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 journalArticle

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

Fingerprint

primates
Transplantation Tolerance
leukocytes
Primates
Allografts
antigens
Leukocytes
Antigens
transplantation
antibodies
Dichlororibofuranosylbenzimidazole
Interleukin-6 Receptors
Immune Tolerance
Tumor Necrosis Factor Receptors
Regulatory T-Lymphocytes
Sirolimus
interleukins
Macaca mulatta
Transcriptome
Immunotherapy

ASJC Scopus subject areas

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

Cite this

Singh, A., Ramachandran, S., Graham, M. L., Daneshmandi, S., Heller, D., Suarez-Pinzon, W. L., ... Hering, B. J. (2019). Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nature communications, 10(1), [3495]. https://doi.org/10.1038/s41467-019-11338-y
Singh, Amar ; Ramachandran, Sabarinathan ; Graham, Melanie L. ; Daneshmandi, Saeed ; Heller, David ; Suarez-Pinzon, Wilma Lucia ; Balamurugan, Appakalai N. ; Ansite, Jeffrey D. ; Wilhelm, Joshua J. ; Yang, Amy ; Zhang, Ying ; Palani, Nagendra P. ; Abrahante, Juan E. ; Burlak, Christopher ; Miller, Stephen D. ; Luo, Xunrong ; Hering, Bernhard J. / Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. In: Nature communications. 2019 ; Vol. 10, No. 1.
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Singh, A, Ramachandran, S, Graham, ML, Daneshmandi, S, Heller, D, Suarez-Pinzon, WL, Balamurugan, AN, Ansite, JD, Wilhelm, JJ, Yang, A, Zhang, Y, Palani, NP, Abrahante, JE, Burlak, C, Miller, SD, Luo, X & Hering, BJ 2019, 'Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes', Nature communications, vol. 10, no. 1, 3495. https://doi.org/10.1038/s41467-019-11338-y

Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. / Singh, Amar; Ramachandran, Sabarinathan; Graham, Melanie L.; Daneshmandi, Saeed; Heller, David; Suarez-Pinzon, Wilma Lucia; Balamurugan, Appakalai N.; Ansite, Jeffrey D.; Wilhelm, Joshua J.; Yang, Amy; Zhang, Ying; Palani, Nagendra P.; Abrahante, Juan E.; Burlak, Christopher; Miller, Stephen D.; Luo, Xunrong; Hering, Bernhard J.

In: Nature communications, Vol. 10, No. 1, 3495, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes

AU - Singh, Amar

AU - Ramachandran, Sabarinathan

AU - Graham, Melanie L.

AU - Daneshmandi, Saeed

AU - Heller, David

AU - Suarez-Pinzon, Wilma Lucia

AU - Balamurugan, Appakalai N.

AU - Ansite, Jeffrey D.

AU - Wilhelm, Joshua J.

AU - Yang, Amy

AU - Zhang, Ying

AU - Palani, Nagendra P.

AU - Abrahante, Juan E.

AU - Burlak, Christopher

AU - Miller, Stephen D.

AU - Luo, Xunrong

AU - Hering, Bernhard J.

PY - 2019/12/1

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N2 - 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.

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Singh A, Ramachandran S, Graham ML, Daneshmandi S, Heller D, Suarez-Pinzon WL et al. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nature communications. 2019 Dec 1;10(1). 3495. https://doi.org/10.1038/s41467-019-11338-y