Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice. PIDO expressing murine islets maintain robust dynamic insulin secretion in vitro and when transplanted in allogeneic hyperglycemic murine recipients reverse pre-existing streptozotocin-induced and autoimmune diabetes in the absence of pharmacological immunosuppression for more than 50 and 8 weeks, respectively, and is dependent on host CD4 competence. Additionally, PIDO expression in allografts preserves endocrine functional viability of islets and promotes a localized tolerogenic milieu characterized by the suppression of host CD8 T cell and phagocyte recruitment and accumulation of FOXP3⁺ Tregs. Furthermore, in the canine model of xenogeneic islet transplantation, muscle implanted PIDO-expressing porcine islets displayed physiological glucose-responsive insulin secretion competency in euglycemic recipient for up to 20 weeks. In conclusion, the PIDO transgenic technology enables host CD4⁺ T cell-modulated immune evasiveness and long-term functional viability of islet allo- and xenografts in immune-competent recipients without the need for pharmacological immune suppression and would allow for improved outcomes for tissue transplantation.

中文翻译：

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在没有全身免疫抑制的免疫活性小鼠中，表达 PD-L1 和 IDO 融合蛋白的胰岛同种异体移植物可逃避免疫排斥并逆转先前存在的糖尿病

对于控制不佳的糖尿病，同种异体胰岛移植是一种很有前途的实验性疗法。尽管有药理学免疫抑制作用，但长期的胰岛植入仍然难以捉摸。在这里，我们设计了一种合成的融合转基因偶联 PD-L1 和吲哚胺双加氧酶 [以下简称 PIDO]，其组成型表达可防止移植到免疫活性小鼠中的基因工程胰岛同种异体移植物的免疫破坏。表达 PIDO 的小鼠胰岛在体外保持强劲的动态胰岛素分泌，当移植到同种异体高血糖小鼠受体中时，在没有药理学免疫抑制的情况下分别逆转预先存在的链脲佐菌素诱导和自身免疫性糖尿病超过 50 周和 8 周，并且依赖于宿主CD4 能力。此外，⁺ Tregs。此外，在异种胰岛移植的犬模型中，肌肉植入的表达 PIDO 的猪胰岛在血糖正常的接受者中显示生理葡萄糖反应性胰岛素分泌能力长达 20 周。总之，PIDO 转基因技术使宿主 CD4 ⁺ T 细胞调节的免疫逃避和胰岛同种异体移植物和异种移植物在免疫能力强的受体中具有长期功能活力，而无需药物免疫抑制，并将改善组织移植的结果.