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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We gratefully acknowledge the excellent and expert care, husbandry, and training of our animals by the team at the University of Minnesota’s Preclinical Research Center, coordinated by Lucas Mutch and Jody Janecek. We thank Brian E. Flanagan, Jean Witson, Kate Mueller, Thomas Gilmore, Anders Matson, Zach Swanson, and Steven Kass of the Schulze Diabetes Institute at the University of Minnesota; Roger Wiseman of the Wisconsin National Primate Research Center’s Genetics Services Unit; and I-Ting Chow and Cynthia Cousens-Jacobs of the Tetramer Core Facility at the Benaroya Research Institute at Virginia Mason. We thank Keith A. Reimann of the NIH Nonhuman Primate Reagent Resource (R24 OD010976, U24 AI126683) for providing the anti-CD40 antibody 2C10R4; Timothy D. O’Brien of the Comparative Pathology Section in the University of Minnesota’s Department of Veterinary Population Medicine, faculty/staff members of the University of Minnesota’s Genomics Center for consultation and for execution of TCR sequencing and transcriptome studies; faculty/staff members of Northwestern University’s HLA laboratory, directed by Anat Tambur, for their assistance in measuring PRA and DSA; and Mary Knatterud, PhD, of the University of Minnesota’s Department of Surgery, and Neeta Adhikari, PhD, for editing the manuscript. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of the Nonhuman Primate Transplantation Tolerance Cooperative Study Group under Award Number U01AI102463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by funds provided by the Diabetes Research and Wellness Foundation, the Transplant Division in the University of Minnesota’s Department of Surgery, and individual philanthropy through the University of Minnesota Foundation.
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