A combination hydrogel microparticle-based vaccine prevents type 1 diabetes in non-obese diabetic mice.

Young Mee Yoon,Clive H Wasserfall,Mark A Atkinson,Martha Campbell-Thompson,Benjamin G Keselowsky,Jamal S Lewis,Matthew R Carstens

doi:10.1038/srep13155

Young Mee Yoon, Clive H Wasserfall + Show 5 more

Open Access

https://doi.org/10.1038/srep13155

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Journal: Scientific Reports	Publication Date: Aug 17, 2015
Citations: 75	License type: CC BY 4.0

Affiliation: University of Florida

Abstract

Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrixTM peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple subcutaneous injections of the insulin containing formulation resulted in formation of granulomas, which resolved by 28 weeks. Histological analysis of these granulomas indicated infiltration of a diverse cadre of immune cells, with characteristics reminiscent of a tertiary lymphoid organ, suggesting the creation of a microenvironment to recruit and educate immune cells. These results demonstrate the feasibility of this injectable hydrogel/MP based vaccine system to prevent T1D.

Highlights

Particulate vaccines, and a possible mechanism of antigen-specific tolerance induction could be via inducing anti-inflammatory cytokine production, antigen-specific T cell anergy, deletion, or regulatory T cell population[10,11,12,13]
To validate the compatibility of the two materials, and verify their ability to form a 3D hydrogel when combined, PLGA MPs were added to PuraMatrixTM and incubated for 1 h to promote gelation (Fig. 1A)
Scanning electron microscope (SEM) imaging showed the surface of the scaffold and confirmed that the MPs were well incorporated into the hydrogel (Fig. 1B)

Summary

Introduction

Particulate vaccines, and a possible mechanism of antigen-specific tolerance induction could be via inducing anti-inflammatory cytokine production, antigen-specific T cell anergy, deletion, or regulatory T cell population[10,11,12,13]. Several studies indicate that CpG has an ability to boost anti-inflammatory effects through inducing IL-10 secretion, FoxP3+ regulatory T cells in animal models for autoimmune arthritis and T1D32,33. Along these lines, Mellor et al, showed intravenous CpG induced an immunoregulatory enzyme indoleamine 2,3-dioxygenase in splenic CD19+ dendritic cells in B6 mice and suppressed T cell stimulatory functions[34]. GM-CSF, was utilized as a chemoattractant, since it has the ability to promote recruitment of circulating monocytes, lymphocytes, and neutrophils This cytokine can activate and increase the function of antigen presenting cells dendritic cell and macrophage populations[35,36]. We formulated a combination hydrogel MP vaccine and investigated prevention of T1D in non-obese diabetic (NOD) mice

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