Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis
- Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Newcastle Upon Tyne, UK
- Correspondence to Dr Catharien Hilkens, Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK;
- Accepted 5 April 2010
- Published Online First 15 June 2010
Objectives Tolerogenic dendritic cells (tolDCs) constitute a promising experimental treatment for targeting autoreactive T cells in autoimmune diseases, including rheumatoid arthritis (RA). The authors' goal is to bring tolDC therapy for RA to the clinic. Here the authors address key translational issues related to the manufacturing of tolDCs from RA patients with current good manufacturing practice (cGMP)-compliant reagents, the stability of tolDCs, and the selection of suitable quality control markers.
Methods Human monocyte-derived tolDCs were established from RA patients and healthy controls (HCs) using the immunosuppressive drugs dexamethasone and vitamin D3, and the cGMP-grade immunomodulator, monophosphoryl lipid A, in the cGMP-compliant medium, CellGroDC. The functionality of tolDCs and tolDC-modulated autologous CD4 T cells was determined by flow cytometry, [3H]thymidine incorporation and ELISA.
Results Clinical-grade tolDCs established from patients with RA exhibit a typical tolerogenic phenotype of reduced costimulatory molecules, low production of proinflammatory cytokines and impaired stimulation of autologous antigen-specific T cells, comparable to HC tolDCs. Toll-like receptor 2 (TLR-2) was highly expressed by tolDCs but not mature DCs. Furthermore, tolDCs suppressed mature DC-induced T cell proliferation, interferon γ and interleukin 17 production, and rendered T cells hyporesponsive to further stimulation. Importantly, tolDCs were phenotypically stable in the absence of immunosuppressive drugs and were refractory to further challenge with proinflammatory mediators.
Conclusions tolDCs established from patients with RA are comparable to those derived from healthy donors. TLR-2 was identified as an ideal marker for quality control of tolDCs. Potently tolerogenic and highly stable, these tolDCs are a promising cellular therapeutic for tailored immunomodulation in the treatment of RA.
Funding JGW Patterson Foundation, Arthritis Research Campaign.
Competing interests None.
Ethics approval This study was conducted with the approval of the Newcastle and North Tyneside Research Ethics Committee 2.
Provenance and peer review Not commissioned; externally peer reviewed.
This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl