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

Natalie A. O’Neill, MD; Tianshu Zhang, MD, PhD; Gheorghe Braileanu, PhD; Xiangfei Cheng, MD, PhD; Alena Hershfeld, MS; Wenji Sun, MD, PhD; Keith A. Reimann, PhD; Sia Dahi, MD; Natalia Kubicki, MD; Wessam Hassanein, MD; Christopher Laird, MD; Arielle Cimeno, MD; Agnes M. Azimzadeh, PhD; Richard N. Pierson, MD

doi:10.1097/TXD.0000000000000761

Transplantation Direct (Feb 2018)

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

Natalie A. O’Neill, MD,
Tianshu Zhang, MD, PhD,
Gheorghe Braileanu, PhD,
Xiangfei Cheng, MD, PhD,
Alena Hershfeld, MS,
Wenji Sun, MD, PhD,
Keith A. Reimann, PhD,
Sia Dahi, MD,
Natalia Kubicki, MD,
Wessam Hassanein, MD,
Christopher Laird, MD,
Arielle Cimeno, MD,
Agnes M. Azimzadeh, PhD,
Richard N. Pierson, MD

Affiliations

Natalie A. O’Neill, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Tianshu Zhang, MD, PhD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Gheorghe Braileanu, PhD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Xiangfei Cheng, MD, PhD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Alena Hershfeld, MS: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Wenji Sun, MD, PhD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Keith A. Reimann, PhD: 2 MassBiologics, University of Massachusetts Medical School, Boston, MA.
Sia Dahi, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Natalia Kubicki, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Wessam Hassanein, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Christopher Laird, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Arielle Cimeno, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Agnes M. Azimzadeh, PhD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
Richard N. Pierson, MD: 1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

DOI: https://doi.org/10.1097/TXD.0000000000000761
Journal volume & issue: Vol. 4, no. 2
p. e344

Abstract

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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 αCD40 (2C10R4, d0-90) either alone or with the addition of delayed ICOS-Ig (d63-110). Results. 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+ 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.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

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