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

Nature Communications
Amar SinghBernhard J Hering

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.

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Citations

Apr 8, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lalit BatraEsma S Yolcu
Jul 14, 2020·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Shuangjin YuXunrong Luo
Apr 1, 2020·Transplantation·Natasha M RogersPhilip J O'Connell
Jan 2, 2020·Surgical Neurology International·Sergio Canavero, Xiaoping Ren
Jan 6, 2021·Tissue Engineering. Part B, Reviews·Rei KuwabaraPaul de Vos
Mar 16, 2021·Frontiers in Immunology·Irma Husain, Xunrong Luo
Apr 19, 2021·Trends in Molecular Medicine·Ana Rita SousaMariana B Oliveira
May 14, 2021·Frontiers in Immunology·Yun SongLiang Fang
Jun 29, 2021·Frontiers in Immunology·Ece Canan SayitogluMaria Grazia Roncarolo
Oct 28, 2021·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Melanie L GrahamBernhard J Hering

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Methods Mentioned

BETA
enzyme-linked immunosorbent spot
genotyping
enzyme-linked immunosorbent assay
ELISA
flow cytometry
fluorescence-activated cell sorting
FACS
PCR

Software Mentioned

Reactome
Hisat2
Immune Epitope Database Analysis
Cuffdiff
limma
R Foundation for Statistical Computing
FlowJo
R
Ingenuity Pathway Analysis Software
FACSDIVA

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