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Lookup NU author(s): Dr Rachel Harry, Dr Amy AndersonORCiD, Professor John IsaacsORCiD, Professor Catharien Hilkens
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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.
Author(s): Harry RA, Anderson AE, Isaacs JD, Hilkens CM
Publication type: Article
Publication status: Published
Journal: Annals of the Rheumatic Diseases
Year: 2010
Volume: 69
Issue: 11
Pages: 2042-2050
Print publication date: 15/06/2010
ISSN (print): 0003-4967
ISSN (electronic): 1468-2060
Publisher: BMJ Group
URL: http://dx.doi.org/10.1136/ard.2009.126383
DOI: 10.1136/ard.2009.126383
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