Cibinetide protects human pancreatic islets from inflammation and improves engraftment in a mouse model

Intra-portal pancreatic islet transplantation (PITx) is a promising treatment for Type 1 Diabetes, but faces significant challenges, primarily the instant blood mediated inflammatory reaction (IBMIR). This innate immune response causes immediate and substantial loss of transplanted islets, limiting long-term success and requiring multiple donor pancreases. Current strategies often fall short in effectively mitigating this early graft loss. Cibinetide, a non-hematopoietic erythropoietin analogue, has previously shown islet-protective effects in mouse PITx, suggesting its potential to address the critical early survival gap in human islet transplantation.

Researchers investigated cibinetide's efficacy on human islets and its impact on IBMIR. Human islets were cultured with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured, alongside dynamic glucose perfusion assay for function. To model IBMIR, human islets were incubated in a heparinized polyvinyl chloride tubing system with ABO-compatible blood for 60 minutes. Furthermore, human islets were transplanted into athymic mice livers via the portal vein, with or without perioperative cibinetide treatment. Mice were sacrificed six days post-transplantation for analysis of human insulin, C-peptide, and CD11b+ cell infiltration.

Cibinetide demonstrated significant protective effects on human islets. During culture with pro-inflammatory cytokines, cibinetide maintained human islet ATP levels and reduced caspase 3/7 activity, indicating preserved viability and reduced apoptosis. It also improved the islets' insulin secreting capacity, as assessed by dynamic glucose perfusion assay. In the PVC loop system, simulating IBMIR, cibinetide administration reduced IBMIR-induced platelet consumption, suggesting a direct anti-inflammatory effect. The most impactful finding from the in vivo model was: Cibinetide treatment in human islet to athymic mice PITx led to an increased amount of human insulin in the livers and higher serum human C-peptide levels, indicating improved islet engraftment and function. Histological examination further revealed reduced CD11b+ cell infiltration in recipient livers, suggesting attenuated immune response and inflammation around the islet grafts.