Adenosine A(2A) Agonist Administration Improves Islet Transplant Outcome: Evidence for the Role of Innate Immunity in Islet Graft Rejection

作者：Chhabra Preeti; Wang Kunjie; Zeng Qiang; Jecmenica Mladen; Langman Linda; Linden Joel; Ketchum Robert J; Brayman Kenneth L^*

来源：Cell Transplantation, 2010, 19(5): 597-612.

DOI：10.3727/096368910X491806

• Early islet loss
• Adenosine receptor agonists in islet transplantation
• Peritransplant islet graft survival
• Innate immunity in early islet graft loss

Activation of adenosine A(2A) 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 A(2A) 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 A(2A)AR antagonist abrogated ATL's protective effect, reducing SI (1.11 +/- 0.42). ATL treatment of A(2A)AR(+/+) islet/A(2A)AR(-/-) leukocyte cocultures failed to protect islet SI), implicating leukocytes as likely targets of A(2A)AR 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 A(2A) 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.

• 出版日期2010
• 单位四川大学