Abstract
BackgroundAutologous 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.MethodsCell 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.ResultsAll 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.ConclusionsHSP-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.
Highlights
Autologous tolerogenic dendritic cells are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses
Pro‐inflammatory heat-shock proteins (HSP)‐specific T‐cells are present in IA patients Our initial studies investigated whether immunodominant pan-DR-binding peptides from bacterial HSP40, mycobacterial-HSP60 (p1 and p3) and myc-HSP70 (B29) [14, 15, 18] could be recognised by peripheral blood C D4+ T-cells of healthy donors and IA patients (Table 1)
In the majority of cases, donors responded to one HSP only, but in around 10% of cases there was a detectable response to all four HSP peptides (Additional file 2: Fig S1)
Summary
Autologous tolerogenic dendritic cells (tolDC) are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses. Current treatments involve chronic immunosuppression in a non-antigen specific manner. We recently conducted a clinical trial of autologous tolDC treatment in both RA and psoriatic arthritis (PsA) patients, confirming the safety and feasibility of this approach [3]. Because tolDC act in a highly targeted manner, it is imperative to monitor changes in antigen-specific T-cells, rather than measuring systemic immune markers. Loading of tolDC with known antigens will enable immune monitoring in a highly specific manner. Future therapeutic studies with tolDC can be greatly improved by loading tolDC with relevant and known antigens, facilitating immune monitoring at the antigen-specific level and defining biomarkers of tolDC effectiveness
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