Pilot Study of Delayed ICOS/ICOS-L Blockade With αCD40 to Modulate Pathogenic Alloimmunity in a Primate Cardiac Allograft Model

Transplantation Direct
Natalie A O'NeillRichard N Pierson

Abstract

Inducible costimulator (ICOS) is rapidly upregulated with T-cell stimulation and may represent an escape pathway for T-cell costimulation in the setting of CD40/CD154 costimulation blockade. Induction treatment exhibited no efficacy in a primate renal allograft model, but rodent transplant models suggest that the addition of delayed ICOS/ICOS-L blockade may prolong allograft survival and prevent chronic rejection. Here, we ask whether ICOS-Ig treatment, timed to anticipate ICOS upregulation, prolongs NHP cardiac allograft survival or attenuates pathogenic alloimmunity. Cynomolgus monkey heterotopic cardiac allograft recipients were treated with αCD40 (2C10R4, d0-90) either alone or with the addition of delayed ICOS-Ig (d63-110). Median allograft survival was similar between ICOS-Ig + αCD40 (120 days, 120-125 days) and αCD40 (124 days, 89-178 days) treated animals, and delayed ICOS-Ig treatment did not prevent allograft rejection in animals with complete CD40 receptor coverage. Although CD4+TEMcells were decreased in peripheral blood (115 ± 24) and mLNs (49 ± 1.9%) during ICOS-Ig treatment compared with monotherapy (214 ± 27%,P= 0.01; 72 ± 9.9%,P= 0.01, respectively), acute and chronic rejection scores and kinetics of alloAb ela...Continue Reading

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Citations

Nov 7, 2019·Journal of Cellular Physiology·Alireza MardomiSaeid Abediankenari
Jul 19, 2020·Molecular Immunology·Shima AfzaliAliakbar Amirzargar
Apr 10, 2021·Xenotransplantation·Richard N Pierson, Wayne J Hawthorne
Apr 29, 2021·Transplantation·Kevin LouisDiana Metes

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Methods Mentioned

BETA
Illumina sequencing
biopsies
biopsy
enzyme-linked immunosorbent assay
flow cytometry
PCR

Clinical Trials Mentioned

NCT01127321
NCT02520791

Software Mentioned

GraphPad
GraphPad InStat
FlowJo

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