Kidney Xenotransplantation from Genetically Engineered Pigs to Baboons with FDA-Approved Immunosuppressive Therapy

T. Yamamoto¹, H. Hara¹, J. Foote¹, E. C. Klein², H. J. Schuurman³, L. Wang¹, Q. Li¹, H. Zhou¹, J. Li¹, J. A. Tector¹, Z. Zhang², M. Ezzelarab², R. Lovingood¹, D. Ayares⁴, D. E. Eckhoff¹, D. K. Cooper¹, H. Iwase¹

¹University of Alabama at Birmingham, Birmingham, AL, ²University of Pittsburgh, Pittsburgh, PA, ³Schubiomed Consultancy, Utrecht, Netherlands, ⁴Revivicor, Blacksburg, VA

Meeting: 2019 American Transplant Congress

Abstract number: 272

Keywords: Immunosuppression, Kidney transplantation, Pig, Xenoreactive antibodies

Session Information

Session Name: Concurrent Session: Xenotransplantation

Session Type: Concurrent Session

Date: Monday, June 3, 2019

Session Time: 2:30pm-4:00pm

Presentation Time: 3:30pm-3:42pm

Location: Room 310

*Purpose: Genetically-engineered pigs might present a solution to the critical shortage of organs for clinical transplantation. The aims of this study were to evaluate the efficacy of FDA-approved immunosuppressive agents in pig-to-baboon kidney xenotransplantation, and compare the results with those achieved using an anti-CD40mAb-based regimen.

*Methods: Ten kidney transplants were carried out in baboons using GTKO/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Immunosuppressive therapy consisted of induction with ATG and anti-CD20mAb, and maintenance with either (i) regimens using only FDA-approved drugs (tacrolimus + abatacept [CTLA4-Ig] or tacrolimus + rapamycin or mycophenolate mofetil) (GpA, n=5) or (ii) an anti-CD40 mAb + rapamycin regimen (GpB, n=5). (All 10 baboons received corticosteroids, IL-6R blockade [tocilizumab], and TNF-α blockade [etanercept].) Baboons were followed by clinical/laboratory monitoring of kidney function and coagulation/inflammatory/immune parameters. At euthanasia, morphologic and immunohistochemical studies were performed on the kidney grafts.

*Results: One GpB baboon was euthanized on day 4 for acute gastric dilatation, and was excluded from analysis. The mean survival in GpB (n=4) was 181+/-40.5 days (median 186 days), which was significantly longer than in GpA (15+/-5.0 days; median 13 days) (p<0.01). All GpA baboons were euthanized for antibody-mediated rejection, whereas 3 of 4 of GpB were euthanized for infectious complications. At euthanasia, the serum creatinine was not significantly different between the two groups (GpA 1.78+/-0.45 vs GpB 2.18+/-0.91mg/dl). Only GpA baboons developed features of consumptive coagulopathy. On histopathological examination of the grafts, the incidence of thrombotic microangiopathic glomerulopathy, glomerular/interstitial thrombi, arterial vasculitis, and peritubular capillary inflammation was significantly higher in GpA than in GpB (p<0.05). There was a significant negative correlation between all of the histopathological features of thrombotic microangiopathy and changes in coagulation parameters (platelet count and plasma fibrinogen).

*Conclusions: Our data suggest that regimens based on current FDA-approved immunosuppressive agents may be insufficient to prevent immune-mediated genetically-engineered pig kidney graft injury even when the grafts express a human coagulation-regulatory protein. However, analogues of anti-CD40 mAb (which achieved significantly longer survival) are currently in phase2 clinical trials.

To cite this abstract in AMA style:

Yamamoto T, Hara H, Foote J, Klein EC, Schuurman HJ, Wang L, Li Q, Zhou H, Li J, Tector JA, Zhang Z, Ezzelarab M, Lovingood R, Ayares D, Eckhoff DE, Cooper DK, Iwase H. Kidney Xenotransplantation from Genetically Engineered Pigs to Baboons with FDA-Approved Immunosuppressive Therapy [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/kidney-xenotransplantation-from-genetically-engineered-pigs-to-baboons-with-fda-approved-immunosuppressive-therapy/. Accessed November 22, 2024.

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