Selective CD28 Inhibition Modulates Alloimmunity and Cardiac Allograft Vasculopathy in Anti–CD154-Treated Monkeys. Issue 3 (March 2018)

• Record Type: Journal Article
• Authors: Zhang, Tianshu; Azimzadeh, Agnes M.; Sun, Wenji; O'Neill, Natalie A.; Sievert, Evelyn; Bergbower, Emily; Braileanu, Gheorghe; Burdorf, Lars; Cheng, Xiangfei; Monahan, Thomas; Dahi, Siamak; Harris, Donald G.; Rybak, Elana; Welty, Emily; Kronfli, Anthony; Avon, Chris; Pierson, Richard N.
• Is Part Of: Transplantation. Volume 102:Issue 3(2018)
• Publication Date: 2018-03
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000002044
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Selective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that the checkpoint immune regulators cytotoxic T lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. We previously showed that blocking CD28 using a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked to alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney and heart transplantation. Here, we explored the efficacy of combining a 3-week "induction" sc28AT treatment with prolonged CD154 blockade. Methods: Cynomolgus monkey heterotopic cardiac allograft recipients received sc28AT (10 mg/kg, d0-20, n = 3), hu5C8 (10-30 mg/kg, d0-84, n = 4), or combination (n = 6). Graft survival was monitored by telemetry. Protocol biopsies and graft explants were analyzed for International Society of Heart and Lung Transplantation acute rejection grade and cardiac allograft vasculopathy score. Alloantibody, T-cell phenotype and regulatory T cells were analyzed by flow cytometry. Immunochemistry and gene expression (NanoString) characterized intra-graft cellular infiltration. Results: Relative to modest prolongation of median graft survival time with sc28AT alone (34 days), hu5C8 (133 days), and sc28AT + hu5C8 (141 days) prolonged survival to a similar extent. CD28 blockade at induction, added to hu5C8, significantly attenuated the severity of acute rejection and cardiac allograft vasculopathy during the first 3 months after transplantation relative to hu5C8 alone. These findings were associated with decreased proportions of circulating CD8 + and CD3 + CD28 − T cells, and modulation of inflammatory gene expression within allografts. Conclusions: Induction with sc28AT promotes early cardiac allograft protection in hu5C8-treated NHPs. These results support further investigation of prolonged selective CD28 inhibition with CD40/CD154 blockade in NHP transplants. Abstract : Short selective CD28 blockade combined with prolonged anti-CD154-treatement in heart transplanted primates decreased severity of acute rejection and of cardiac allograft vasculopathy as well as maintained levels of CD4+Treg. Although it did not prolong survival over anti-CD154 treatment, these results warrant more prolonged treatments with selective CD28 blockade. Supplemental digital content is available in the text.