Adenosine A2A Agonist Administration Improves Islet Transplant Outcome: Evidence for the Role of Innate Immunity in Islet Graft Rejection
Abstract:Activation of adenosine A2A receptors inhibits inflammation in ischemia/reperfusion injury, and protects against cell damage at the injury site. Following transplantation 50% of islets die due to inflammation and apoptosis. This study investigated the effects of adenosine A2A receptor agonists (ATL146e and ATL313) on glucose-stimulated insulin secretion (GSIS) in vitro and transplanted murine syngeneic islet function in vivo. Compared to vehicle controls, ATL146e (100 nM) decreased insulin stimulation index [SI, (insulin)high glucose/(insulin)low glucose] (2.36 ± 0.22 vs. 3.75 ± 0.45; n = 9; p < 0.05). Coculture of islets with syngeneic leukocytes reduced SI (1.41 ± 0.17; p < 0.05), and this was restored by ATL treatment (2.57 ± 0.18; NS). Addition of a selective A2AAR antagonist abrogated ATL's protective effect, reducing SI (1.11 ± 0.42). ATL treatment of A2AAR+/+ islet/A2AAR−/− leukocyte cocultures failed to protect islet function (SI), implicating leukocytes as likely targets of A2AAR agonists. Diabetic recipient C57BL/6 mice (streptozotocin; 250 mg/kg, IP) received islet transplants to either the renal subcapsular or hepatic-intraportal site. Recipient mice receiving ATL therapy (ATL 146e or ATL313, 60 ng/kg/min, IP) achieved normoglycemia more rapidly than untreated recipients. Histological examination of grafts suggested reduced cellular necrosis, fibrosis, and lymphocyte infiltration in agonist-treated animals. Administration of adenosine A2A receptor agonists (ATL146e or ATL313) improves in vitro GSIS by an effect on leukocytes, and improves survival and functional engraftment of transplanted islets by inhibiting inflammatory islet damage in the peritransplant period, suggesting a potentially significant new strategy for reducing inflammatory islet loss in clinical transplantation.
Document Type: Research Article
Affiliations: Department of Surgery, University of Virginia, Charlottesville, VA, USA
Publication date: 2010-05-01
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