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

• Published in: Nature communications 2019-08, Vol.10 (1), p.3495-16, Article 3495
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/31; 38; 631/250/1619/554; 631/250/1854/2812; 631/250/2152/569/2495; 692/308/575; Adoptive Transfer; Allografts; Allografts - immunology; Animals; Antibodies; Antigens; Apoptosis; Apoptosis - immunology; CD40 antigen; Disease Models, Animal; Female; Gene expression; Graft Rejection - immunology; Graft Rejection - prevention & control; Graft Survival - immunology; Humanities and Social Sciences; Humans; Immune Tolerance; Immunological tolerance; Immunosuppressive Agents - therapeutic use; Immunotherapy; Interleukin 6; Islets of Langerhans - immunology; Islets of Langerhans Transplantation - adverse effects; Leukocytes; Macaca mulatta; Major histocompatibility complex; Male; multidisciplinary; Pancreatic islet transplantation; Peptides; Primates; Rapamycin; Science; Science (multidisciplinary); Splenocytes; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - transplantation; Tissue Donors; Transplantation; Transplantation, Homologous - adverse effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11338-y

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. Injection of donor apoptotic cells induces graft tolerance in mice. Here the authors combine this approach with short immunosuppressive therapy to achieve long-term tolerance to allogeneic islets and restoration of normoglycemia in diabetic nonhuman primates, and delineate cellular and molecular correlates of tolerance induction.