Jun-Seop Shin1,2,3,4, Byoung-Hoon Min1,2,4, Jong-Min Kim1,3,4, Jung-Sik Kim1,2,3,4, Il Hee Yoon1,2,4, Hyun Je Kim1,2,4,5, Yong-Hee Kim1,2, Jae Yool Jang1, Hee Jung Kang6, Dong-Gyun Lim7, Jongwon Ha1,8, Sang-Joon Kim1,9, Chung-Gyu Park1,2,3,4,5,10. 1. Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea. 2. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea. 3. Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea. 4. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. 5. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. 6. Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea. 7. National Medical Center, Seoul, Korea. 8. Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. 9. Myong-Ji Hospital, Koyang-si, Kyeonggi-do, Korea. 10. Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Abstract
BACKGROUND: Islet allotransplantation is a promising way to treat some type 1 diabetic (T1D) patients with frequent hypoglycemic unawareness, and islet xenotransplantation is emerging to overcome the problem of donor organ shortage. Our recent study showing reproducible long-term survival of porcine islets in non-human primates (NHPs) allows us to examine whether autologous regulatory T-cell (Treg) infusion at peri-transplantation period would induce transplantation tolerance in xenotransplantation setting. METHODS: Two diabetic rhesus monkeys were transplanted with porcine islets from wild-type adult Seoul National University (SNU) miniature pigs with immunosuppression by anti-thymoglobulin (ATG), cobra venom factor, anti-CD154 monoclonal antibody (mAb), and sirolimus. CD4(+) CD25(high) CD127(low) autologous regulatory T cells from the recipients were isolated, ex vivo expanded, and infused at the peri-transplantation period. Blood glucose and porcine C-peptide from the recipients were measured up to 1000 days. Maintenance immunosuppressants including a CD40-CD154 blockade were deliberately discontinued to confirm whether transplantation tolerance was induced by adoptively transferred Tregs. RESULTS: After pig islet transplantation via portal vein, blood glucose levels of diabetic recipients became normalized and maintained over 6 months while in immunosuppressive maintenance with a CD40-CD154 blockade and sirolimus. However, the engrafted pig islets in the long-term period were fully rejected by activated immune cells, particularly T cells, when immunosuppressants were stopped, showing a failure of transplantation tolerance induction by autologous Tregs. CONCLUSIONS: Taken together, autologous Tregs infused at the peri-transplantation period failed to induce transplantation tolerance in pig-to-NHP islet xenotransplantation setting.
BACKGROUND: Islet allotransplantation is a promising way to treat some type 1 diabetic (T1D) patients with frequent hypoglycemic unawareness, and islet xenotransplantation is emerging to overcome the problem of donor organ shortage. Our recent study showing reproducible long-term survival of porcine islets in non-human primates (NHPs) allows us to examine whether autologous regulatory T-cell (Treg) infusion at peri-transplantation period would induce transplantation tolerance in xenotransplantation setting. METHODS: Two diabeticrhesus monkeys were transplanted with porcine islets from wild-type adult Seoul National University (SNU) miniature pigs with immunosuppression by anti-thymoglobulin (ATG), cobra venom factor, anti-CD154 monoclonal antibody (mAb), and sirolimus. CD4(+) CD25(high) CD127(low) autologous regulatory T cells from the recipients were isolated, ex vivo expanded, and infused at the peri-transplantation period. Blood glucose and porcine C-peptide from the recipients were measured up to 1000 days. Maintenance immunosuppressants including a CD40-CD154 blockade were deliberately discontinued to confirm whether transplantation tolerance was induced by adoptively transferred Tregs. RESULTS: After pig islet transplantation via portal vein, blood glucose levels of diabetic recipients became normalized and maintained over 6 months while in immunosuppressive maintenance with a CD40-CD154 blockade and sirolimus. However, the engrafted pig islets in the long-term period were fully rejected by activated immune cells, particularly T cells, when immunosuppressants were stopped, showing a failure of transplantation tolerance induction by autologous Tregs. CONCLUSIONS: Taken together, autologous Tregs infused at the peri-transplantation period failed to induce transplantation tolerance in pig-to-NHP islet xenotransplantation setting.
Authors: David K C Cooper; Richard N Pierson; Bernhard J Hering; Muhammad M Mohiuddin; Jay A Fishman; Joachim Denner; Curie Ahn; Agnes M Azimzadeh; Leo H Buhler; Peter J Cowan; Wayne J Hawthorne; Takaaki Kobayashi; David H Sachs Journal: Transplantation Date: 2017-08 Impact factor: 4.939
Authors: Frances T Lee; Anil Dangi; Sahil Shah; Melanie Burnette; Yong-Guang Yang; Allan D Kirk; Bernhard J Hering; Stephen D Miller; Xunrong Luo Journal: Am J Transplant Date: 2020-01-21 Impact factor: 8.086