Immunology Research Centre, St Vincent's Hospital, Melbourne, Victoria, Australia.
Diabetes. 2013 Jun;62(6):2026-35. doi: 10.2337/db12-0625. Epub 2013 Jan 30.
Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell-mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell-mediated injury.
胰岛细胞移植的长期成功受到胰岛移植物存活的限制，因为胰岛移植物存活是胰岛移植作为 1 型糖尿病潜在治疗方法的一个限制因素。许多因素会损害胰岛的存活，包括复发性糖尿病。我们研究了是否 CD39（一种促进细胞外腺苷生成的外核苷酸酶）能够减轻 T 细胞介导的多次小剂量链脲佐菌素（MLDS）模型中的糖尿病。CD39 缺失（CD39KO）、野生型（WT）和过表达 CD39（CD39TG）的小鼠接受 MLDS 处理。进行了过继转移实验以描绘组织特异性过表达 CD39 的功效。使用突变小鼠和药理学抑制来研究腺苷信号的作用。CD39 的表达水平影响对 MLDS 诱导的糖尿病的易感性。与 WT 小鼠相比，CD39KO 小鼠更快且更频繁地发生糖尿病。相比之下，CD39TG 小鼠受到保护。CD39 的过表达通过激活腺苷 A2A 受体和腺苷 A2B 受体提供保护。过继转移实验表明，组织特异性过表达 CD39 可提供强大的保护，表明这可能是保护胰岛移植物免受 T 细胞介导的损伤的一种有用策略。
