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Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons

A Comparison of Two Immunosuppressive Regimens

Yamamoto, Takayuki MD, PhD1; Hara, Hidetaka MD, PhD1; Foote, Jeremy DVM, PhD2; Wang, Liaoran MD1,3; Li, Qi1,3; Klein, Edwin C. DVM, PhD4; Schuurman, Hendrik Jan PhD5; Zhou, Hongmin MD1,6; Li, Juan1,3; Tector, A. Joseph MD, PhD1; Zhang, Zhongqiang MD, PhD7,8; Ezzelarab, Mohamed MD, PhD7; Lovingood, Ray Pharm D9; Ayares, David PhD10; Eckhoff, Devin E. MD1; Cooper, David K.C. MD, PhD1; Iwase, Hayato MD, PhD1

doi: 10.1097/TP.0000000000002796
Original Basic Science–General
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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.

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.

Received 25 January 2019. Revision received 19 April 2019.

Accepted 23 April 2019.

T.Y., H.H., D.K.C.C., and H.I. designed the research. T.Y., D.K.C.C., and H.I. wrote the article. T.Y., H.H., J.F., L.W., Q.L., E.C.K., H.J.S., H.Z., J.L., A.J.T., Z.Z., M.E., R.L., D.A., D.E.E., D.K.C.C., and H.I. performed the research. T.Y. and J.F. participated in the data analysis.

D.A. is an employee of Revivicor, Blacksburg, VA. H.J.S. is director of SchuBiomed Consultancy, Utrecht, The Netherlands, and provides consultancy in the biomedical sector worldwide. The other authors declare no conflicts of interest.

T.Y. has been supported in part by the Uehara Memorial Foundation in Japan. Work on xenotransplantation at the University of Alabama at Birmingham is supported in part by NIH NIAID U19 grant AI090959. Anti-CD40 2C10R4 used in these studies was provided by the NIH NHP Reagent Resource funded by NIH grants AI126683 and OD010976.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Hayato Iwase MD, PhD, Xenotransplantation Program, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL 35233. (hiwase@uabmc.edu).

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