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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
1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
2 ITUN - Institut de transplantation urologie-néphrologie
3 Transplant Immunology Unit [Padua, Italy]
4 CORIT - Consortium for Research in Organ Transplantation [Padua, Italy]
5 Effimune SAS [Nantes]
6 Département de Pathologie [CHU Nantes]
7 Department of Biological & Biomedical Sciences [Glasgow, UK]
8 UCL - University College of London [London]
9 Institute of Clinical Sciences - Department of Surgery [Gothenburg, Sweden]
10 Department of Nephrology [Leiden, The Netherlands]
11 Department of Cardiologic, Thoracic and Vascular Sciences [Padua, Italy]
12 Department of Medicine [Boston, MA, USA]
13 School of Paediatrics and Reproductive Health [Adelaide, Australia]
14 Immunology Research Centre [Melbourne, VIC, Australia]
15 Transplantation Biology Research Center [Boston, MA, USA]
16 Avantea [Cremona, Italy]
17 Department of Veterinary Medical Science [Ozzano Emilia, 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.
Keywords : xenoantibody xenotransplantation translational research/science Animal models: nonhuman primate basic (laboratory) research/science genetics immunosuppression/immune modulation immunosuppressive regimens kidney transplantation/nephrology plasmapheresis/plasma exchange
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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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