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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2019

Open Access 01-12-2019 | Candida Balanitis | Research

Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis

Authors: Rachel Spiering, Manon A. A. Jansen, Matthew J. Wood, Anshorulloh A. Fath, Oliver Eltherington, Amy E. Anderson, Arthur G. Pratt, Willem van Eden, John D. Isaacs, Femke Broere, Catharien M. U. Hilkens

Published in: Journal of Translational Medicine | Issue 1/2019

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Abstract

Background

Autologous tolerogenic dendritic cells (tolDC) are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses. Here, we investigated two outstanding priorities for clinical development: (i) the suitability of using heat-shock proteins (HSP), abundant in inflamed synovia, as surrogate autoantigens to be presented by tolDC and (ii) identification of functional biomarkers that confirm tolDC regulatory activity.

Methods

Cell proliferation dye-labelled human peripheral blood mononuclear cells of IA (rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) patients or healthy donors were cultured with HSP40-, HSP60- and HSP70-derived peptides or recall antigens (e.g. tuberculin purified protein derivative (PPD)) in the presence or absence of tolDC or control DC for 9 days. Functional characteristics of proliferated antigen-specific T-cells were measured using flow cytometry, gene expression profiling and cytokine secretion immunoassays. Repeated measures analysis of variance (ANOVA) with Bonferroni correction for comparisons between multiple groups and paired Student t test for comparisons between two groups were used to determine significance.

Results

All groups showed robust CD4+ T-cell responses towards one or more HSP-derived peptide(s) as assessed by a stimulation index > 2 (healthy donors: 78%, RA: 73%, PsA: 90%) and production of the cytokines IFNγ, IL-17A and GM-CSF. Addition of tolDC but not control DC induced a type 1 regulatory (Tr1) phenotype in the antigen-specific CD4+ T-cell population, as identified by high expression of LAG3, CD49b and secretion of IL-10. Furthermore, tolDC inhibited bystander natural killer (NK) cell activation in a TGFβ dependent manner.

Conclusions

HSP-specific CD4+ T-cells are detectable in the majority of RA and PsA patients and can be converted into Tr1 cells by tolDC. HSP-loaded tolDC may therefore be suitable for directing T regulatory responses to antigens in inflamed synovia of IA patients. Tr1 markers LAG3, CD49b and IL-10 are suitable biomarkers for future tolDC clinical trials.
Appendix
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Metadata
Title
Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis
Authors
Rachel Spiering
Manon A. A. Jansen
Matthew J. Wood
Anshorulloh A. Fath
Oliver Eltherington
Amy E. Anderson
Arthur G. Pratt
Willem van Eden
John D. Isaacs
Femke Broere
Catharien M. U. Hilkens
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-019-2128-4

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