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Heterotopic thoracic cardiac pig‐to‐baboon xenotransplantation

Heterotopic thoracic cardiac pig‐to‐baboon xenotransplantation The heterotopic thoracic cardiac transplantation model combines the benefit of examining the immunological responses to the xenograft under a working heart condition with the recipient heart as a back up. We performed the world‐wide first heterotopic thoracic cardiac xenotransplantations in a pig‐to‐baboon model. In a series of 10 animals we tested the feasibility of different immunmodulatory strategies. Double‐ or triple‐transgenic pig hearts (GalT‐KO/hCD46/±hTM) were used as donors. Heterotopic thoracic heart transplantation was performed according to the technique of Barnard and Losman. Basic immunosuppression consisted of Tacrolimus (target blood level 20–30 ng/ml), Mycophenolate (target blood level 2–3 μg/ml) and tapering steroids (beginning with 10 mg/kg, over eight days decreasing to a maintainance dose of 0.3 mg/kg), starting at the day of transplantation. Rituximab (375 mg/m 2 ) was administered 4 and 2 weeks before transplantation. Antithymocyte globulin (1.5 mg/kg/24 h) induction therapy was applied during the first postoperative days. An average of 19 immunoadsorption cycles was performed twice, two days pre‐transplant and on operative day. By doing so, the total plasma concentration of IgG antibodies were reduced by approximately 80% in the recipients. Human anti‐CMV‐IgG (150 mg/kg) was given immediately after each immunoadsorption in order to supply IgG and avoid a rebound. In case of rejection, high dose steroids (10 mg/kg), antityhmocyte globulin (1.5 mg/kg/24 h) or Bortezomib (0.03 mg/kg) were administered in combination with repeated immunoadsorption. Overall survival was 14 ± 4.6 days. Four animals died during the perioperative course because of technical mishaps, like cerebral air embolism, congenital aortic insufficiency and global hypoxia (n=2). Excluding these baboons, the mean survival time was 22 ± 5.7 days (maximum survival of 50 days) [1]; main reasons were treatment resistant acute humoral xenograft rejection (n=3) and overtreatment (n=3). Heterotopic thoracic heart transplantation seems to be feasible and combines the benefit of a working heart model with the safety of heterotopic transplantation in case of rejection. However, delayed humoral xenograft rejection is the next barrier before initiating a clinical trial. Reference 1. B auer A , P ostrach J , T hormann Met al. First experience with heterotopic thoracic pig‐to‐baboon cardiac xenotransplantation. Xenotransplantation 2010; 17: 243–249. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

Heterotopic thoracic cardiac pig‐to‐baboon xenotransplantation

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Publisher
Wiley
Copyright
© 2012 John Wiley & Sons A/S
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1111/j.1399-3089.2011.00680_8.x
Publisher site
See Article on Publisher Site

Abstract

The heterotopic thoracic cardiac transplantation model combines the benefit of examining the immunological responses to the xenograft under a working heart condition with the recipient heart as a back up. We performed the world‐wide first heterotopic thoracic cardiac xenotransplantations in a pig‐to‐baboon model. In a series of 10 animals we tested the feasibility of different immunmodulatory strategies. Double‐ or triple‐transgenic pig hearts (GalT‐KO/hCD46/±hTM) were used as donors. Heterotopic thoracic heart transplantation was performed according to the technique of Barnard and Losman. Basic immunosuppression consisted of Tacrolimus (target blood level 20–30 ng/ml), Mycophenolate (target blood level 2–3 μg/ml) and tapering steroids (beginning with 10 mg/kg, over eight days decreasing to a maintainance dose of 0.3 mg/kg), starting at the day of transplantation. Rituximab (375 mg/m 2 ) was administered 4 and 2 weeks before transplantation. Antithymocyte globulin (1.5 mg/kg/24 h) induction therapy was applied during the first postoperative days. An average of 19 immunoadsorption cycles was performed twice, two days pre‐transplant and on operative day. By doing so, the total plasma concentration of IgG antibodies were reduced by approximately 80% in the recipients. Human anti‐CMV‐IgG (150 mg/kg) was given immediately after each immunoadsorption in order to supply IgG and avoid a rebound. In case of rejection, high dose steroids (10 mg/kg), antityhmocyte globulin (1.5 mg/kg/24 h) or Bortezomib (0.03 mg/kg) were administered in combination with repeated immunoadsorption. Overall survival was 14 ± 4.6 days. Four animals died during the perioperative course because of technical mishaps, like cerebral air embolism, congenital aortic insufficiency and global hypoxia (n=2). Excluding these baboons, the mean survival time was 22 ± 5.7 days (maximum survival of 50 days) [1]; main reasons were treatment resistant acute humoral xenograft rejection (n=3) and overtreatment (n=3). Heterotopic thoracic heart transplantation seems to be feasible and combines the benefit of a working heart model with the safety of heterotopic transplantation in case of rejection. However, delayed humoral xenograft rejection is the next barrier before initiating a clinical trial. Reference 1. B auer A , P ostrach J , T hormann Met al. First experience with heterotopic thoracic pig‐to‐baboon cardiac xenotransplantation. Xenotransplantation 2010; 17: 243–249.

Journal

Xenotransplantation – Wiley

Published: Jan 1, 2012

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