Treatment with dexamethasone and monophosphoryl lipid a removes disease-associated transcriptional signatures in monocyte-derived dendritic cells from rheumatoid arthritis patients and confers tolerogenic features
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2016-10-25Metadata
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García González, Paulina
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Treatment with dexamethasone and monophosphoryl lipid a removes disease-associated transcriptional signatures in monocyte-derived dendritic cells from rheumatoid arthritis patients and confers tolerogenic features
Author
- García González, Paulina;
- Schinnerling, Katina;
- Sepúlveda Gutiérrez, Alejandro;
- Maggi, Jaxaira;
- Hoyos, Lorena;
- Morales, Rodrigo;
- Mehdi, Ahmed;
- Nel, Hendrik;
- Soto Sáez, Lilian;
- Pesce Reyes, Bárbara;
- Molina Sampayo, María Carmen;
- Cuchacovich Turteltaub, Miguel;
- Larrondo Lillo, Milton;
- Neira, Oscar;
- Catalán Martina, Diego;
- Hilkens, Catharien M.;
- Thomas, Ranjeny;
- Verdugo Salgado, Ricardo;
- Aguillón Gutiérrez, Juan Carlos;
Abstract
Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro. Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.
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This work was supported by Fondecyt-Chile 1140553, and Millennium Institute on Immunology and Immunotherapy P09-016-F.
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Front. Immunol. 7:458.
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