An Approach to Controlling Inflammation and Coagulation in Pig‐to‐Baboon Cardiac Xenotransplantation
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INTRODUCTION: Inflammatory responses and coagulation disorders are a relevant challenge for successful cardiac xenotransplantation on its way to the clinic. To cope with this, an effective and clinically practicable anti-inflammatory and anti-coagulatory regimen is needed. The inflammatory and coagulatory response can be reduced by genetic engineering of the organ-source pigs. Furthermore, there are several therapeutic strategies to prevent or reduce inflammatory responses and coagulation disorders following xenotransplantation. However, it is still unclear, which combination of drugs should be used in the clinical setting. To elucidate this, we present data from pig-to-baboon orthotopic cardiac xenotransplantation experiments using a combination of several anti-inflammatory drugs. METHODS: Genetically modified piglets (GGTA1-KO, hCD46/hTBM transgenic) were used for orthotopic cardiac xenotransplantation into captive-bred baboons (n = 14). All animals received an anti-inflammatory drug therapy including a C1 esterase inhibitor, an IL-6 receptor antagonist, a TNF-α inhibitor, and an IL-1 receptor antagonist. As an additive medication, acetylsalicylic acid and unfractionated heparin were administered. The immunosuppressive regimen was based on CD40/CD40L co-stimulation blockade. During the experiments, leukocyte counts, levels of C-reactive protein (CRP) as well as systemic cytokine and chemokine levels and coagulation parameters were assessed at multiple timepoints. Four animals were excluded from further data analyses due to porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) infections (n = 2) or technical failures (n = 2). RESULTS: Leukocyte counts showed a relevant perioperative decrease, CRP levels an increase. In the postoperative period, leukocyte counts remained consistently within normal ranges, CRP levels showed three further peaks after about 35, 50, and 80 postoperative days. Analyses of cytokines and chemokines revealed different patterns. Some cytokines, like IL-8, increased about 2-fold in the perioperative period, but then decreased to levels comparable to the preoperative values or even lower. Other cytokines, such as IL-12/IL-23, decreased in the perioperative period and stayed at these levels. Besides perioperative decreases, there were no relevant alterations observed in coagulation parameters. In summary, all parameters showed an unremarkable course with regard to inflammatory responses and coagulation disorders following cardiac xenotransplantation and thus showed the effectiveness of our approach. CONCLUSION: Our preclinical experience with the anti-inflammatory drug therapy proved that controlling of inflammation and coagulation disorders in xenotransplantation is possible and well-practicable under the condition that transmission of pathogens, especially of PCMV/PRV to the recipient is prevented because PCMV/PRV also induces inflammation and coagulation disorders. Our anti-inflammatory regimen should also be applicable and effective in the clinical setting of cardiac xenotransplantation.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- An Approach to Controlling Inflammation and Coagulation in Pig‐to‐Baboon Cardiac Xenotransplantation
- Date Crossref
- 01/07/2024
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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LMU Klinikum pays non établi dans la noticeÉtablissement de santé
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Ludwig-Maximilians-Universität München pays non établi dans la noticeUniversité ou école supérieure
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Institut für Chirurgische Forschung pays non établi dans la noticeStructure de recherche
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Medizinische Hochschule Hannover pays non établi dans la noticeUniversité ou école supérieure
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Freie Universität Berlin pays non établi dans la noticeUniversité ou école supérieure
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Paul Ehrlich Institut Cell and Gene Therapy pays non établi dans la noticeStructure de recherche
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Technical University of Munich Chair of Biological Chemistry pays non établi dans la noticeUniversité ou école supérieure
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Department of Anaesthesiology University Hospital Department of Anaesthesiology pays non établi dans la noticeUniversité ou école supérieure
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Transregional Collaborative Research Center 127 Walter Brendel Centre of Experimental Medicine LMU Munich Munich Germany pays non établi dans la noticeStructure de recherche
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Institute of Transfusion Medicine and Transplant Engineering Hannover Medical School Hannover Germany pays non établi dans la noticeStructure de recherche
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Department of Cardiac Surgery University Hospital pays non établi dans la noticeUniversité ou école supérieure
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Institute of Molecular Animal Breeding and Biotechnology Gene Center and Department of Veterinary Sciences pays non établi dans la noticeStructure de recherche
LMU Klinikum, Ludwig-Maximilians-Universität München et Institut für Chirurgische Forschung, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.