TY - JOUR
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.
N1 - Publisher Copyright:
© 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2019/12/1
Y1 - 2019/12/1
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.
AB - 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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U2 - 10.1038/s41467-019-11338-y
DO - 10.1038/s41467-019-11338-y
M3 - Article
C2 - 31375697
AN - SCOPUS:85070071601
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3495
ER -
