Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham School of Medicine, Birmingham, AL.
Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL.
Diabetes. 2020 Sep;69(9):1948-1960. doi: 10.2337/db20-0248. Epub 2020 Jun 25.
Type 1 diabetes (T1D) is an autoimmune disease of insulin-producing β-cells. Islet transplantation is a promising treatment for T1D, but long-term graft viability and function remain challenging. Oxidative stress plays a key role in the activation of alloreactive and autoreactive immunity toward the engrafted islets. Therefore, targeting these pathways by encapsulating islets with an antioxidant may delay immune-mediated rejection. Utilizing a layer-by-layer approach, we generated nanothin encapsulation materials containing tannic acid (TA), a polyphenolic compound with redox scavenging and anti-inflammatory effects, and poly(N-vinylpyrrolidone) (PVPON), a biocompatible polymer. We hypothesize that transplantation of PVPON/TA-encapsulated allogeneic C57BL/6 islets into diabetic NOD mice will prolong graft function and elicit localized immunosuppression. In the absence of systemic immunosuppression, diabetic recipients containing PVPON/TA-encapsulated islets maintained euglycemia and delayed graft rejection significantly longer than those receiving nonencapsulated islets. Transplantation of PVPON/TA-encapsulated islets was immunomodulatory because gene expression and flow cytometric analysis revealed significantly decreased immune cell infiltration, synthesis of reactive oxygen species, inflammatory chemokines, cytokines, CD8 T-cell effector responses, and concomitant increases in alternatively activated M2 macrophage and dendritic cell phenotypes. Our results provide evidence that reducing oxidative stress following allotransplantation of PVPON/TA-encapsulated islets can elicit localized immunosuppression and potentially delay graft destruction in future human islet transplantation studies.
1 型糖尿病（T1D）是一种胰岛素产生β细胞的自身免疫性疾病。胰岛移植是治疗 T1D 的一种有前途的方法，但长期移植物的存活和功能仍然具有挑战性。氧化应激在针对移植胰岛的同种异体反应性和自身反应性免疫的激活中起关键作用。因此，通过用具有抗氧化作用的物质包裹胰岛来靶向这些途径，可能会延迟免疫介导的排斥反应。我们利用层层（layer-by-layer）方法生成了包含单宁酸（TA）的纳米薄包裹材料，TA 是一种具有氧化还原清除和抗炎作用的多酚化合物，以及聚（N-乙烯基吡咯烷酮）（PVPON），一种生物相容性聚合物。我们假设将 PVPON/TA 包裹的同种异体 C57BL/6 胰岛移植到糖尿病 NOD 小鼠中，将延长移植物功能并引发局部免疫抑制。在没有全身免疫抑制的情况下，含有 PVPON/TA 包裹胰岛的糖尿病受体的血糖维持正常，并且移植物排斥明显延迟，比接受未包裹胰岛的受体长。PVPON/TA 包裹胰岛的移植具有免疫调节作用，因为基因表达和流式细胞术分析显示免疫细胞浸润、活性氧物质合成、炎症趋化因子、细胞因子、CD8 T 细胞效应反应显著减少，同时替代激活的 M2 巨噬细胞和树突状细胞表型增加。我们的结果提供了证据，表明在同种异体移植 PVPON/TA 包裹胰岛后降低氧化应激可以引发局部免疫抑制，并可能在未来的人类胰岛移植研究中延迟移植物破坏。
