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; X. Tillou; J.  Branchereau; N.  Dilek; N.  Poirier; M. Chatelais; B. Charreau; D. Minault; J. Hervouet; K. Renaudin; C. Crossan; L. Scobie; Y. Takeuchi; M. Diswall; M.E. Breimer; N. Klar; M.R. Daha; P.  Simioni; S.C.  Robson; M.B.  Nottle; E.J.  Salvaris; P.J.  Cowan; A.J.F.  d'Apice; D.H.  Sachs; K.  Yamada; I.  Lagutina; R.  Duchi; A.  Perota; G.  Lazzari; C.  Galli; E.  Cozzi; J.‐P.  Soulillou; B. Vanhove; G.  Blancho

doi:10.1111/ajt.12988

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, X. Tillou, J. Branchereau, N. Dilek, N. Poirier, M. Chatelais, B. Charreau, D. Minault, J. Hervouet, K. Renaudin, C. Crossan, L. Scobie, Y. Takeuchi, M. Diswall, M.E. Breimer, N. Klar, M.R. Daha, P. Simioni, S.C. Robson, M.B. NottleE.J. Salvaris, P.J. Cowan, A.J.F. d'Apice, D.H. Sachs, K. Yamada, I. Lagutina, R. Duchi, A. Perota, G. Lazzari, C. Galli, E. Cozzi, J.‐P. Soulillou, B. Vanhove, G. Blancho

Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	358–370
Number of pages	13
Journal	American Journal of Transplantation
Volume	15
Issue number	2
Early online date	22 Jan 2015
DOIs	https://doi.org/10.1111/ajt.12988
Publication status	Published - Feb 2015

Keywords

xenotransplantation
immunosuppression
xenografts
genetics

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10.1111/ajt.12988

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Le Bas-Bernardet, S., Tillou, X., Branchereau, J., Dilek, N., Poirier, N., Chatelais, M., Charreau, B., Minault, D., Hervouet, J., Renaudin, K., Crossan, C., Scobie, L., Takeuchi, Y., Diswall, M., Breimer, M. E., Klar, N., Daha, M. R., Simioni, P., Robson, S. C., ... Blancho, G. (2015). 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, 15(2), 358–370. https://doi.org/10.1111/ajt.12988

Le Bas-Bernardet, S. ; Tillou, X. ; Branchereau, J. ; Dilek, N. ; Poirier, N. ; Chatelais, M. ; Charreau, B. ; Minault, D. ; Hervouet, J. ; Renaudin, K. ; Crossan, C. ; Scobie, L. ; Takeuchi, Y. ; Diswall, M. ; Breimer, M.E. ; Klar, N. ; Daha, M.R. ; Simioni, P. ; Robson, S.C. ; Nottle, M.B. ; Salvaris, E.J. ; Cowan, P.J. ; d'Apice, A.J.F. ; Sachs, D.H. ; Yamada, K. ; Lagutina, I. ; Duchi, R. ; Perota, A. ; Lazzari, G. ; Galli, C. ; Cozzi, E. ; Soulillou, J.‐P. ; Vanhove, B. ; Blancho, G. . / Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons. In: American Journal of Transplantation. 2015 ; Vol. 15, No. 2. pp. 358–370.

@article{83fed59b7ac6427faf193f7b1cde81f8,

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. ",

keywords = "xenotransplantation, immunosuppression, xenografts, genetics",

author = "{Le Bas-Bernardet}, S. and X. Tillou and J. Branchereau and N. Dilek and N. Poirier and M. Chatelais and B. Charreau and D. Minault and J. Hervouet and K. Renaudin and C. Crossan and L. Scobie and Y. Takeuchi and M. Diswall and M.E. Breimer and N. Klar and M.R. Daha and P. Simioni and S.C. Robson and M.B. Nottle and E.J. Salvaris and P.J. Cowan and A.J.F. d'Apice and D.H. Sachs and K. Yamada and I. Lagutina and R. Duchi and A. Perota and G. Lazzari and C. Galli and E. Cozzi and J.‐P. Soulillou and B. Vanhove and G. Blancho",

year = "2015",

month = feb,

doi = "10.1111/ajt.12988",

language = "English",

volume = "15",

pages = "358–370",

journal = "American Journal of Transplantation",

issn = "1600-6135",

publisher = "John Wiley & Sons ",

number = "2",

}

Le Bas-Bernardet, S, Tillou, X, Branchereau, J, Dilek, N, Poirier, N, Chatelais, M, Charreau, B, Minault, D, Hervouet, J, Renaudin, K, Crossan, C , Scobie, L, Takeuchi, Y, Diswall, M, Breimer, ME, Klar, N, Daha, MR, Simioni, P, Robson, SC, Nottle, MB, Salvaris, EJ, Cowan, PJ, d'Apice, AJF, Sachs, DH, Yamada, K, Lagutina, I, Duchi, R, Perota, A, Lazzari, G, Galli, C, Cozzi, E, Soulillou, JP, Vanhove, B & Blancho, G 2015, '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, vol. 15, no. 2, pp. 358–370. https://doi.org/10.1111/ajt.12988

Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons. / Le Bas-Bernardet, S.; Tillou, X.; Branchereau, J. ; Dilek, N. ; Poirier, N. ; Chatelais, M.; Charreau, B.; Minault, D.; Hervouet, J.; Renaudin, K.; Crossan, C.; Scobie, L.; Takeuchi, Y.; Diswall, M.; Breimer, M.E.; Klar, N.; Daha, M.R.; Simioni, P. ; Robson, S.C. ; Nottle, M.B. ; Salvaris, E.J. ; Cowan, P.J. ; d'Apice, A.J.F. ; Sachs, D.H. ; Yamada, K. ; Lagutina, I. ; Duchi, R. ; Perota, A. ; Lazzari, G. ; Galli, C. ; Cozzi, E. ; Soulillou, J.‐P. ; Vanhove, B.; Blancho, G. .

In: American Journal of Transplantation, Vol. 15, No. 2, 02.2015, p. 358–370.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons

AU - Le Bas-Bernardet, S.

AU - Tillou, X.

AU - Branchereau, J.

AU - Dilek, N.

AU - Poirier, N.

AU - Chatelais, M.

AU - Charreau, B.

AU - Minault, D.

AU - Hervouet, J.

AU - Renaudin, K.

AU - Crossan, C.

AU - Scobie, L.

AU - Takeuchi, Y.

AU - Diswall, M.

AU - Breimer, M.E.

AU - Klar, N.

AU - Daha, M.R.

AU - Simioni, P.

AU - Robson, S.C.

AU - Nottle, M.B.

AU - Salvaris, E.J.

AU - Cowan, P.J.

AU - d'Apice, A.J.F.

AU - Sachs, D.H.

AU - Yamada, K.

AU - Lagutina, I.

AU - Duchi, R.

AU - Perota, A.

AU - Lazzari, G.

AU - Galli, C.

AU - Cozzi, E.

AU - Soulillou, J.‐P.

AU - Vanhove, B.

AU - Blancho, G.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - xenotransplantation

KW - immunosuppression

KW - xenografts

KW - genetics

U2 - 10.1111/ajt.12988

DO - 10.1111/ajt.12988

M3 - Article

VL - 15

SP - 358

EP - 370

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 2

ER -