Developing immune-regulatory materials using immobilized monosaccharides with immune-instructive properties.

M A Alobaid,M I Gibson,A M Ghaemmaghami,S-J Richards,M R Alexander

doi:10.1016/j.mtbio.2020.100080

M A Alobaid, M I Gibson + Show 3 more

Open Access

https://doi.org/10.1016/j.mtbio.2020.100080

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Abstract

New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC–T cell co-cultures where DCs cultured on the ‘regulatory’ monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable.

Highlights

The immune system plays a central role in response to foreign materials we are exposed to, from pathogens to biomaterials used for therapeutic purposes [1]
The C-type lectin receptors (CLRs) are amongst many Pattern recognition receptor (PRR) expressed by Dendritic cells (DCs) and belong to a family of carbohydrate-binding proteins that recognize a broad repertoire of self and non-self ligands, with diverse functions in innate and adaptive immunity and maintaining homeostasis [10]
To investigate the effect of surface-immobilized monosaccharides on DC phenotype and IDO activity, immature and LPS-stimulated DCs were cultured on the monosaccharide-immobilized polystyrene plates containing different ratios of amino-fucose, amino-mannose, and aminogalactose for 24 h followed by flow cytometric analysis of their surface phenotype and quantifying kynurenine in the supernatant as a surrogate for IDO activity

Summary

Introduction

The immune system plays a central role in response to foreign materials we are exposed to, from pathogens to biomaterials used for therapeutic purposes [1]. Different CLRs recognize different carbohydrate moieties, and interaction between a given CLR and its ligand could influence DC phenotype and cytokine profile as well as downstream events leading to T cell polarization [11,12] Prime examples of these are the carbohydrate moieties decorating allergens and pathogen glycoproteins, which modulate the immune response depending on their CLR counterparts [12,13,14,15] leading to inflammatory responses or immune evasion [16,17,18]. In parallel to their role in initiating immune responses, DCs play a key role in maintaining tissue homeostasis and immune regulation. This is exemplified in tumors with high IDO activity leading to depletion of tryptophan and an increase in kynurenine levels that suppresses the immune activity that contributes to the survival of the tumor [23]

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