Localized Immunosuppression With Tannic Acid Encapsulation Delays Islet Allograft and Autoimmune-Mediated Rejection
Localized Immunosuppression With Tannic Acid Encapsulation Delays Islet Allograft and Autoimmune-Mediated Rejection
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DOI：
10.2337/db20-0248
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发表时间：
2020-09-01
期刊：
影响因子：
7.7
通讯作者：
Tse, Hubert M.
中科院分区：
文献类型：
--
作者：
Barra, Jessie M.;Kozlovskaya, Veronika;Tse, Hubert M.
1型糖尿病（T1 D）是一种产生胰岛素的β细胞的自身免疫性疾病。胰岛移植是T1 D的一种有希望的治疗方法，但长期移植物存活力和功能仍然具有挑战性。氧化应激在同种异体反应性和自身反应性免疫对移植胰岛的激活中起关键作用。因此，通过用抗氧化剂包封胰岛来靶向这些途径可能会延迟免疫介导的排斥反应。利用一层一层的方法，我们产生的nanothin封装材料含有单宁酸（TA），多酚化合物与氧化还原清除和抗炎作用，和聚（N-乙烯基吡咯烷酮）（PVPON），生物相容性聚合物。我们推测，移植PVPON/TA封装的同种异体C57 BL/6胰岛到糖尿病NOD小鼠将延长移植物功能，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包封的胰岛的糖尿病受者比那些接受非包封胰岛的受者维持了更长时间的移植物排斥反应和延迟排斥反应。移植PVPON/TA封装的胰岛是免疫调节的，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，炎性趋化因子，细胞因子，CD 8 T细胞效应器反应的合成显着减少，并伴随着交替激活的M2巨噬细胞和树突状细胞表型的增加。我们的研究结果提供的证据表明，减少氧化应激后同种异体移植PVPON/TA封装的胰岛可以引起局部免疫抑制，并可能延迟移植物破坏在未来的人类胰岛移植研究。
Type 1 diabetes (T1D) is an autoimmune disease of insulin-producing beta-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.