Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens

Hayato Iwase, Burcin Ekser, Vikas Satyananda, Jay Bhama, Hidetaka Hara, Mohamed Ezzelarab, Edwin Klein, Robert Wagner, Cassandra Long, Jnanesh Thacker, Jiang Li, Hao Zhou, Maolin Jiang, Santosh Nagaraju, Huidong Zhou, Massimiliano Veroux, Pietro Bajona, Martin Wijkstrom, Yi Wang, Carol PhelpsNikolai Klymiuk, Eckhard Wolf, David Ayares, David K C Cooper

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. Methods All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n = 4) expressed additional CD55, and those into Group B (n = 3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n = 2) or abatacept (Regimen 2: n = 2) or anti-CD40mAb+belatacept (Regimen 3: n = 2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. Results Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. Conclusions The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

Original languageEnglish (US)
Pages (from-to)211-220
Number of pages10
JournalXenotransplantation
Volume22
Issue number3
DOIs
StatePublished - May 1 2015

Fingerprint

Heterotopic Transplantation
Papio
Heart Transplantation
Swine
Thrombotic Microangiopathies
Thrombocytopenia
Galactosyltransferases
T-Lymphocytes
Transplants
Immunologic Monitoring
Thrombomodulin
Gene Knockout Techniques
Antilymphocyte Serum
Euthanasia
human THBD protein
Abatacept
Immunosuppression
Fibrinogen
Cicatrix
Heparin

Keywords

  • baboon
  • complement-regulatory proteins
  • costimulation blockade
  • heart
  • pig
  • thrombomodulin
  • thrombotic microangiopathy
  • xenotransplantation
  • α1,3-galactosyltransferase gene-knockout

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. / Iwase, Hayato; Ekser, Burcin; Satyananda, Vikas; Bhama, Jay; Hara, Hidetaka; Ezzelarab, Mohamed; Klein, Edwin; Wagner, Robert; Long, Cassandra; Thacker, Jnanesh; Li, Jiang; Zhou, Hao; Jiang, Maolin; Nagaraju, Santosh; Zhou, Huidong; Veroux, Massimiliano; Bajona, Pietro; Wijkstrom, Martin; Wang, Yi; Phelps, Carol; Klymiuk, Nikolai; Wolf, Eckhard; Ayares, David; Cooper, David K C.

In: Xenotransplantation, Vol. 22, No. 3, 01.05.2015, p. 211-220.

Research output: Contribution to journalArticle

Iwase, H, Ekser, B, Satyananda, V, Bhama, J, Hara, H, Ezzelarab, M, Klein, E, Wagner, R, Long, C, Thacker, J, Li, J, Zhou, H, Jiang, M, Nagaraju, S, Zhou, H, Veroux, M, Bajona, P, Wijkstrom, M, Wang, Y, Phelps, C, Klymiuk, N, Wolf, E, Ayares, D & Cooper, DKC 2015, 'Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens', Xenotransplantation, vol. 22, no. 3, pp. 211-220. https://doi.org/10.1111/xen.12167
Iwase, Hayato ; Ekser, Burcin ; Satyananda, Vikas ; Bhama, Jay ; Hara, Hidetaka ; Ezzelarab, Mohamed ; Klein, Edwin ; Wagner, Robert ; Long, Cassandra ; Thacker, Jnanesh ; Li, Jiang ; Zhou, Hao ; Jiang, Maolin ; Nagaraju, Santosh ; Zhou, Huidong ; Veroux, Massimiliano ; Bajona, Pietro ; Wijkstrom, Martin ; Wang, Yi ; Phelps, Carol ; Klymiuk, Nikolai ; Wolf, Eckhard ; Ayares, David ; Cooper, David K C. / Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. In: Xenotransplantation. 2015 ; Vol. 22, No. 3. pp. 211-220.
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T1 - Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens

AU - Iwase, Hayato

AU - Ekser, Burcin

AU - Satyananda, Vikas

AU - Bhama, Jay

AU - Hara, Hidetaka

AU - Ezzelarab, Mohamed

AU - Klein, Edwin

AU - Wagner, Robert

AU - Long, Cassandra

AU - Thacker, Jnanesh

AU - Li, Jiang

AU - Zhou, Hao

AU - Jiang, Maolin

AU - Nagaraju, Santosh

AU - Zhou, Huidong

AU - Veroux, Massimiliano

AU - Bajona, Pietro

AU - Wijkstrom, Martin

AU - Wang, Yi

AU - Phelps, Carol

AU - Klymiuk, Nikolai

AU - Wolf, Eckhard

AU - Ayares, David

AU - Cooper, David K C

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Background Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. Methods All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n = 4) expressed additional CD55, and those into Group B (n = 3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n = 2) or abatacept (Regimen 2: n = 2) or anti-CD40mAb+belatacept (Regimen 3: n = 2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. Results Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. Conclusions The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

AB - Background Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. Methods All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n = 4) expressed additional CD55, and those into Group B (n = 3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n = 2) or abatacept (Regimen 2: n = 2) or anti-CD40mAb+belatacept (Regimen 3: n = 2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. Results Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. Conclusions The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

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