BACKGROUND: The recent generation of alpha1,3-galactosyltransferase gene-knockout (GalT-KO) pigs has allowed investigation of the survival of GalT-KO pig organs in nonhuman primates. METHODS: Heterotopic heart transplantation from GalT-KO pigs was carried out in baboons (n=8) using a human antihuman CD154 monoclonal antibody-based immunosuppressive regimen. RESULTS: In six of the eight cases, graft survival extended to between approximately 2 and 6 months. All grafts developed thrombotic microangiopathy (TM). In particular, the clinical course of one baboon in which the graft functioned for 179 days is summarized. This baboon received aspirin (40 mg on alternate days) from day 4 in addition to heparin, which may have been a factor in the delay of onset and progression of TM and in prolonged graft survival. Maintenance therapy with anti-CD154 mAb, mycophenolate mofetil, and methylprednisolone was associated with persistently low numbers of CD3CD4 and CD3CD8 cells. Despite persisting depletion of these cells, no infectious complications occurred. CONCLUSIONS: It remains to be established whether TM is related to a very low level of natural preformed or T-cell-induced antibody deposition on the graft, inducing endothelial activation and injury, or to molecular incompatibilities in the coagulation mechanisms between pig and baboon, or to both. However, function of a pig organ in a baboon for a period approaching six months, which has not been reported previously, lends encouragement that the barriers to xenotransplantation will eventually be overcome.
BACKGROUND: The recent generation of alpha1,3-galactosyltransferase gene-knockout (GalT-KO) pigs has allowed investigation of the survival of GalT-KO pig organs in nonhuman primates. METHODS: Heterotopic heart transplantation from GalT-KO pigs was carried out in baboons (n=8) using a human antihuman CD154 monoclonal antibody-based immunosuppressive regimen. RESULTS: In six of the eight cases, graft survival extended to between approximately 2 and 6 months. All grafts developed thrombotic microangiopathy (TM). In particular, the clinical course of one baboon in which the graft functioned for 179 days is summarized. This baboon received aspirin (40 mg on alternate days) from day 4 in addition to heparin, which may have been a factor in the delay of onset and progression of TM and in prolonged graft survival. Maintenance therapy with anti-CD154 mAb, mycophenolate mofetil, and methylprednisolone was associated with persistently low numbers of CD3CD4 and CD3CD8 cells. Despite persisting depletion of these cells, no infectious complications occurred. CONCLUSIONS: It remains to be established whether TM is related to a very low level of natural preformed or T-cell-induced antibody deposition on the graft, inducing endothelial activation and injury, or to molecular incompatibilities in the coagulation mechanisms between pig and baboon, or to both. However, function of a pig organ in a baboon for a period approaching six months, which has not been reported previously, lends encouragement that the barriers to xenotransplantation will eventually be overcome.
Authors: Agnes M Azimzadeh; Sean S Kelishadi; Mohamed B Ezzelarab; Avneesh K Singh; Tiffany Stoddard; Hayato Iwase; Tianshu Zhang; Lars Burdorf; Evelyn Sievert; Chris Avon; Xiangfei Cheng; David Ayares; Keith A Horvath; Philip C Corcoran; Muhammad M Mohiuddin; Rolf N Barth; David K C Cooper; Richard N Pierson Journal: Xenotransplantation Date: 2015-07-14 Impact factor: 3.907
Authors: Bao-Ngoc H Nguyen; Agnes M Azimzadeh; Carsten Schroeder; Thomas Buddensick; Tianshu Zhang; Amal Laaris; Megan Cochrane; Henk-Jan Schuurman; David H Sachs; James S Allan; Richard N Pierson Journal: Xenotransplantation Date: 2011 Mar-Apr Impact factor: 3.907
Authors: Mohamed B Ezzelarab; Burcin Ekser; Gabriel Echeverri; Hidetaka Hara; Corin Ezzelarab; Cassandra Long; Pietro Bajona; Bertha Garcia; Noriko Murase; David Ayares; David K C Cooper Journal: Xenotransplantation Date: 2012 Jul-Aug Impact factor: 3.907
Authors: N Navarro-Alvarez; J A Shah; A Zhu; J Ligocka; H Yeh; N Elias; I Rosales; R Colvin; A B Cosimi; J F Markmann; M Hertl; D H Sachs; P A Vagefi Journal: Am J Transplant Date: 2016-02-05 Impact factor: 8.086