title: Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons.
abstract: Galactosyl-transferase KO (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 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 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 porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (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.
authors.affiliation: Institut de Transplantation- Urologie- Néphrologie (ITUN), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 1064, Centre Hospitalier Universitaire (CHU) de Nantes, Université de Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.forename: X
authors.initials: X
authors.lastname: Tillou
authors.forename: J
authors.initials: J
authors.lastname: Branchereau
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authors.lastname: Dilek
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authors.lastname: Poirier
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authors.lastname: Châtelais
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authors.lastname: Charreau
authors.forename: D
authors.initials: D
authors.lastname: Minault
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authors.lastname: Hervouet
authors.forename: K
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authors.lastname: Renaudin
authors.forename: C
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authors.lastname: Crossan
authors.forename: L
authors.initials: L
authors.lastname: Scobie
authors.forename: Y
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: M
authors.initials: M
authors.lastname: Diswall
authors.forename: M E
authors.initials: ME
authors.lastname: Breimer
authors.forename: N
authors.initials: N
authors.lastname: Klar
authors.forename: M R
authors.initials: MR
authors.lastname: Daha
authors.forename: P
authors.initials: P
authors.lastname: Simioni
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
authors.forename: M B
authors.initials: MB
authors.lastname: Nottle
authors.forename: E J
authors.initials: EJ
authors.lastname: Salvaris
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: A J F
authors.initials: AJ
authors.lastname: d'Apice
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: I
authors.initials: I
authors.lastname: Lagutina
authors.forename: R
authors.initials: R
authors.lastname: Duchi
authors.forename: A
authors.initials: A
authors.lastname: Perota
authors.forename: G
authors.initials: G
authors.lastname: Lazzari
authors.forename: C
authors.initials: C
authors.lastname: Galli
authors.forename: E
authors.initials: E
authors.lastname: Cozzi
authors.forename: J-P
authors.initials: JP
authors.lastname: Soulillou
authors.forename: B
authors.initials: B
authors.lastname: Vanhove
authors.forename: G
authors.initials: G
authors.lastname: Blancho
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001327:Autoimmune Diseases; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D050718:Complement C1 Inhibitor Protein / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000502:physiology; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics*; D055786:Gene Knockout Techniques; D006085:Graft Survival / Q000502:physiology*; D064593:Heterografts; D007113:Immunity, Innate / Q000502:physiology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000601:surgery / Q000821:virology; D016030:Kidney Transplantation; D023421:Models, Animal; D048530:Papio anubis; D010951:Plasma Exchange; D011719:Pyrazines / Q000627:therapeutic use*; D034421:Sus scrofa; D014779:Virus Replication / Q000502:physiology
chemical_list: D001897:Boronic Acids; D050718:Complement C1 Inhibitor Protein; D007166:Immunosuppressive Agents; D011719:Pyrazines; D000069286:Bortezomib; D005700:Galactosyltransferases
keywords: Animal models: nonhuman primate; basic (laboratory) research/science; genetics; immunosuppression/immune modulation; immunosuppressive regimens; kidney transplantation/nephrology; plasmapheresis/plasma exchange; translational research/science; xenoantibody; xenotransplantation