Takayuki Yamamoto1, Hidetaka Hara1, Jeremy Foote2, Liaoran Wang1,3, Qi Li1,3, Edwin C Klein4, Hendrik Jan Schuurman5, Hongmin Zhou1,6, Juan Li1,3, A Joseph Tector1, Zhongqiang Zhang7,8, Mohamed Ezzelarab7, Ray Lovingood9, David Ayares10, Devin E Eckhoff1, David K C Cooper1, Hayato Iwase1. 1. Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL. 2. Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL. 3. Second Affiliated Hospital, University of South China, Hengyang City, Hunan, China. 4. Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA. 5. Schubiomed Consultancy, Utrecht, The Netherlands. 6. Department of Cardiothoracic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 7. Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA. 8. Department of General Surgery and Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. 9. Kirklin Clinic Pharmacy, University of Alabama at Birmingham, Birmingham, AL. 10. Revivicor, Blacksburg, VA.
Abstract
BACKGROUND: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. METHODS: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. RESULTS: The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. CONCLUSIONS: Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.
BACKGROUND: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. METHODS: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. RESULTS: The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. CONCLUSIONS: Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pigkidney graft failure.
Authors: David K C Cooper; Jeremy B Foote; Mariyam Javed; Huy Q Nguyen; Mohamed H Bikhet; Christophe Hansen-Estruch; David Ayares; Hidetaka Hara Journal: Xenotransplantation Date: 2021-11-30 Impact factor: 3.907
Authors: Jeremy B Foote; Abhijit Jagdale; Takayuki Yamamoto; Hidetaka Hara; Mohamed H Bikhet; Henk-Jan Schuurman; Huy Q Nguyen; Mohamed Ezzelarab; David Ayares; Douglas J Anderson; Huma Fatima; Devin E Eckhoff; David K C Cooper; Hayato Iwase Journal: Xenotransplantation Date: 2021-10-13 Impact factor: 3.788
Authors: Abhijit Jagdale; Huy Nguyen; Hayato Iwase; Jeremy B Foote; Takayuki Yamamoto; Mariyam Javed; David Ayares; Douglas J Anderson; Devin E Eckhoff; David K C Cooper; Hidetaka Hara Journal: Transpl Immunol Date: 2022-01-31 Impact factor: 2.032
Authors: Guoqiang Zhang; Hayato Iwase; Qi Li; Takayuki Yamamoto; Abhijit Jagdale; Mohamed B Ezzelarab; David Ayares; David K C Cooper; Hidetaka Hara; Gangcheng Wang Journal: Front Immunol Date: 2021-12-08 Impact factor: 7.561
Authors: Mohamed H Bikhet; Christophe Hansen-Estruch; Mariyam Javed; Dalis E Collins; Jeremy B Foote; David Ayares; Hidetaka Hara; David K C Cooper Journal: Immun Inflamm Dis Date: 2022-01-20