Localized Immunosuppression With Tannic Acid Encapsulation Delays Islet Allograft and Autoimmune-Mediated Rejection

Abstract

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.

The role of NADPH oxidases in infectious and inflammatory diseases

“…The goal of this therapy would be to induce tolerance to autoantigens associated with T1D by dampening ROS, which results in antigen hyporesponsiveness [ 285 ]. We have also used PVPON and tannic acid-containing biomaterials to encapsulate islets for transplantation into diabetic recipients [ 286 ]. Encapsulation with the PVPON and tannic acid-containing biomaterial delays islet allograft and autoimmune-mediated rejection after transplantation into diabetic recipients [ 286 ].…”

“…We have also used PVPON and tannic acid-containing biomaterials to encapsulate islets for transplantation into diabetic recipients [ 286 ]. Encapsulation with the PVPON and tannic acid-containing biomaterial delays islet allograft and autoimmune-mediated rejection after transplantation into diabetic recipients [ 286 ].…”

Xenotransplantation of tannic acid‐encapsulated neonatal porcine islets decreases proinflammatory innate immune responses

“…For detection of STAT1 and STAT6, islet grafts were excised 2 days post-transplantation from NOD.Rag recipients (n = 3-4), flash-frozen in optimal cutting temperature compound, cut to 6 μm, fixed with 4% paraformaldehyde followed by cold methanol, and performed immunofluorescence as described. 29 For insulin immunohistochemistry, sections were incubated with 10% hydrogen peroxide (Fisher Scientific), blocked in non-specific serum, and incubated with primary antibody. Sections were incubated with species-specific biotinylated secondary antibody (1:200; Vector Laboratories) followed by peroxidase-streptavidin, substrate-chromogen (diaminobenzidine (DAB)).…”

“…RNA isolation, cDNA conversion, and gene expression analysis were performed as described. 29,30 cDNA was amplified on a Roche LightCycler 480 by quantitative PCR using TaqMan gene expression assays from Applied Biosystems:…”

“…Our previously published data demonstrated that (PVPON/TA) encapsulation of mouse islets can diminish in vitro proinflammatory cytokine and chemokine production, autoreactive T-cell migration, and delay islet allograft rejection. 21,22,29 Therefore, we sought to determine whether xenotransplanted (PVPON/TA)-encapsulated NPIs were immunoprotective against proinflammatory innate immune responses.…”