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

Autor: Mohamed Ezzelarab, Burcin Ekser, Hidetaka Hara, David Ayares, Edwin Klein, Cassandra Long, Martin Wijkstrom, Yi Wang, David K. C. Cooper, Maolin Jiang, Hayato Iwase, Eckhard Wolf, Pietro Bajona, Massimiliano Veroux, Robert Wagner, Huidong Zhou, Vikas Satyananda, Nikolai Klymiuk, Jiang Li, Santosh Nagaraju, Carol Phelps, Jay K. Bhama, J. Thacker, Hao Zhou
Rok vydání: 2015
Předmět:
Graft Rejection
Thrombotic microangiopathy
Swine
Thrombomodulin
medicine.medical_treatment
Xenotransplantation
Transplantation
Heterologous
Immunology
chemical and pharmacologic phenomena
Belatacept
Article
baboon – complement-regulatory proteins – costimulation blockade – heart – pig – thrombomodulin – thrombotic microangiopathy – xenotransplantation – a1
3-galactosyltransferase gene-knockout
Animals
Genetically Modified
3-galactosyltransferase gene-knockout
biology.animal
baboon – complement-regulatory proteins – costimulation blockade – heart – pig – thrombomodulin – thrombotic microangiopathy – xenotransplantation – a1
medicine
Animals
Humans
Heart transplantation
Transplantation
biology
Abatacept
Graft Survival
Heart
medicine.disease
Heart Transplantation
Immunosuppressive Agents
Papio
medicine.drug
Baboon
Zdroj: Xenotransplantation. 22:211-220
ISSN: 0908-665X
Popis: 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.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.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 for4 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.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.
Databáze: OpenAIRE
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