Publikationsdatenbank

An approach to controlling inflammation and coagulation in pig‐to‐baboon cardiac xenotransplantation (2024)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Bender, Martin

Reichart, Bruno

Figueiredo, Constanca

Burgmann, Jonathan M.

Leuschen, Maria

Wall, Felicia

Radan, Julia

Neumann, Elisabeth

Mokelke, Maren

Buttgereit, Ines

Michel, Sebastian

Ellgass, Reinhard

Egerer, Stefanie

Lange, Andreas

Baehr, Andrea

Kessler, Barbara

Kemter, Elisabeth

Klymiuk, Nikolai

Denner, Joachim (WE 5)

Godehardt, Antonia W.

Tönjes, Ralf R.

Hagl, Christian

Gebauer, Michaela

Binder, Uli

Skerra, Arne

Ayares, David

Wolf, Eckhard

Schmoeckel, Michael

Brenner, Paolo

Längin, Matthias

Abicht, Jan‐Michael

Quelle

Xenotransplantation : the official journal of the International Xenotransplantation Association, a section of The Transplantation Society

Bandzählung: 31

Heftzählung: 4

Seiten: e12877

ISSN: 1399-3089

Sprache

Englisch

Verweise

URL (Volltext): https://onlinelibrary.wiley.com/doi/10.1111/xen.12877

DOI: 10.1111/xen.12877

Pubmed: 39077824

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.