期刊
CELL TRANSPLANTATION
卷 19, 期 5, 页码 597-612出版社
COGNIZANT COMMUNICATION CORP
DOI: 10.3727/096368910X491806
关键词
Early islet loss; Adenosine receptor agonists in islet transplantation; Peritransplant islet graft survival; Innate immunity in early islet graft loss
资金
- Focus to Cure Diabetes Foundation
- National Institutes of Health [R01 HL37942]
- Juvenile Diabetes Research Foundation [5-2006-997, 1-2008-79]
- Adenosine Therapeutics Group (Charlottesville, VA), of PGxHealth LLC, a Division of Clinical Data, Inc.
- Adenosine Therapeutics Group
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL037942] Funding Source: NIH RePORTER
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 function (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.
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