Xenotransplantation of Genetically Modified Neonatal Pig Islets Cures Diabetes in Baboons

• DOI: 10.3389/fimmu.2022.898948
• Publication Date: 2022-06-16T06:24:35Z
• Authors: Wayne J. Hawthorne; Evelyn J. Salvaris; Yi Vee Chew; Heather Burns; Joanne Hawkes; Helen Barlow; Min Hu; Andrew M. Lew; Mark B. Nottle; Philip J. O’Connell; Peter J. Cowan
• Keywords: Xenotransplantation; Immunosuppression; Allotransplantation

Xenotransplantation using porcine donors is rapidly approaching clinical applicability as an alternative therapy for treatment of many end-stage diseases including type 1 diabetes. Porcine neonatal islet cell clusters (NICC) have normalised blood sugar levels relatively short periods in the preclinical diabetic rhesus model but met with limited success stringent baboon model. Here we report that NICC from genetically modified (GM) pigs deleted αGal and expressing human complement regulators CD55 CD59 can cure diabetes long-term immunosuppressed baboons, maximum graft survival exceeding 22 months. Five baboons were transplanted intraportally 9,673 – 56,913 equivalents (IEQ) per kg recipient weight. Immunosuppression consisted T depletion anti-CD2 mAb, tacrolimus first 4 months, maintenance belatacept anti-CD154; no anti-inflammatory or cytomegalovirus (CMV) prophylaxis/treatment was given. This protocol well tolerated, all recipients maintaining gaining Recipients became insulin-independent at a mean 87 ± 43 days post-transplant remained 397 174 days. Maximum 675 Liver biopsies showed functional islets staining endocrine components, evidence inflammatory blood-mediated reaction (IBMIR) minimal leukocytic infiltration. The costimulation blockade-based immunosuppressive prevented anti-pig antibody response recipients. In conclusion, demonstrate genetic modification donor pig enables attenuation early xenograft injury, conjunction judicious immunosuppression provides excellent function