Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model

• Type of Material: Article
• Authors: Miriam Manook, Duke University; Walter J. Flores, University of Massachusetts; Robin Schmitz, Duke University; Zachary Fitch, Duke University; Janghoon Yoon, Duke University; Yeeun Bae, Duke University; Brian Shaw, Duke University; Allan Kirk, Duke University; Melissa Harnois, Duke University; Sallie Permar, Duke University; Alton Farris III, Emory University; Diogo M. Magnani, University of Massachusetts; Jean Kwun, Duke University; Stuart Knechtle, Duke University
• Language: English
• Date: 2021-06-02
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Manook, Flores, Schmitz, Fitch, Yoon, Bae, Shaw, Kirk, Harnois, Permar, Farris, Magnani, Kwun and Knechtle
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.660900
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 660900
• End Page: 660900
• 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 Nonhuman Primate Transplantation Tolerance Cooperative Study Group under U19AI131471 (awarded to SK).
• Keywords: IgG; INHIBITOR; RECEPTOR; NONHUMAN-PRIMATES; non-human primate (NHP); Life Sciences & Biomedicine; FcRn; REJECTION; Science & Technology; sensitization; PLASMAPHERESIS; alloantibody; Immunology
• Research Categories: Health Sciences, Immunology; Biology, Cell

Abstract

Background: In transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA. Methods: Six (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression. Results: Circulating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (p<0.05), while using a DSA assay. T-cell flow cross match (TFXM) was reduced to 40.6±12.5% of baseline, and B-cell FXCM to 52.2±19.3%. Circulating total IgM and DSA IgM were unaffected by treatment. Pathogen-specific antibodies (anti-gB and anti-tetanus toxin IgG) were significantly reduced for 14d post infusion. Post-transplant, circulating IgG responded to anti-FcRn mAb treatment, but DSA increased rapidly. Conclusion: Targeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.