An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

Abstract

The efficacy of pancreatic islet transplantation (PITx) is reduced due to severe inflammatory responses triggered by the islet isolation and transplantation procedures. ARA 290, an innate repair receptor agonist, has anti-apoptotic and anti-inflammatory properties and it has been shown to improve clinical symptoms caused by inflammation in sarcoidosis patients and type 2 diabetes. We here investigated whether ARA 290 treatment would improve the efficacy of PITx in a rat pancreatic islet transplantation model. For islets co-cultured with proinflammatory cytokines, addition of ARA290 showed better viability [percent of naïve control in MTT assay: 54.6 ± 5.2 vs. 75.2 ± 6.4], insulin release [stimulation index in static glucose stimulated insulin secretion tests of 1.05 ± 0.63 vs. 2.61 ± 0.89], and reduced apoptosis [caspase3/7 activity182 ± 18 vs. 152 ± 18 luminescence/dsDNA(ng)] (islets with cytokines vs. islets with ARA290+cytokines, respectively, all p<0.05). In order to mimic the clinical situation, islets were isolated after prolonged cold ischemia (18 h). The addition of ARA 290 into preservation solution, however, did not improve islet yields or function. As a marginal syngeneic PITx, 220 syngeneic rat islets were transplanted under the kidney capsule of streptozotocin-induced diabetic rats and the recipients were treated with ARA 290 (120 µg/kg/day) for two weeks after PITx. In this model, no beneficial effect of ARA 290 treatment was observed. Our results indicated that ARA 290 protected rat pancreatic islets from cytokine-induced damage and apoptosis, but did not improve PITx perhaps due to poor penetration of ARA290 into transplant site or low IRR expression. ARA 290 could be useful as an agent to reduce islet injury caused by severe inflammation.