DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice

Chang, Ying; Yap, Solomon; Ge, Xin Janet; Piganelli, Jon D.; Bertera, Suzanne; Giannokakis, N; Mathews, Clayton E.; Prud’homme, Gérald J.; Trucco, Massimo

doi:10.1038/sj.gt.3302578

Cited by 15 publications

(10 citation statements)

References 51 publications

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“…Moreover, hepatocytedirected gene transfer resulted in a significant reversal of T1D when combined with a suboptimal, per se ineffective, dose of anti-CD3 mAb. Several gene transfer-based approaches to prevent/treat T1D have been investigated (38)(39)(40)(41)(42)(43)(44). Administration of AAV (39,40) or mRNA (41) encoding for cytokines resulted in prevention of T1D.…”

Section: Discussionmentioning

confidence: 99%

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs

et al. 2015

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Antigen (Ag)-specific tolerance in type 1 diabetes (T1D) in human has not been achieved yet. Targeting lentiviral vector (LV)-mediated gene expression to hepatocytes induces active tolerance toward the encoded Ag. The insulin B chain 9-23 (InsB9-23) is an immunodominant T cell epitope in nonobese diabetic (NOD) mice. To determine whether auto-Ag gene transfer to hepatocytes induces tolerance and control of T1D, NOD mice were treated with integrase-competent LVs (ICLVs) that selectively target the expression of InsB9-23 to hepatocytes. ICLV treatment induced InsB9-23-specific effector T cells but also FoxP3(+) regulatory T cells (Tregs), which halted islet immune cell infiltration, and protected from T1D. Moreover, ICLV treatment combined with a single suboptimal dose of anti-CD3 monoclonal antibody (mAb) is effective in T1D reversal. Splenocytes from LV.InsB9-23-treated mice, but not from LV.OVA (ovalbumin)-treated control mice, stopped diabetes development, demonstrating that protection is Ag-specific. Depletion of CD4(+)CD25(+)FoxP3(+) T cells led to diabetes progression, indicating that Ag-specific FoxP3(+) Tregs mediate protection. Integrase-defective LVs (IDLVs).InsB9-23, which alleviate the concerns for insertional mutagenesis and support transient transgene expression in hepatocytes, were also efficient in protecting from T1D. These data demonstrate that hepatocyte-targeted auto-Ag gene expression prevents and resolves T1D and that stable integration of the transgene is not required for this protection. Gene transfer to hepatocytes can be used to induce Ag-specific tolerance in autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs

et al. 2015

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“…Recent results in a study in which newly diagnosed patients with Type 1 diabetes were vaccinated did not show any benefit of vaccination [18]. Beside GAD, the antigens heat shock protein [64] and CTLA4 [65] have been considered to be appropriate for vaccination. CTLA4 is an immunoglobulin fusion protein (abatacept), with the ability to block interaction between CD80 and CD86 on antigen-presenting cells and CD28 on T cells.…”

Section: Intervention Trials With Specific Immune Suppressionmentioning

confidence: 97%

Immunotherapy for Type 1 diabetes: past and future

Landin‐Olsson¹,

Erlanson–Albertsson²

2012

Diabetes Management

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“…A less conventional alternative to protein antigen delivery lets the body produce specific antigens in cells or sites amenable for tolerance induction following gene transfer . Plasmid DNA encoding autoantigens such as insulin or its InsB 9‐23 immunodominant peptide prevented disease in NOD mice and was given to recent‐onset T1D patients in a phase 1 trial . Data from this trial demonstrated both safety and diminution of insulin‐reactive CD8 + T cells, thus tolerogenic DNA vaccines merit consideration for prevention trials.…”

Section: Overview Of the Current Landscape Of Non‐cell Therapiesmentioning

confidence: 99%

Concise Review: Cell-Based Therapies and Other Non-Traditional Approaches for Type 1 Diabetes

et al. 2016

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The evolution of Type 1 diabetes (T1D) therapy has been marked by consecutive shifts, from insulin replacement to immunosuppressive drugs and targeted biologics (following the understanding that T1D is an autoimmune disease), and to more disease‐specific or patient‐oriented approaches such as antigen‐specific and cell‐based therapies, with a goal to provide efficacy, safety, and long‐term protection. At the same time, another important paradigm shift from treatment of new onset T1D patients to prevention in high‐risk individuals has taken place, based on the hypothesis that therapeutic approaches deemed sufficiently safe may show better efficacy if applied early enough to maintain endogenous β cell function, a concept supported by many preclinical studies. This new strategy has been made possible by capitalizing on a variety of biomarkers that can more reliably estimate the risk and rate of progression of the disease. More advanced (“omic”‐based) biomarkers that also shed light on the underlying contributors of disease for each individual will be helpful to guide the choice of the most appropriate therapies, or combinations thereof. In this review, we present current efforts to stratify patients according to biomarkers and current alternatives to conventional drug‐based therapies for T1D, with a special emphasis on cell‐based therapies, their status in the clinic and potential for treatment and/or prevention. Stem Cells 2016;34:809–819

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DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice

Cited by 15 publications

References 51 publications

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs

Immunotherapy for Type 1 diabetes: past and future

Concise Review: Cell-Based Therapies and Other Non-Traditional Approaches for Type 1 Diabetes

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DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice

Cited by 15 publications

References 51 publications

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 + T regs

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 + T regs

Immunotherapy for Type 1 diabetes: past and future

Concise Review: Cell-Based Therapies and Other Non-Traditional Approaches for Type 1 Diabetes

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Product

Resources

About

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs

Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 ⁺ T _regs