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Journal articles
Bortezomib, C1-Inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-Transgenic GalT-KO Pig Kidney Xenografts in Baboons
S. Le Bas-Bernardet
1, 2, 3, 4
X. Tillou
1, 2
J. Branchereau
1, 2
N. Dilek
1, 2, 5
N. Poirier
1, 2, 5
M. Châtelais
1, 2, 3, 4
B. Charreau
1, 2, 3, 4
D. Minault
1, 2
J. Hervouet
1, 2
K. Renaudin
6
C. Crossan
3, 4, 7
L. Scobie
3, 4, 7
Y. Takeuchi
4, 3, 8
M. Diswall
9
M. Breimer
9
N. Klar
4, 3, 10
M. Daha
3, 4, 10
P. Simioni
11
S. Robson
12
M. Nottle
13
E Salvaris
14
P Cowan
14
A d'Apice
14
D. Sachs
15
K. Yamada
15
I. Lagutina
16
R. Duchi
16
A. Perota
16
G. Lazzari
16
C. Galli
16, 17
E. Cozzi
3, 4
J.-P Soulillou
1, 2
B. Vanhove
1, 2, 5
Gilles Blancho
1, 2, *
*
Corresponding author
S. Le Bas-Bernardet 1, 2, 3, 4
Author
X. Tillou 1, 2
Author
J. Branchereau 1, 2
Author
N. Dilek 1, 2, 5
Author
N. Poirier 1, 2, 5
Author
M. Châtelais 1, 2, 3, 4
Author
B. Charreau 1, 2, 3, 4
Author
D. Minault 1, 2
Author
B. Vanhove 1, 2, 5
Author
Gilles Blancho 1, 2
Correspondent author
1
U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie (CHU Nantes - Hôtel Dieu - 30 Bd Jean Monnet 44093 Nantes Cedex 01. - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1064 (101, rue de Tolbiac, 75013 Paris - France)
- UFR MEDECINE - Université de Nantes - UFR de Médecine et des Techniques Médicales (1 rue Gaston Veil BP 53508 44035 NANTES Cedex 1 - France)
- UN - Université de Nantes (1, quai de Tourville - BP 13522 - 44035 Nantes cedex 1 - France)
2
ITUN - Institut de transplantation urologie-néphrologie (France)
- UN - Université de Nantes (1, quai de Tourville - BP 13522 - 44035 Nantes cedex 1 - France)
- CHU Nantes - Centre hospitalier universitaire de Nantes (1 Place Alexis-Ricordeau, 44000 Nantes - France)
4
CORIT - Consortium for Research in Organ Transplantation [Padua, Italy] (Padua - Italy)
5
Effimune SAS [Nantes] (France)
6
Département de Pathologie [CHU Nantes] (France)
- CHU Nantes - Centre hospitalier universitaire de Nantes (1 Place Alexis-Ricordeau, 44000 Nantes - France)
7
Department of Biological & Biomedical Sciences [Glasgow, UK] (United Kingdom)
- GCU - Glasgow Caledonian University (Cowcaddens Road Glasgow G4 0BA Scotland, UK - United Kingdom)
8
UCL - University College of London [London] (Gower Street, London WC1E 6BT - United Kingdom)
9
Institute of Clinical Sciences - Department of Surgery [Gothenburg, Sweden] (Sweden)
- Sahlgrenska Academy at University of Gothenburg [Göteborg] (Box 430, SE-40530 Göteborg - Sweden)
10
Department of Nephrology [Leiden, The Netherlands] (Netherlands)
- Leiden University Medical Center (LUMC) (Netherlands)
11
Department of Cardiologic, Thoracic and Vascular Sciences [Padua, Italy] (Italy)
- University of Padua [Italy] (Italy)
12
Department of Medicine [Boston, MA, USA] (330 Brookline Ave Boston, MA 02215 - United States)
- BIDMC - Beth Israel Deaconess Medical Center [Boston] (330 Brookline Avenue,
Boston, MA 02215 - United States)
- HMS - Harvard Medical School [Boston] (25 Shattuck Street Boston, MA 02115 - United States)
13
School of Paediatrics and Reproductive Health [Adelaide, Australia] (Adelaide, SA 5006 - Australia)
- University of Adelaide (Adelaide, South Australia, 5005 Australia - Australia)
- Robinson Research Institute (Ground Floor, Norwich Centre
55 King William Road
North Adelaide SA 5006 - Australia)
- University of Adelaide (Adelaide, South Australia, 5005 Australia - Australia)
14
Immunology Research Centre [Melbourne, VIC, Australia] (41 Victoria Parade, Fitzroy VIC 3065. - Australia)
- St Vincent's Hospital Melbourne [Australia] (41 Victoria Parade, Fitzroy VIC 3065. - Australia)
15
Transplantation Biology Research Center [Boston, MA, USA] (Massachusetts General Hospital, Boston, MA, USA - United States)
- HMS - Harvard Medical School [Boston] (25 Shattuck Street Boston, MA 02115 - United States)
- Massachusetts General Hospital [Boston] (55 Fruit Street Boston, MA 02114 - United States)
16
Avantea [Cremona, Italy] (Italy)
17
Department of Veterinary Medical Science [Ozzano Emilia, Italy] (Italy)
- University of Bologna (Via Zamboni, 33 - 40126 Bologna - Italy)
Abstract : Galactosyl-transferase knockout (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 Inhibitor combined with cyclophosphamide or bortezomib with or without 2–3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 to 15 with signs of acute humoral rejection, in contrast to untreated controls (n=2) which lost their grafts on day 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of PERV transmission but some showed evidence of PCMV replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection.
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https://www.hal.inserm.fr/inserm-02148475
Contributor : Sylvie Le Bihan <>
Submitted on : Wednesday, June 5, 2019 - 3:12:10 PM
Last modification on : Wednesday, November 25, 2020 - 5:14:02 PM
Contributor : Sylvie Le Bihan <>
Submitted on : Wednesday, June 5, 2019 - 3:12:10 PM
Last modification on : Wednesday, November 25, 2020 - 5:14:02 PM
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Identifiers
- HAL Id : inserm-02148475, version 1
- DOI : 10.1111/ajt.12988
- PUBMED : 25612490
- PUBMEDCENTRAL : PMC4306235
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Citation
S. Le Bas-Bernardet, X. Tillou, J. Branchereau, N. Dilek, N. Poirier, et al.. Bortezomib, C1-Inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-Transgenic GalT-KO Pig Kidney Xenografts in Baboons. American Journal of Transplantation, Wiley, 2015, 15 (2), pp.358-370. ⟨10.1111/ajt.12988⟩. ⟨inserm-02148475⟩
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