italy.

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http://dx.doi.org/10.1155/2018/6191359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904776PMC
February 2019

Jewish, Christian and Muslim theological perspectives about xenotransplantation.

Xenotransplantation 2018 05 24;25(3):e12400. Epub 2018 Apr 24.

Department of Surgery, Xenotransplantation Program, University of Alabama Birmingham, Birmingham, AL, USA.

Background: This paper is based on a theological symposium presented at the International Xenotransplantation Association's 14th Congress held in Baltimore, MD, September, 2017.

Methods: The information explores the Jewish, Christian and Muslim theological perceptions and perspectives about cross-species (ie pig-to-human) organ transplantation, the genetic alterations required in the organ-source pig, and their potential to influence individual acceptance of the procedure.

Results/conclusions: This work should not be considered as the ultimate word about individual theological views, but rather as part of an ongoing conversation that will hopefully lead to wider consideration and exploration of these issues as xenotransplantation science advances towards clinical trials.
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http://dx.doi.org/10.1111/xen.12400DOI Listing
May 2018

Endodontic treatment of canine teeth in a cynomolgus monkey ( Macaca fascicularis).

Lab Anim 2018 Jun 10;52(3):308-312. Epub 2017 Nov 10.

1 Department of Animal Medicine, Production and Health, University of Padova, Italy.

A case of bilateral superior canine tooth pulp necrosis in an 18-year-old male Macaca fascicularis is described . A skull computed tomography scan was performed to confirm the diagnostic suspicion. A successful bilateral endodontic treatment with coronotomy was performed using rotary nickel-titanium instruments. Post-operative dental radiographs confirmed the correct positioning of the sealant. A rapid and excellent clinical recovery was obtained after each surgery. This innovative approach may contribute to improving the quality of root canal treatments provided to non-human primates.
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http://dx.doi.org/10.1177/0023677217737568DOI Listing
June 2018

Single-center experience in urgent lung transplantation program in a country with a shortage of donors: Does the end justify the means?

Clin Transplant 2017 Dec 28;31(12). Epub 2017 Nov 28.

Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.

In rapidly deteriorating patients awaiting lung transplantation (LT), supportive strategies are only temporary and urgent lung transplant (ULT) remains the last option. The few publications on this topic report conflicting results. According to the Italian national program, patients on mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) may be included in urgent list. We reviewed our experience from January 2012 to December 2014 with ULT and elective lung transplantation (ELT), focusing on outcomes. In the study period, 16 patients received ULT, while 51 received ELT. Among ULT, 1 patient (5.8%) died in waiting list (WL) while 16 patients underwent LT with a median WL time of 6 days. ELT WL mortality was 13.5%, and median WL time 368 days. In-hospital mortality was lower in ELT group (5.8% vs 37.5%, P < .01), while the other postoperative outcomes were not significantly different. For ULT patients, the highest impact risk factors for in-hospital mortality were pretransplant plasma transfusion, recipient Pseudomonas aeruginosa colonization, and high level of reactive C-protein and lactic acid. A ULT program with an accurate recipient selection allows earlier transplantation, reducing WL mortality, with acceptable outcomes, although with a higher in-hospital mortality. Larger studies are needed to validate our results.
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http://dx.doi.org/10.1111/ctr.13129DOI Listing
December 2017

The mechanisms of rejection in solid organ transplantation.

Transfus Apher Sci 2017 Aug 8;56(4):498-505. Epub 2017 Jul 8.

Department of Transfusion Medicine, Padua University Hospital, Padova, Italy. Electronic address:

Organ transplantation represents the preferred treatment option for many patients in terminal organ failure. The half-life of transplanted organs, however, is still far from being satisfactory with the vast majority of the organs failing within the first two decades following transplantation. At this stage, it has become apparent that rejection (prevalently mediated by humoral events) remains the primary cause of graft loss after the first year. In this light, studies are underway to better comprehend the immune events underlying graft rejection and novel immunosuppressive strategies are being explored. In this context, therapeutic apheresis techniques, that include therapeutic plasma exchange (TPE), immunoadsorption (IA) and extracorporeal photochemotherapy (ECP), represent an important adjunct in the current immunosuppressive armamentarium. This article briefly reviews our current understanding of the immune process underlying rejection of a solid organ transplant and describes the principal areas of application of therapeutic apheresis techniques in transplantation.
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http://dx.doi.org/10.1016/j.transci.2017.07.005DOI Listing
August 2017

Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.

Diabetes 2017 04 12;66(4):987-993. Epub 2017 Jan 12.

IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France

Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and -glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate--acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies.
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http://dx.doi.org/10.2337/db16-1060DOI Listing
April 2017

Progress in Clinical Encapsulated Islet Xenotransplantation.

Transplantation 2016 Nov;100(11):2301-2308

1 Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA. 2 Otsuka Pharmaceutical Factory, Tateiwa, Muya-cho, Naruto Tokushima, Japan. 3 Hospital Eva Peron de San Martin, Buenos Aires, Argentina. 4 Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka City, Fukuoka, Japan. 5 Laboratory of Surgery and Transplantation, Catholic University of Louvain, Brussels, Belgium. 6 Gene Center, LMU Munich and German Center for Diabetes Research (DZD), Munich, Germany. 7 Transplantation Immunology Unit, Padua University Hospital, and the Consortium for Research in Organ Transplantation (CORIT), Padua, Italy.

At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077652PMC
http://dx.doi.org/10.1097/TP.0000000000001371DOI Listing
November 2016

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves.

Xenotransplantation 2016 09 9;23(5):381-92. Epub 2016 Sep 9.

Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel.

Background: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients.

Methods: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG.

Results: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/μg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts.

Conclusions: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.
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http://dx.doi.org/10.1111/xen.12260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036590PMC
September 2016