Background/Purpose

We carried out a phase I clinical trial of tolerising autologous peripheral blood DCs exposed to 4 citrullinated self-peptides (“Rheumavax”) in 29 HLA-DR shared epitope (SE)+ anti-citrullinated peptide antibody+ DMARD-treated rheumatoid arthritis (RA) patients, of whom 18 received Rheumavax. This study aimed to evaluate immune biomarkers of treatment and of clinical response to Rheumavax.

Methods

Frozen peripheral blood mononuclear cells (PBMC) were analysed for T cell, B cell, monocyte and DC subsets by flow cytometry (FACS) at baseline, 6 days, 4, 8, 12 and 24 weeks after Rheumavax, and Luminex and ELISA assays were used to measure 108 serum analytes. PBMC were stimulated ex vivo for 5 days with each of the delivered citrullinated peptides, or with control citrullinated aggrecan peptide or tetanus toxoid antigens. Proliferation and cytokine production were measured. To identify relevant markers of change, we used sparse partial least squares linear multivariate approach, multilinear regression, ANOVA and t tests.  

Results

Median disease duration of recruited patients was 2 years. At baseline, 9 of 18 patients assigned to Rheumavax had an incomplete response to DMARDs with a swollen joint count (SJC) of at least 1; 9 had minimal disease activity. One month after Rheumavax, SJC of patients with active disease at baseline reduced by a mean of 5 joints and SJC of those with inactive disease did not change. Immune effects of Rheumavax were first expected 6 days after administration. Using a multiple linear regression to model the effect of changes in PB cells at day 6 on clinical response, we found that reduction in the proportions of CD25+CD127+ activated CD4+ T cells and CD14loCD16- monocytes, and increased proportions of CD25-CD127+CD4+ naive cells, CD56+CD16+ NK cells and Foxp3+CD127loCD25hi Treg cells predicted the reduction in SJC 1 month after Rheumavax with R² of 0.85 (p=0.0001). Relative to controls, treated patients had an increased proportion of PB CD25+CD127-CD4+ induced (i)Treg from 6 days until 8 weeks after Rheumavax.  Specific increase in IL-10 production in response to delivered cit-peptides occurred ex vivo in 4 patients, increased iTreg in 8 patients and an increase in IL-10 and iTreg in 4 patients post-Rheumavax treatment. Reduction in 12 pro-inflammatory cytokines, chemokines and metabolic factors in serum discriminated the 1 month response in Rheumavax treated and untreated patients. Consistent with their clinical and inflammatory improvement, treated patients had an increased proliferative response to tetanus toxoid ex vivo within 6 days of Rheumavax.

Conclusion

These data suggest that autologous tolerising DCs exposed to citrullinated peptides improved disease control in RA patients with prior partial response to DMARDs through reduction in circulating activated T cells and dendritic cell precursors, induction of Treg and lytic NK cells, and suppression of systemic inflammation, thereby restoring regulatory balance and immune function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multiple-mechanisms-of-tolerance-characterize-the-immune-response-to-autologous-modified-dendritic-cells-exposed-to-citrullinated-peptides-in-patients-with-rheumatoid-arthritis/