C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Robin Schmitz, Zachary W. Fitch, Paul M. Schroder, Ashley Y. Choi, Miriam Manook, Janghoon Yoon, Mingqing Song, John S. Yi, Sanjay Khandelwal, Gowthami M. Arepally, Alton B. Farris, Edimara S. Reis, John D. Lambris, Jean Kwun, Stuart J. Knechtle
Abstract
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.