Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes

Kroger, Charles J.; Clark, Matthew; Qin, Ke; Tisch, Roland

doi:10.3389/fimmu.2018.01891

Cited by 27 publications

(19 citation statements)

References 238 publications

(227 reference statements)

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“…Cell-based therapies using ex vivo administration of Ag-specific autologous regulatory T cells (Tregs) are in clinical testing to examine the efficacy of these immunosuppressive cells to delay autoimmune diseases such as type 1 diabetes (T1D) (12,13). Adoptive transfer of expanded Foxp3 + Tregs has shown promise in mice; however, technical limitations of human Tregs expansion ex vivo still need to be overcome (14). In addition to the use of Tregs, transfer of immunomodulatory dendritic cells (DCs) can restore Ag-specific peripheral tolerance and induce anergy in effector T cells (15,16).…”

Section: Introductionmentioning

confidence: 99%

Dampening Antigen-Specific T Cell Responses with Antigens Encapsulated in Polyphenolic Microcapsules

et al. 2020

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Efficient T cell activation and effector responses require an antigenic peptide presented on the MHC complex to the TCR (signal 1), costimulatory molecule interactions between T cells and APCs (signal 2), and the synthesis of innate immune-derived proinflammatory cytokines and reactive oxygen species (signal 3). We previously demonstrated that the third signal dissipation impairs autoreactive T cell activation. In this study, we tested the hypothesis that encapsulation of Ag with an antioxidant-containing biomaterial would induce Ag-specific hyporesponsiveness. We cocultured bone marrow-derived dendritic cells with microcapsules composed of multilayer-assembled poly(N-vinylpyrrolidone) (PVPON) and the antioxidant tannic acid (TA). LPS-activated dendritic cells cocultured with (PVPON/TA) microcapsules displayed a decrease in TNF-a, IL-12p70, and CXCL10 synthesis. To study Agspecific T cell responses, we incorporated chicken OVA into the (PVPON/TA) multilayers and stimulated OT-II splenocytes in a primary recall assay. Flow cytometric analysis demonstrated a significant inhibition of CD4 T cell activation markers, upregulation of CTLA-4 and PD-1, and blunted secretion of IL-2, IFN-g, TNF-a, and CXCL10 by ELISA. To test microcapsule efficacy in vivo, we immunized OT-II mice with (PVPON/TA)-OVA microcapsules and performed an OVA recall assay. Immunization of OT-II mice with (PVPON/TA)-OVA microcapsules elicited a decrease in CD4 T cell differentiation and effector responses including IFN-g, TNF-a, CCL3, and CCL5 by ELISA compared with OVA immunization alone. These data show that microcapsules composed of antioxidant and encapsulated Ags can effectively blunt innate immune-derived proinflammatory third signal synthesis necessary for Ag-specific effector T cell responses and present a prospective strategy for T cell-mediated autoimmunity. ImmunoHorizons, 2020, 4: 530-545.

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Section: Introductionmentioning

confidence: 99%

Dampening Antigen-Specific T Cell Responses with Antigens Encapsulated in Polyphenolic Microcapsules

et al. 2020

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“…The most promising intervention to date is the use of the anti-CD3 antibody teplizumab that was recently shown to delay disease onset in individuals predicted to develop T1D within a few years 3 . However, no intervention exists that can reverse established disease without broad immunosuppression 4 . To overcome this critical issue, we sought to determine if genetic modifications exist that render transplanted beta cells resistant to autoimmune killing.…”

mentioning

confidence: 99%

Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes

et al. 2020

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Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, here we show that deleting RNLS , a GWAS candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modeling identified the FDA-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, leading to disease reversal. Further, pargyline could prevent or delay diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.

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“…were concentrated on the mechanism of autoimmunity [25] and genetically relevant loci in human leukocyte antigen (HLA) [26,27], which might benefit for T1D prediction and prevention [28]. Here in the present study, the mechanism of EZH2/ZBTB16 in T1D inhibition by FBW7 is clarified, suggesting that FBW7 is a promising target for T1D therapy.…”

Section: Discussionmentioning

confidence: 70%

E3 ubiquitin ligase FBW7-mediated ubiquitination of EZH2 prevents type I diabetes in NOD mice

Tian

Zhang

2020

Preprint

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Background Type I diabetes (T1D) is a heritable autoimmune disease targeting pancreatic beta cells. This study explores the molecular mechanism of E3 ubiquitin ligase FBW7 in reducing the occurrence of T1D. Methods The protein expression of FBW7, EZH2, and ZBTB16 was quantified in non-obese diabetic (NOD) mouse model of streptozotocin-induced T1D. Next, splenocytes and pancreatic beta cells were isolated to measure production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Besides, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by immunoprecipitation (IP) assay. Last, chromatin immunoprecipitation (ChIP) assay was employed to determine the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Results We found downregulated FBW7 and ZBTB16, and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited the production of pro-inflammatory cytokines in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. Conclusion FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

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Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes

Cited by 27 publications

References 238 publications

Dampening Antigen-Specific T Cell Responses with Antigens Encapsulated in Polyphenolic Microcapsules

Dampening Antigen-Specific T Cell Responses with Antigens Encapsulated in Polyphenolic Microcapsules

Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes

E3 ubiquitin ligase FBW7-mediated ubiquitination of EZH2 prevents type I diabetes in NOD mice

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