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

• Type of Material: Article
• Authors: Robin Schmitz, Duke University; Zachary W. Fitch, Duke University; Paul M. Schroder, Duke University; Ashley Y. Choi, Duke University; Miriam Manook, Duke University; Janghoon Yoon, Duke University; Mingqing Song, Duke University; John S. Yi, Duke University; Sanjay Khandelwal, Duke University; Gowthami M. Arepally, Duke University; Alton Farris III, Emory University; Edimara S. Reis, University of Pennsylvania; John D. Lambris, University of Pennsylvania; Jean Kwun, Duke University; Stuart Knechtle, Emory University
• Language: English
• Date: 2021-09-15
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-021-25745-7
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 12
• Issue: 1
• Start Page: 5456
• End Page: 5456
• Grant/Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of the NHP Transplantation Tolerance Cooperative Study Group under the U19AI131471 (awarded to S.J.K.) and P01-AI068730 (awarded to J.D.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Rhesus-specific anti-thymocyte globulin (rhATG) used in this study was provided by the NIH Nonhuman Primate Reagent Resource (R24 OD010976, U24 AI126683).
• Keywords: DENDRITIC CELLS; MODEL; HLA ANTIBODIES; Science & Technology; Science & Technology - Other Topics; ACCOMMODATION; TRANSPLANTATION; KIDNEY ALLOGRAFTS; COMPSTATIN; C5A; RECIPIENTS; DESENSITIZATION; Multidisciplinary Sciences
• Research Categories: Biology, Neuroscience; Biology, Cell; Health Sciences, Medicine and Surgery

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.