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 Sda) and triple xenoantigen (Gal, Sda, 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.
Bibliographical notePublisher Copyright:
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
- Animals, Genetically Modified
- Antibiotic Prophylaxis
- Antibodies, Monoclonal/pharmacology
- Graft Rejection/immunology
- Immune Tolerance
- Immunosuppressive Agents/pharmacology
- Kidney Transplantation
- Macaca mulatta
- Models, Animal
- Transplantation, Heterologous
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't