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Localized immunosuppression with tannic acid encapsulation delays islet allograft and autoimmune-mediated rejection

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posted on 2020-06-25, 21:55 authored by Ada AdminAda Admin, Jessie M. Barra, Veronika Kozlovskaya, Eugenia Kharlampieva2, Hubert M. Tse
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 non-encapsulated islets. Transplantation of (PVPON/TA)-encapsulated islets was immunomodulatory as gene expression and flow cytometric analysis revealed significantly decreased in immune cell infiltration, synthesis of ROS, 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.

Funding

This work was supported by an NIH/NIDDK R01 award (DK099550) (HMT), JDRF award SRA-2016-270-S-B (HMT), JDRF award 2-SRA-2019-692-S-B (HMT), NSF research grant NSF-DMR 1608728 (EK), NIH NIGMS (T32.GM109780) Translational and Molecular Sciences (JMB), and NIH NIGMS (T32.GM008111) Cell, Molecular, and Developmental Biology T32 training grant (JMB).

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