Donor Pre-treatment with IL-1 Receptor Antagonist Attenuates Inflammation and Improves Functional Potency in Islets from Brain-Dead Non-human Primates

Most pancreas and islet grafts are recovered from brain-dead (BD) donors. In this study we characterized the early inflammatory response induced by brain death in pancreata and islets from non-human primate donors and evaluated the effect of targeted anti-inflammatory intervention in the protection of pancreatic islets prior to transplantation. Brain-dead donors were monitored for 6 hours and assigned to three experimental groups. Group 1: BD-untreated donors (BD-UT) (n=7), Group 2: BD + donor pre-treatment with IL-1ra (n=6) and Group 3: Non-BD animals serving as controls (n=7). We observed an IL-1ra dependent reduction in the mobilization and activation of neutrophils from bone marrow and a significantly reduced accumulation of CD68+ leukocytes in the pancreas and islets after brain death induction. Donor treatment with IL-1ra significantly decreased chemokine mRNA expression (MCP-1, IL-8 and MIP-1a) and attenuated the activation of circulating neutrophils and intra-islet macrophages as demonstrated by a reduction in intracellular IL-1β, IL-6, MCP-1 and MIP-1α expression. As a result, IL-1ra dramatically improved viability, mitochondrial membrane polarity and islet engraftment in mice transplanted using a minimal islet mass. These results suggest that early immunomodulation targeting inflammation in the brain-dead donor may represent an effective therapeutic strategy to improve islet quality and function prior to transplantation.