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Duke University School of Medicine

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Sci. Transl. Med., Jun 12 2024, 16 (751) | https://doi.org/10.1126/scitranslmed.adk6152 Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig

Miriam Manook^1†‡, Danae Olaso^1†, Imran Anwar¹, Isabel DeLaura¹, Janghoon Yoon¹, Yeeun Bae¹, Andrew Barbas¹, Brian Shaw¹, Dimitrios Moris¹, Mingqing Song¹, Alton B. Farris², Kathryn Stiede³, Michele Youd^3§, Stuart Knechtle^1*, Jean Kwun^1*

¹Duke Transplant center, Duke University School of Medicine, durham, NC 27710, USA..

²Department of Pathology, Emory University School of Medicine, atlanta, GA 30322, USA..

³eGenesis Inc, Cambridge, MA 02140, USA..

^*Corresponding authors: Jean Kwun, Stuart Knechtle

^†These author contributed equally to this work.

^‡Present address: Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.

^§Present address: Zenas BioPharma, Waltham, Ma 02451, USA.

Abstract

Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney from GGTA1 (α1,3-galactosyltransferase) knockout pigs expressing the human CD55 transgene (1KO.1TG) and were maintained on an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen. These recipients developed de novo xenoreactive antibodies and experienced xenograft rejection with evidence of thrombotic microangiopathy and antibody-mediated rejection (AMR). In comparison, three highly allosensitized rhesus macaques receiving a kidney from GGTA1, CMAH (cytidine monophospho- N-acetylneuraminic acid hydroxylase), and b4GNT2/ b4GALNT2 (β-1,4- N-acetyl-galactosaminyltransferase 2) knockout pigs expressing seven human transgenes including human CD46, CD55, CD47, THBD (thrombomodulin), PROCR (protein C receptor), TNFAIP3 (tumor necrosis factor-α-induced protein 3), and HMOX1 (heme oxygenase 1) (3KO.7TG) experienced significantly prolonged graft survival and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients who received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-14)
연구진국외 연구진
분야 의약학 > 면역의학

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