Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes

Amar Singh, Sabarinathan Ramachandran, Melanie L. Graham, Saeed Daneshmandi, David Heller, Wilma Lucia Suarez-Pinzon, Appakalai N. Balamurugan, Jeffrey D. Ansite, Joshua J. Wilhelm, Amy Yang, Ying Zhang, Nagendra P. Palani, Juan E. Abrahante, Christopher Burlak, Stephen D. Miller, Xunrong Luo, Bernhard J. Hering*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.

Original languageEnglish (US)
Article number3495
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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