دورية أكاديمية
Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig.
| العنوان: | Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig. |
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| المؤلفون: | Manook M; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Olaso D; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Anwar I; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., DeLaura I; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Yoon J; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Bae Y; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Barbas A; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Shaw B; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Moris D; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Song M; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Farris AB; Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA., Stiede K; eGenesis Inc, Cambridge, MA 02140, USA., Youd M; eGenesis Inc, Cambridge, MA 02140, USA., Knechtle S; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA., Kwun J; Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA. |
| المصدر: | Science translational medicine [Sci Transl Med] 2024 Jun 12; Vol. 16 (751), pp. eadk6152. Date of Electronic Publication: 2024 Jun 12. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Graft Survival*/immunology , Transplantation, Heterologous* , Animals, Genetically Modified* , Galactosyltransferases*/genetics , Galactosyltransferases*/deficiency , Graft Rejection*/immunology , Graft Rejection*/prevention & control , Transgenes* , Gene Knockout Techniques*, Animals ; Humans ; Swine ; Macaca mulatta ; Kidney Transplantation |
| مستخلص: | 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. |
| معلومات مُعتمدة: | R01 AI175411 United States AI NIAID NIH HHS; R21 AI151398 United States AI NIAID NIH HHS; R24 OD010976 United States OD NIH HHS; U24 AI126683 United States AI NIAID NIH HHS |
| المشرفين على المادة: | EC 2.4.1.- (Galactosyltransferases) EC 2.4.1.- (alpha-1,3-galactosyltransferase 1, porcine) |
| تواريخ الأحداث: | Date Created: 20240612 Date Completed: 20240612 Latest Revision: 20240626 |
| رمز التحديث: | 20240626 |
| DOI: | 10.1126/scitranslmed.adk6152 |
| PMID: | 38865482 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.adk6152 |