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Biomedicines
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Xenotransplantation: Targeting Acute Vascular Rejection and Endothelial Activation
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Xenotransplantation: Targeting Acute Vascular Rejection and Endothelial Activation

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 3973

Special Issue Editor

Dr. Konrad Fischer

E-Mail Website
Guest Editor
Chair of Livestock Biotechnology, Technical University of Munich, Freising, Germany
Interests: xenotransplantation; translational pig models; livestock engineering; immunology; allergy development

Special Issue Information

Dear Colleagues,

Acute vascular rejection (AVR) still presents a major hurdle to long-term xenograft acceptance. Although several transgene combinations and knockouts have been described, xenografts are still undergoing AVR. New insights into innate and adaptive immune responses as well as detailed characterizations of signaling pathways are necessary to further optimize the pigs and protect the xenografts. In this Special Issue, we focus on the role of the endothelium during AVR, including the endothelial glycocalyx and underlying signaling pathways, and investigate new means of overcoming blood coagulation mechanisms and thrombotic microangiopathy (TMA).

Dr. Konrad Fischer
Guest Editor

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Keywords

  • endothelial activation
  • endothelial protection
  • thrombotic microangiopathy
  • glycocalyx
  • acute vascular rejection

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Published Papers (3 papers)

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Research

21 pages, 6530 KiB  
Article
Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation
by Martin Bender, Jan-Michael Abicht, Bruno Reichart, Elisabeth Neumann, Julia Radan, Maren Mokelke, Ines Buttgereit, Maria Leuschen, Felicia Wall, Sebastian Michel, Reinhard Ellgass, Stig Steen, Audrius Paskevicius, Andreas Lange, Barbara Kessler, Elisabeth Kemter, Nikolai Klymiuk, Joachim Denner, Antonia W. Godehardt, Ralf R. Tönjes, Jonathan M. Burgmann, Constança Figueiredo, Anastasia Milusev, Valentina Zollet, Neda Salimi-Afjani, Alain Despont, Robert Rieben, Stephan Ledderose, Christoph Walz, Christian Hagl, David Ayares, Eckhard Wolf, Michael Schmoeckel, Paolo Brenner, Uli Binder, Michaela Gebauer, Arne Skerra and Matthias Länginadd Show full author list remove Hide full author list
Biomedicines 2024, 12(8), 1927; https://doi.org/10.3390/biomedicines12081927 - 22 Aug 2024
Viewed by 991
Abstract
The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses [...] Read more.
The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively resulted in animal survival with a rate comparable to a previous study that utilized anti-CD40 monotherapy. Importantly, no incidence of thromboembolic events associated with the administration of the anti-CD40L PAS-Fab was observed. Two experiments failed early because of technical reasons, two were terminated deliberately after 90 days with the baboons in excellent condition and two were extended to 120 and 170 days, respectively. Unexpectedly, and despite the absence of any clinical signs, histopathology revealed fungal infections in all four recipients. This study provides, for the first time, insights into a combination therapy with anti-CD40/anti-CD40L antibodies to block this immune checkpoint. Full article
(This article belongs to the Special Issue Xenotransplantation: Targeting Acute Vascular Rejection and Endothelial Activation)
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14 pages, 25616 KiB  
Article
Reduction in Xenogeneic Epitopes on Porcine Endothelial Cells by Periodate Oxidation
by Jonas Thom, Nathalie Roters, Slavica Schuemann, Birgit Andrée, Falk F. R. Buettner, Andres Hilfiker, Tobias Goecke and Robert Ramm
Biomedicines 2024, 12(7), 1470; https://doi.org/10.3390/biomedicines12071470 - 3 Jul 2024
Viewed by 809
Abstract
Background: Patterns of humoral immune responses represent a major hurdle in terms of pig-to-human xenotransplantation approaches. The best-known xenogeneic glycan antigens present in pigs are the αGal (Galili antigen) and the non-human sialic acid Neu5Gc. As there are further differences between porcine and [...] Read more.
Background: Patterns of humoral immune responses represent a major hurdle in terms of pig-to-human xenotransplantation approaches. The best-known xenogeneic glycan antigens present in pigs are the αGal (Galili antigen) and the non-human sialic acid Neu5Gc. As there are further differences between porcine and human cellular surface glycosylation, a much broader range of glycan epitopes with xeno-reactive relevance can be anticipated. Therefore, we set out to chemically modify porcine cellular surface glycans in a global approach by applying sodium periodate (NaIO4) oxidation. Methods: Porcine endothelial cells were exposed to oxidation with 1 to 5 mM NaIO4 for different time periods at 37 °C or 4 °C and under static or dynamic conditions. The impact on cellular survival was determined by applying live/dead assays. Oxidation of αGal-epitopes was assessed by fluorescence microscopy-based quantification of isolectin-B4 (IL-B4) staining. Overall immunogenicity of porcine cells was determined by human serum antibody binding. Results: Treatment of porcine endothelial cells and tissues with NaIO4 led to reduced binding of the αGal-specific IL-B4 and/or human serum antibodies. NaIO4 was revealed to be cytotoxic when performed at elevated temperatures and for a prolonged time. However, by applying 2 mM NaIO4 for 60 min at 4 °C, a high extent of cellular viability and a relevant reduction in detectable αGal epitope were observed. No differences were detected irrespectively on whether the cells were oxidized under static or flow conditions. Conclusions: Glycan epitopes on living cells can be oxidized with NaIO4 while maintaining their viability. Accordingly, this strategy holds promise to prevent immune reactions mediated by preformed anti-glycan antibodies. Full article
(This article belongs to the Special Issue Xenotransplantation: Targeting Acute Vascular Rejection and Endothelial Activation)
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15 pages, 1351 KiB  
Article
The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation—First Insights
by Martin Bender, Jan-Michael Abicht, Bruno Reichart, Maria Leuschen, Felicia Wall, Julia Radan, Elisabeth Neumann, Maren Mokelke, Ines Buttgereit, Sebastian Michel, Reinhard Ellgass, Katja Gieseke, Stig Steen, Audrius Paskevicius, Joachim Denner, Antonia W. Godehardt, Ralf R. Tönjes, Christian Hagl, David Ayares, Eckhard Wolf, Michael Schmoeckel, Paolo Brenner, Martin B. Müller and Matthias Länginadd Show full author list remove Hide full author list
Biomedicines 2024, 12(6), 1336; https://doi.org/10.3390/biomedicines12061336 - 16 Jun 2024
Cited by 2 | Viewed by 1598
Abstract
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune [...] Read more.
Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune responses as well as detailed characterizations of signaling pathways are necessary. In allotransplantation, endothelial cells and their sugar-rich surface—the endothelial glycocalyx—are known to influence organ rejection. In xenotransplantation, however, only in vitro data exist on the role of the endothelial glycocalyx so far. Thus, in the current study, we analyzed the changes of the endothelial glycocalyx components hyaluronan, heparan sulfate and syndecan-1 after pig-to-baboon cardiac xenotransplantations in the perioperative (n = 4) and postoperative (n = 5) periods. These analyses provide first insights into changes of the endothelial glycocalyx after pig-to-baboon cardiac xenotransplantation and show that damage to the endothelial glycocalyx seems to be comparable or even less pronounced than in similar human settings when current strategies of cardiac xenotransplantation are applied. At the same time, data from the experiments where current strategies, like non-ischemic preservation, growth inhibition or porcine cytomegalovirus (a porcine roseolovirus (PCMV/PRV)) elimination could not be applied indicate that damage of the endothelial glycocalyx also plays an important role in cardiac xenotransplantation. Full article
(This article belongs to the Special Issue Xenotransplantation: Targeting Acute Vascular Rejection and Endothelial Activation)
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