Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.
Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.
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DOI：
10.1111/ajt.17162
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发表时间：
2022-11
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影响因子：
--
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同种异体胰岛移植是治疗糖尿病控制不佳的一种很有前途的实验性治疗方法。尽管有药物免疫抑制，长期胰岛移植仍然难以实现。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]，其组成性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的鼠胰岛在体外维持稳健的动态胰岛素分泌，并且当移植到同种异体高血糖鼠受体中时，在不存在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的糖尿病和自身免疫性糖尿病超过50周和8周，并且依赖于宿主CD 4能力。此外，同种异体移植物中的PIDO表达保留了胰岛的内分泌功能活力，并促进了局部的致耐受性环境，其特征在于抑制宿主CD 8 T细胞和吞噬细胞募集以及FOXP 3 + T细胞的积累。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受体中表现出生理性葡萄糖响应性胰岛素分泌能力长达20周。总之，PIDO转基因技术使宿主CD 4 + T细胞调节的免疫逃避性和胰岛同种和异种移植物在免疫功能正常的受者中的长期功能活力成为可能，而不需要药理学免疫抑制，并且可以改善组织移植的结果。对包含PD-L1和IDO的新型重组融合蛋白在胰岛中的表达进行基因工程改造，通过CD 8 + T细胞抑制和FoxP 3 + Treg募集局部调节宿主免疫应答，预防移植胰岛的急性和慢性同种异体移植物排斥，并逆转自身免疫性糖尿病。
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. Gene engineering the expression of a novel recombinant fusion protein comprising PD‐L1 and IDO in pancreatic islets prevents acute and chronic allograft rejection of transplanted islets and reverses autoimmune diabetes by local modulation of host immune responses through CD8+ T cell suppression and FoxP3+ Treg recruitment.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
--
作者：
Litzenburger UM;Opitz CA;Sahm F;Rauschenbach KJ;Trump S;Winter M;Ott M;Ochs K;Lutz C;Liu X;Anastasov N;Lehmann I;Höfer T;von Deimling A;Wick W;Platten M
通讯作者：
Platten M
DOI：
10.1056/nejmra1911109
发表时间：
2020-09-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bluestone JA;Anderson M
通讯作者：
Anderson M
影响因子：
2.9
作者：
Kin, T;Iwata, H;Nakajima, Y
通讯作者：
Nakajima, Y
影响因子：
5
作者：
Huang L;Baban B;Johnson BA 3rd;Mellor AL
通讯作者：
Mellor AL