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1. Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation.

Author

Bender, Martin, Abicht, Jan-Michael, Reichart, Bruno, Neumann, Elisabeth, Radan, Julia, Mokelke, Maren, Buttgereit, Ines, Leuschen, Maria, Wall, Felicia, Michel, Sebastian, Ellgass, Reinhard, Steen, Stig, Paskevicius, Audrius, Lange, Andreas, Kessler, Barbara, Kemter, Elisabeth, Klymiuk, Nikolai, Denner, Joachim, Godehardt, Antonia W., and Tönjes, Ralf R.

Subjects
IMMUNE checkpoint proteins, HEART transplantation, MYCOSES, XENOTRANSPLANTATION, SURVIVAL rate
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 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. [ABSTRACT FROM AUTHOR]

Published
2024
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2. The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation—First Insights.

Author

Bender, Martin, Abicht, Jan-Michael, Reichart, Bruno, Leuschen, Maria, Wall, Felicia, Radan, Julia, Neumann, Elisabeth, Mokelke, Maren, Buttgereit, Ines, Michel, Sebastian, Ellgass, Reinhard, Gieseke, Katja, Steen, Stig, Paskevicius, Audrius, Denner, Joachim, Godehardt, Antonia W., Tönjes, Ralf R., Hagl, Christian, Ayares, David, and Wolf, Eckhard

Subjects
GLYCOCALYX, XENOTRANSPLANTATION, HEPARAN sulfate, XENOGRAFTS, PRESERVATION of organs, tissues, etc., ENDOTHELIAL cells
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 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. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Evidence for Microchimerism in Baboon Recipients of Pig Hearts

Author

Jhelum, Hina, primary, Bender, Martin, additional, Reichart, Bruno, additional, Mokelke, Maren, additional, Radan, Julia, additional, Neumann, Elisabeth, additional, Krabben, Ludwig, additional, Abicht, Jan-Michael, additional, Kaufer, Benedikt, additional, Längin, Matthias, additional, and Denner, Joachim, additional

Published
2023
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4. Consistent success in life-supporting porcine cardiac xenotransplantation

Author

Längin, Matthias, Mayr, Tanja, Reichart, Bruno, Michel, Sebastian, Buchholz, Stefan, Guethoff, Sonja, and Dashkevich, Alexey

Subjects
Heart transplantation -- Analysis -- Research, Xenotransplantation -- Research, Genetic engineering -- Usage, Cardiac patients, Animal genetic engineering, Immunotherapy, Galactose, Genetically modified organisms, Antigenic determinants, Surgery, Genetically modified animals, Heart failure, Swine, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need.sup.1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative.sup.4. Genetically multi-modified pig hearts that lack galactose-[alpha]1,3-galactose epitopes ([alpha]1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons.sup.5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once.sup.6. Here we show that [alpha]1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation.sup.7. [alpha]1,3-galactosyltransferase-knockout pig hearts that express human CD46 and human thrombomodulin require non-ischaemic preservation with continuous perfusion and post-transplantation growth control to ensure long-term orthotopic function of the xenograft in baboons., Author(s): Matthias Längin [sup.1] [sup.2] , Tanja Mayr [sup.1] [sup.2] , Bruno Reichart [sup.2] , Sebastian Michel [sup.3] , Stefan Buchholz [sup.3] , Sonja Guethoff [sup.2] [sup.3] , Alexey Dashkevich [...]

Published
2018
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8. Consensus statement on heart xenotransplantation in children: Toward clinical translation

Author

Konstantinov, Igor E., primary, Cooper, David K.C., additional, Adachi, Iki, additional, Bacha, Emile, additional, Bleiweis, Mark S., additional, Chinnock, Richard, additional, Cleveland, David, additional, Cowan, Peter J., additional, Fynn-Thompson, Francis, additional, Morales, David L.S., additional, Mohiuddin, Muhammad M., additional, Reichart, Bruno, additional, Rothblatt, Martine, additional, Roy, Nathalie, additional, Turek, Joseph W., additional, Urschel, Simon, additional, West, Lori, additional, and Wolf, Eckhard, additional

Published
2022
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9. New methods for noninvasive monitoring of rejection after heart transplantation

Author

Reichenspumer, Hermann, Haberl, Ralph, Angermann, Christiane, Anthuber, Matthias, Osterholzer, Georg, Kemkes, Bemhard M., Hammer, Claus, Gokel, Joachim M., and Reichart, Bruno

Subjects
17th Annual Symposium
Abstract

Between August 1981 and February 1987, 67 orthotopic heart transplants and three heart-lung transplants were performed in 69 patients at the University of Munich Hospital. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and prednisone. The diagnosis of acute rejection was based on cytoimmunologic monitoring, frequency analysis of fast Fourier transformed surface electrocardiograms (FFT-ECGs), and two-dimensional echocardiography. The results of these diagnostic methods were compared to the findings provided by endomyocardial biopsies, which were performed simultaneously with the noninvasive studies. Seventy patients underwent cytoimmunologic monitoring. In 88% of all rejection episodes, this technique revealed activated lymphocytes and lymphoblasts in the mononuclear concentrate of the peripheral blood samples; the presence of such cells is known to be an extremely early sign of acute rejection. Twenty-six patients were monitored by means of FFT-ECG. In 20 of the 21 cases of rejection, this method disclosed significant changes in the frequency spectrum of the QRS complex in the 70- to 110-Hz range; in 12 cases, these changes were the earliest sign of acute rejection. Therefore, FFT-ECG had a sensitivity of 95%. All of the QRS changes were reversible with rejection therapy. Forty-five patients were subjected to two-dimensional echocardiography. In 31 of the 35 cases of rejection, the echocardiogram showed a significant increase in the left ventricular wall thickness and a decrease in the left ventricular cross-sectional area during mild rejection. Moderate or severe rejection was characterized by an increase in the diastolic area, as well as a decrease in the systolic area change and in the diastolic maximum velocity of area change. Thus, two-dimensional echocardiography had a sensitivity of 89%. In the recent cases, the diagnosis of rejection was based on noninvasive methods alone. After rejection therapy had been instituted, endomyocardial biopsies were performed to assess the effectiveness of the treatment. With noninvasive rejection monitoring, the number of endomyocardial biopsies performed during the first three postoperative months was only 2.8 per patient; in comparison with invasive rejection monitoring, noninvasive follow-up was associated with a 75% reduction in the need for biopsy.

Published
2022

10. Author Correction: Consistent success in life-supporting porcine cardiac xenotransplantation

Author

Längin, Matthias, Mayr, Tanja, Reichart, Bruno, Michel, Sebastian, Buchholz, Stefan, Guethoff, Sonja, Dashkevich, Alexey, Baehr, Andrea, Egerer, Stefanie, Bauer, Andreas, Mihalj, Maks, Panelli, Alessandro, Issl, Lara, Ying, Jiawei, Fresch, Ann Kathrin, Buttgereit, Ines, Mokelke, Maren, Radan, Julia, Werner, Fabian, Lutzmann, Isabelle, Steen, Stig, Sjöberg, Trygve, Paskevicius, Audrius, Qiuming, Liao, Sfriso, Riccardo, Rieben, Robert, Dahlhoff, Maik, Kessler, Barbara, Kemter, Elisabeth, Kurome, Mayuko, Zakhartchenko, Valeri, Klett, Katharina, Hinkel, Rabea, Kupatt, Christian, Falkenau, Almuth, Reu, Simone, Ellgass, Reinhard, Herzog, Rudolf, Binder, Uli, Wich, Günter, Skerra, Arne, Ayares, David, Kind, Alexander, Schönmann, Uwe, Kaup, Franz-Josef, Hagl, Christian, Wolf, Eckhard, Klymiuk, Nikolai, Brenner, Paolo, and Abicht, Jan-Michael

Published
2019
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33. Organ transplants of the future: planning for innovations including xenotransplantation.

Author

Cozzi, Emanuele, Schneeberger, Stefan, Bellini, Maria Irene, Berglund, Erik, Böhmig, Georg, Fowler, Kevin, Hoogduijn, Martin, Jochmans, Ina, Marckmann, Georg, Marson, Lorna, Neuberger, James, Oberbauer, Rainer, Pierson, Richard N., Reichart, Bruno, Scobie, Linda, White, Colin, and Naesens, Maarten

Subjects
TRANSPLANTATION of organs, tissues, etc., XENOTRANSPLANTATION, CLINICAL medicine, XENOGRAFTS, GENETIC models
Abstract

Summary: The future clinical application of animal‐to‐human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen‐free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first‐in‐human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first‐in‐human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders. [ABSTRACT FROM AUTHOR]

Published
2021
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