TY - JOUR
T1 - Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model
AU - Manook, Miriam
AU - Flores, Walter J.
AU - Schmitz, Robin
AU - Fitch, Zachary
AU - Yoon, Janghoon
AU - Bae, Yeeun
AU - Shaw, Brian
AU - Kirk, Allan
AU - Harnois, Melissa
AU - Permar, Sallie
AU - Farris, Alton B.
AU - Magnani, Diogo M.
AU - Kwun, Jean
AU - Knechtle, Stuart
N1 - Funding Information:
We would like to gratefully acknowledge the DLAR (Duke Laboratory Animal Resources) and SLACR (Surgery Large Animal Core Research) staffs and the expert assistance of Drs. Kyha Williams and Felicita Smith for animal care. We also want to acknowledge Ashley Morgan (Duke U) for her contribution in reviewing the manuscript. Rhesus ATG and anti-FcRn mAb used in this study were provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116, U24 AI126683).
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).
Publisher Copyright:
© Copyright © 2021 Manook, Flores, Schmitz, Fitch, Yoon, Bae, Shaw, Kirk, Harnois, Permar, Farris, Magnani, Kwun and Knechtle.
PY - 2021/6/2
Y1 - 2021/6/2
N2 - 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.
AB - 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.
KW - FcRn
KW - IgG
KW - alloantibody
KW - non-human primate (NHP)
KW - sensitization
UR - http://www.scopus.com/inward/record.url?scp=85108144785&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.660900
DO - 10.3389/fimmu.2021.660900
M3 - Article
C2 - 34149698
AN - SCOPUS:85108144785
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 660900
ER -