Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro

Tirth R Ghimire,Robert A Benson,Paul Garside,James M Brewer

doi:10.1016/j.imlet.2012.06.002

Tirth R Ghimire, Robert A Benson + Show 2 more

Open Access

https://doi.org/10.1016/j.imlet.2012.06.002

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Abstract

Aluminium adjuvants (alum) have been the only widely approved adjuvants for use in human vaccines since the 1920s, however, the mechanism of action of these adjuvants remains elusive. Due to increasing demand for novel adjuvants, a clearer understanding of the mechanisms that allow these important agents to affect adaptive immune responses will make a significant contribution to the rational design of future vaccines.Using a novel approach to tracking antigen and antigen presentation, we demonstrate that alum induces higher antigen accumulation and increased antigen presentation by dendritic cells (DCs) in vitro. Antigen accumulation was 100-fold higher and antigen presentation 10-fold higher following alum treatment when compared with soluble protein alone. We also observed that alum causes an initial reduction in presentation compared with soluble antigen, but eventually increases the magnitude and duration of antigen presentation. This was associated with reduced protein degradation in DCs following alum treatment. These studies demonstrate the dynamic alterations in antigen processing and presentation induced by alum that underlie enhanced DC function in response to this adjuvant.

Highlights

Despite the tremendous variety of compounds with adjuvant activity, effective adjuvants for use in vaccines against major diseases such as Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), tuberculosis and malaria remain elusive [1]
To determine the suitability of the Ealpha green fluorescent protein (E␣GFP)/YAe system to investigate the impact of alum on antigen uptake and presentation, bone marrow-derived dendritic cell (BMDC) were incubated with protein, alum-adsorbed protein or in the presence of media or alum alone for 24 h
The results suggest that the E␣GFP/YAe system is appropriate for the in vitro study of antigen uptake and presentation by dendritic cells (DCs) following alum treatment

Summary

Introduction

Despite the tremendous variety of compounds with adjuvant activity, effective adjuvants for use in vaccines against major diseases such as Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), tuberculosis and malaria remain elusive [1]. A significant obstacle to the development of new and improved adjuvants is our lack of knowledge of their mechanism of action. This is true of the aluminium adjuvants (alum) that have been applied in many vaccines since the 1920s [2]. It has been proposed that vaccine adjuvants act indirectly via DCs or other antigen presenting cells (APCs) to induce and enhance the activation of antigen-specific T cells and subsequently the adaptive immune response. CD4+ T cells play a central role in cell-mediated immunity and are activated in response to specific vaccine-derived, peptide epitopes bound to MHC class II (MHCII) molecules, displayed on the surface of APCs [3,4,5]. DCs possess highly controlled antigen processing functions utilising lysosomal proteases and pH changes optimal for the generation of peptides

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