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Open Access Adenosine A2A Agonist Administration Improves Islet Transplant Outcome: Evidence for the Role of Innate Immunity in Islet Graft Rejection

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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.

Keywords: Adenosine receptor agonists in islet transplantation; Early islet loss; Innate immunity in early islet graft loss; Peritransplant islet graft survival

Document Type: Research Article

DOI: https://doi.org/10.3727/096368910X491806

Affiliations: Department of Surgery, University of Virginia, Charlottesville, VA, USA

Publication date: 2010-05-01

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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