PLG Scaffold Delivered Antigen-Specific Regulatory T Cells Induce Systemic Tolerance in Autoimmune Diabetes
PLG Scaffold Delivered Antigen-Specific Regulatory T Cells Induce Systemic Tolerance in Autoimmune Diabetes
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DOI：
10.1089/ten.tea.2012.0643
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发表时间：
2013-06-01
影响因子：
4.1
通讯作者：
Shea, Lonnie D.
中科院分区：
文献类型：
--
作者：
Graham, John G.;Zhang, Xiaomin;Shea, Lonnie D.
胰岛移植是治疗人类 1 型糖尿病的一种有前景的方法。移植需要全身免疫抑制，这会产生许多有害的副作用。在非肥胖糖尿病 (NOD) 模型中，当胰岛抗原特异性调节性 T 细胞 (Treg) 共定位于肾被膜时，其已被证明可以保护胰岛移植物免受自身免疫破坏。通过将负载胰岛的微孔聚丙交酯乙交酯 (PLG) 支架移植到腹部脂肪中来建立肝外移植部位。这项研究检查了自身免疫移植模型，并确定共定位的 Tregs 是否可以保护肝外和肾外移植部位的胰岛移植物。血糖恢复正常，联合移植的 Tregs 延长了移植物的存活率，包括数个无限期保护的实例。随着时间的推移，移植的Tregs被受体衍生的Tregs取代，这表明胰岛抗原特异性Tregs通过宿主衍生的Tregs诱导对胰岛移植物的耐受。因此，Tregs 在 NOD 模型中提供了针对介导糖尿病的多种自身反应性 T 细胞受体特异性的保护，可能是通过先前描述的感染耐受现象。有趣的是，Tregs 的浸润保护了第二次胰岛移植，表明对胰岛抗原的系统耐受性。总之，PLG支架可以作为胰岛移植的替代递送系统，允许免疫调节细胞在胰岛移植物内共定位，并在自身免疫糖尿病模型中诱导移植物长期存活。这种将免疫调节细胞与胰岛共定位于临床可移植移植位点以在局部和全身水平上影响免疫系统的方法对人类胰岛移植具有潜在的治疗意义。
Islet transplantation is a promising treatment for human type 1 diabetes mellitus. Transplantation requires systemic immunosuppression, which has numerous deleterious side effects. Islet antigen-specific regulatory T cells (Tregs) have been shown to protect islet grafts from autoimmune destruction in the nonobese diabetic (NOD) model when co-localized in the kidney capsule. An extra-hepatic transplant site was established by transplanting islet-loaded microporous poly (lactide-co-glycolide) (PLG) scaffolds into abdominal fat. This study examined an autoimmune transplantation model and determined whether co-localized Tregs could protect islet grafts in an extra-hepatic and extra-renal transplant site. Normoglycemia was restored, and co-transplanted Tregs extended graft survival, including several instances of indefinite protection. Transplanted Tregs were replaced by recipient-derived Tregs over time, indicating that islet antigen-specific Tregs induce tolerance to islet grafts through host-derived Tregs. Thus, Tregs provided protection against a diverse repertoire of autoreactive T-cell-receptor specificities mediating diabetes in the NOD model, possibly through a phenomenon previously described as infectious tolerance. Interestingly, the infiltration by Tregs protected a second islet transplant, indicating systemic tolerance to islet antigens. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that allows for the co-localization of immunomodulatory cells within islet grafts and induces long-term graft survival in an autoimmune diabetes model. This method of co-localizing immunomodulatory cells with islets in a clinically translatable transplant site to affect the immune system on a local and systemic level has potential therapeutic implications for human islet transplantation.