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

Author

Listed:
  • Amar Singh

    (University of Minnesota)

  • Sabarinathan Ramachandran

    (University of Minnesota)

  • Melanie L. Graham

    (University of Minnesota)

  • Saeed Daneshmandi

    (Northwestern University Feinberg School of Medicine)

  • David Heller

    (University of Minnesota)

  • Wilma Lucia Suarez-Pinzon

    (University of Minnesota)

  • Appakalai N. Balamurugan

    (University of Minnesota
    University of Louisville)

  • Jeffrey D. Ansite

    (University of Minnesota)

  • Joshua J. Wilhelm

    (University of Minnesota)

  • Amy Yang

    (Northwestern University Feinberg School of Medicine)

  • Ying Zhang

    (University of Minnesota)

  • Nagendra P. Palani

    (University of Minnesota Genomics Center)

  • Juan E. Abrahante

    (University of Minnesota Informatics Institute)

  • Christopher Burlak

    (University of Minnesota)

  • Stephen D. Miller

    (Northwestern University)

  • Xunrong Luo

    (Northwestern University Feinberg School of Medicine
    Northwestern University Feinberg School of Medicine
    Duke University School of Medicine)

  • Bernhard J. Hering

    (University of Minnesota)

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.

Suggested Citation

  • 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 , 2019. "Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11338-y
    DOI: 10.1038/s41467-019-11338-y
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