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.
FcRn, IgG, alloantibody, non-human primate (NHP), sensitization
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Copyright © 2021 Manook, Flores, Schmitz, Fitch, Yoon, Bae, Shaw, Kirk, Harnois, Permar, Farris, Magnani, Kwun and Knechtle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Manook M, Flores WJ, Schmitz R, Fitch Z, Yoon J, Bae Y, Shaw B, Kirk A, Harnois M, Permar S, Farris AB, Magnani DM, Kwun J, Knechtle S. Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model. Front Immunol. 2021 Jun 2;12:660900. doi: 10.3389/fimmu.2021.660900. PMID: 34149698; PMCID: PMC8207189. Link to article on publisher's site
Frontiers in immunology
Manook M, Flores WJ, Schmitz R, Fitch Z, Yoon J, Bae Y, Shaw B, Kirk A, Harnois M, Permar S, Farris AB, Magnani DM, Kwun J, Knechtle S. (2021). Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model. Open Access Publications by UMass Chan Authors. https://doi.org/10.3389/fimmu.2021.660900. Retrieved from https://escholarship.umassmed.edu/oapubs/4781
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