Ji-Jing Yan, Jong-Min Kim, Sang-Ik Cho, Hyori Kim, Kyungmin Kwak, Hyunil Kim, Eun-Jee Oh, Jaeseok Yang, Chung-Gyu Park, Jong Cheol Jeong, Beom Seok Kim
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引用次数: 0
Abstract
Background: In pig-to-nonhuman primate islet transplantation, reliable, sensitive biomarkers are needed to detect graft damage at an early stage before irreversible islet loss occurs. In our study, we investigated donor-derived cell-free DNA (dd-cfDNA) as an early, noninvasive biomarker of graft injury by analyzing its correlation with porcine C-peptide levels, complement activation markers, and donor-specific antibodies (DSAs).
Methods: Streptozotocin-induced diabetic cynomolgus monkeys received 50 000-100 000 IEQ/kg of intraportal islets from quadruple-knockout (QKO; GGTA1, CMAH, B4GALNT2, and A3GALT2) pigs. Cohort 1 received antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and anti-inflammatory agents (i.e., anakinra, adalimumab, and tocilizumab), whereas Cohort 2 received the same regimen plus rituximab and crovalimab. Graft function and immune responses were assessed by measuring porcine C-peptide levels, complement activation markers, histology, and dd-cfDNA kinetics.
Results: Cohort 1 showed transient porcine C-peptide secretion with marked dd-cfDNA elevation at 7 d postoperatively that coincided with complement activation (i.e., C5a and membrane attack complex (MAC)) and dense CD3+ T-cell and CD68+ macrophage infiltration, which resulted in early graft loss. Cohort 2 maintained stable C-peptide levels, lower dd-cfDNA levels, and reduced complement activation with improved graft preservation. Moreover, dd-cfDNA correlated negatively with C-peptide and positively with C5a but not with MAC. In both cohorts, DSA levels remained unchanged.
Conclusions: Our study revealed that dd-cfDNA levels correlate with graft damage and C5a in QKO porcine islet xenografts, which corroborates dd-cfDNA utility as an early biomarker for predicting instant blood-mediated inflammatory reaction (IBMIR). These findings indicate that dd-cfDNA may be able to detect early islet xenograft damage.
期刊介绍：
Xenotransplantation provides its readership with rapid communication of new findings in the field of organ and tissue transplantation across species barriers.The journal is not only of interest to those whose primary area is xenotransplantation, but also to veterinarians, microbiologists and geneticists. It also investigates and reports on the controversial theological, ethical, legal and psychological implications of xenotransplantation.
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