C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates

Nat Commun. 2021 Sep 15;12(1):5456. doi: 10.1038/s41467-021-25745-7.


Sensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Cell Proliferation / drug effects
  • Complement C3 / antagonists & inhibitors*
  • Complement C3 / immunology
  • Complement C3 / metabolism
  • Cytokines / blood
  • Cytokines / immunology
  • Graft Rejection / immunology
  • Graft Rejection / metabolism
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • Graft Survival / immunology
  • Kidney Transplantation / methods*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Macaca mulatta / immunology*
  • Male
  • Pyridones / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Transplantation, Homologous


  • Antibodies
  • Complement C3
  • Cytokines
  • Pyridones
  • 1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one