Prolonged Xeno-Kidney Graft Survival in Highly Allo-Sensitized Nonhuman Primate Using Triple-Knockout Donor Pigs with 7 Human Transgenes

M. Manook¹, D. Olaso¹, I. Anwar¹, J. Yoon¹, M. Song¹, A. B. Farris², K. Stiede³, K. Hall³, M. Youd³, S. Knechtle¹, J. Kwun¹

¹Surgery, Duke Transplant Center, Durham, NC, ²Pathology, Emory University, Atlanta, GA, ³eGenesis Inc, Cambridge, MA

Meeting: 2022 American Transplant Congress

Abstract number: 80

Keywords: Alloantibodies, HLA antibodies, Kidney transplantation, Xenoreactive antibodies

Topic: Basic Science » Basic Science » 13 - Xenotransplantation

Session Information

Session Name: Xenotransplantation

Session Type: Rapid Fire Oral Abstract

Date: Sunday, June 5, 2022

Session Time: 3:30pm-5:00pm

Presentation Time: 4:00pm-4:10pm

Location: Hynes Room 302

*Purpose: We have previously shown using porcine kidneys from genetically modified knockout alpha 1,3-galactosyltransferase (GGTA1KO) and human decay accelerating factor transgenic (CD55Tg) pigs that compared to naive recipients, xeno-kidney graft survival in highly allo-sensitized non-human primates is shorter. We sought to explore newly available porcine kidneys from triple-knockout (TKO) pigs with additional protective human transgenes in highly allo-sensitized recipients.

*Methods: Ten Rhesus Macaque were allo-sensitized with maximally MAMU-mismatched Rhesus donor skin grafts. Six to eight weeks after the second skin graft, porcine kidneys from TKO with 7 additional human gene pigs (EGEN-2734, provided by eGenesis; n=4) or GGKO/CD55Tg pigs (provided by National Swine Resource and Research Center; n=6) were transplanted into the allo-sensitized NHPs. The immunosuppression regimen consisted of rhesus anti-CD4 and anti-CD8 induction, and anti-CD154 mAb (5C8H1 clone), mycophenolate mofetil, and corticosteroids as maintenance therapy.

*Results: All animals tolerated xeno-kidney transplantation well with no cases of hyperacute rejection. Xeno-kidney graft survival was significantly prolonged with EGEN-2734 compared to GGKO/CD55Tg in highly sensitized recipients (MST = 61d vs. 24d; Figure A). Peak sCr levels by 1 month post-transplantation were significantly reduced (Figure B). AMR scores (g+ptc) and microvascular injury scores (cg+mm) were significantly reduced in EGEN-2734 kidneys at 1month post-transplantation (Figure C).

*Conclusions: Allo-sensitization leads to overall decreased graft survival and increased risk of xenograft loss due to AMR. Kidneys from TKO pigs expressing multiple human proteins prevented early onset of AMR and prolonged graft survival. Further studies in optimizing desensitization and maintenance immunosuppression therapies are warranted to further characterize the clinical utility of xenotransplantation in allosensitized recipients.

To cite this abstract in AMA style:

Manook M, Olaso D, Anwar I, Yoon J, Song M, Farris AB, Stiede K, Hall K, Youd M, Knechtle S, Kwun J. Prolonged Xeno-Kidney Graft Survival in Highly Allo-Sensitized Nonhuman Primate Using Triple-Knockout Donor Pigs with 7 Human Transgenes [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/prolonged-xeno-kidney-graft-survival-in-highly-allo-sensitized-nonhuman-primate-using-triple-knockout-donor-pigs-with-7-human-transgenes/. Accessed December 3, 2024.

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