التفاصيل البيبلوغرافية
| العنوان: |
Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig. |
| المؤلفون: |
Manook, Miriam, Olaso, Danae, Anwar, Imran, DeLaura, Isabel, Yoon, Janghoon, Bae, Yeeun, Barbas, Andrew, Shaw, Brian, Moris, Dimitrios, Song, Mingqing, Farris, Alton B., Stiede, Kathryn, Youd, Michele, Knechtle, Stuart, Kwun, Jean |
| المصدر: |
Science Translational Medicine; 6/12/2024, Vol. 16 Issue 751, p1-14, 14p |
| مصطلحات موضوعية: |
GENE expression, GRAFT survival, TRANSGENES, KIDNEY transplantation, GRAFT rejection |
| 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. Editor's summary: In organ transplantation, highly sensitized individuals are difficult to match and experience higher rates of antibody-mediated rejection (AMR). Xenotransplantation may therefore be a treatment option for these patients. Here, Manook et al. transplanted kidneys from transgenic pigs into highly sensitized rhesus macaques, finding that recipients showed early graft failure due to AMR despite anti-CD154 monoclonal antibody–based immunosuppression. Transplantation of kidneys from pigs further edited to knockout expression of three known carbohydrate xenoantigens and to express seven human transgenes resulted in prolonged graft survival and down-regulation of humoral immune responses, suggesting that highly sensitized individuals may be candidates for xenotransplantation, that humoral responses after transplant are not completely managed with current immunosuppression regimens, and that gene editing of donor pigs may improve outcomes in these individuals. —Melissa L. Norton [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
