Journal
ANNALS OF SURGERY
Volume 274, Issue 3, Pages 473-480Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SLA.0000000000004996
Keywords
antibody-mediated rejection; genetically modified pigs; Kidney transplantation; tesidolumab; xenotransplantation
Categories
Funding
- Novartis
- National Institutes of Health [1RO1AI26322]
- ORIP/OD [P51OD011132]
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The study demonstrates that inhibition of the C5 complement subunit can prolong renal xenotransplant survival in a pig to non-human primate model by reducing early graft loss. However, deleting class I MHC in donor pigs did not improve early antibody-mediated rejection. Additionally, anti-C5 therapy did not allow for the use of tacrolimus instead of anti-CD154, limiting survival to a maximum of 62 days.
Objective: Pig-to-primate renal xenotransplantation is plagued by early antibody-mediated graft loss which precludes clinical application of renal xenotransplantation. We evaluated whether temporary complement inhibition with anti-C5 antibody Tesidolumab could minimize the impact of early antibody-mediated rejection in rhesus monkeys receiving pig kidneys receiving costimulatory blockade-based immunosuppression. Methods: Double (Gal and Sd(a)) and triple xenoantigen (Gal, Sd(a), and SLA I) pigs were created using CRISPR/Cas. Kidneys from DKO and TKO pigs were transplanted into rhesus monkeys that had the least reactive crossmatches. Recipients received anti-C5 antibody weekly for 70 days, and T cell depletion, anti-CD154, mycophenolic acid, and steroids as baseline immunosuppression (n = 7). Control recipients did not receive anti-C5 therapy (n = 10). Results: Temporary anti-C5 therapy reduced early graft loss secondary to antibody-mediated rejection and improved graft survival (P < 0.01). Deleting class I MHC (SLA I) in donor pigs did not ameliorate early antibody-mediated rejection (table). Anti-C5 therapy did not allow for the use of tacrolimus instead of anti-CD154 (table), prolonging survival to a maximum of 62 days. Conclusion: Inhibition of the C5 complement subunit prolongs renal xenotransplant survival in a pig to non-human primate model.
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