Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs.
Animals
Animals, Genetically Modified
Gene Knockout Techniques
Graft Rejection
/ genetics
Graft Survival
/ genetics
Heart Transplantation
/ methods
Heterografts
/ immunology
Immunosuppression Therapy
/ methods
Immunosuppressive Agents
/ pharmacology
Swine
Thrombomodulin
/ immunology
Transplantation, Heterologous
/ methods
Journal
Xenotransplantation
ISSN: 1399-3089
Titre abrégé: Xenotransplantation
Pays: Denmark
ID NLM: 9438793
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
05
12
2017
revised:
20
07
2018
accepted:
10
09
2018
pubmed:
6
10
2018
medline:
27
12
2019
entrez:
6
10
2018
Statut:
ppublish
Résumé
A combination of genetic manipulations of donor organs and target-specific immunosuppression is instrumental in achieving long-term cardiac xenograft survival. Recently, results from our preclinical pig-to-baboon heterotopic cardiac xenotransplantation model suggest that a three-pronged approach is successful in extending xenograft survival: (a) α-1,3-galactosyl transferase (Gal) gene knockout in donor pigs (GTKO) to prevent Gal-specific antibody-mediated rejection; (b) transgenic expression of human complement regulatory proteins (hCRP; hCD46) and human thromboregulatory protein thrombomodulin (hTBM) to avoid complement activation and coagulation dysregulation; and (c) effective induction and maintenance of immunomodulation, particularly through co-stimulation blockade of CD40-CD40L pathways with anti-CD40 (2C10R4) monoclonal antibody (mAb). Using this combination of manipulations, we reported significant improvement in cardiac xenograft survival. In this study, we are reporting the survival of cardiac xenotransplantation recipients (n = 3) receiving xenografts from pigs without the expression of hTBM (GTKO.CD46). We observed that all grafts underwent rejection at an early time point (median 70 days) despite utilization of our previously reported successful immunosuppression regimen and effective control of non-Gal antibody response. These results support our hypothesis that transgenic expression of human thrombomodulin in donor pigs confers an independent protective effect for xenograft survival in the setting of a co-stimulation blockade-based immunomodulatory regimen.
Identifiants
pubmed: 30290025
doi: 10.1111/xen.12465
pmc: PMC6450784
mid: NIHMS989381
doi:
Substances chimiques
Immunosuppressive Agents
0
Thrombomodulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12465Subventions
Organisme : NIAID NIH HHS
ID : U19 AI090959
Pays : United States
Informations de copyright
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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