Frontiers in Immunology (Oct 2016)
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
Abstract
Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases such as rheumatoid arthritis (RA). Here we characterise 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 costimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating towards 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.
Keywords
