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Extended report
TLR9 agonist CpG enhances protective nasal HSP60 peptide vaccine efficacy in experimental autoimmune arthritis
  1. Evelien Zonneveld-Huijssoon1,
  2. Femke van Wijk1,
  3. Sarah Roord1,
  4. Eveline Delemarre1,
  5. Jenny Meerding1,
  6. Wilco de Jager1,
  7. Mark Klein1,
  8. Eyal Raz2,
  9. Salvatore Albani3,4,
  10. Wietse Kuis1,
  11. Marianne Boes1,
  12. Berent J Prakken1,4
  1. 1Department of Pediatric Immunology, Centre for Molecular and Cellular Intervention, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2Department of Medicine, University of California San Diego, San Diego, California, USA
  3. 3Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
  4. 4EUREKA Institute for Translational Medicine, Siracusa, Italy
  1. Correspondence to Berent J Prakken, Department of Pediatric Immunology, University Medical Centre Utrecht, Centre for Molecular and Cellular Intervention, Lundlaan 6, 3584 EA Utrecht, The Netherlands; b.prakken{at}


Objectives Peptide-based immune tolerance induction is considered an attractive treatment option for autoimmune diseases. The authors have developed a novel method that can enhance the induction of protective peptide-specific T-cell responses, using a rat arthritis model. The authors focused on the Toll-like receptor 9 ligand CpG, which was shown to stimulate regulatory T-cell proliferation when added to plasmacytoid dendritic cells (pDC) using in-vitro cultures.

Methods The peptide used is a heat shock protein 60 epitope (p1) that elicits tolerogenic peptide-specific immune responses in human arthritis patients and was recently shown to have protective capacity as a bystander antigen in the rat adjuvant arthritis model. Rats were treated with three nasal doses of p1, CpG or a combination of p1 and CpG. Antigen-presenting cells were studied in nose-draining lymph nodes (mandibular lymph nodes; MLN) after nasal treatment, and T-cell responses were analysed in joint-draining lymph nodes after arthritis induction.

Results Nasal co-administration of p1/CpG significantly augmented the arthritis-protective effect of p1, while CpG treatment alone did not. Co-treatment of p1/CpG increased both the number and activation status of pDC in draining MLN, which was accompanied by amplified p1-specific T-cell proliferation and interleukin (IL)-10 production. During early arthritis, p1-specific IL-10 production was identified at the site of inflammation. P1 and p1/CpG-treated rats showed a greater amount of CD4+FoxP3+ regulatory T cells in the joint-draining lymph nodes, which correlated with lower arthritis scores.

Conclusions These clinical and immunological data suggest the use of CpG as a potent adjuvant for mucosal peptide-specific immune therapy in arthritis.

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  • Funding This study was funded by the Netherlands Organisation for Scientific Research, 5th European Framework Program, Dutch Rheumatoid Arthritis Foundation.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.