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

N. O'Neill,Tianshu Zhang,G. Braileanu,Xiangfei Cheng,A. Hershfeld,Wenji Sun,K. Reimann,S. Dahi,Natalia S. Kubicki,Wessam S. Hassanein,C. Laird,A. Cimeno,A. Azimzadeh,R. Pierson

Published 2018 in Transplantation Direct

ABSTRACT

Background 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. Methods Cynomolgus monkey heterotopic cardiac allograft recipients were treated with &agr;CD40 (2C10R4, d0-90) either alone or with the addition of delayed ICOS-Ig (d63-110). Results Median allograft survival was similar between ICOS-Ig + &agr;CD40 (120 days, 120-125 days) and &agr;CD40 (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+ TEM cells 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 elaboration were similar between groups. Conclusions Delayed ICOS-Ig treatment with the reagent tested is probably ineffective in modulating pathogenic primate alloimmunity in this model.

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