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 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.

Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

“…Despite a recent study has shown no differences in HLA-DR expression in DCs obtained from Chilean RA-patients and HC 22 , our data here shows a strong exacerbation of HLA-DR density in DCs obtained from Chilean RA-patients in comparison to Chilean HC ( Figure 1A). This discrepancy could be due to the different sources of monocytes obtained to be differentiated into DCs: Whereas García-González obtained monocytes from leukopheresis from RA-patients and from buffy-coats from HC 22 , here we obtained monocytes from fresh blood samples from RA-patients and HC.…”

“…This discrepancy could be due to the different sources of monocytes obtained to be differentiated into DCs: Whereas García-González obtained monocytes from leukopheresis from RA-patients and from buffy-coats from HC 22 , here we obtained monocytes from fresh blood samples from RA-patients and HC. Since smoke has been proposed to represent one of the main environmental factors exacerbating disease manifestations and triggering RA 15,16 , we decided to analyse our results confined to the subgroup of smoker and non-smoker RA-patients.…”

“…Moreover, previous data has shown that nicotine promotes the activation of NF-κB, increasing the pro-inflammatory potential of antigen-presenting cells 20,21 . Despite there are previous studies analysing how DCs phenotype is altered in Chilean RA-patients 22 , the impact of smoking in the phenotype of DCs in relation to the severity of disease manifestation in Chilean RA-patients has not been previously addressed. In this study, we evaluated how is the functional phenotype of DCs affected in Chilean RA-patients and how tobacco impacts in DCs functionality and disease manifestation in those patients.…”

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

“…All strategies lead to DCs with regulatory capacities, although some features may vary between protocols. Our group has described a protocol for tolDC generation from peripheral blood monocytes of healthy controls ( 20 ) and rheumatoid arthritis (RA) patients ( 21 ) using Dex to induce a tolerogenic phenotype and subsequent activation with the non-toxic lipopolysaccharide (LPS) analog monophosphoryl lipid A (MPLA) to confer lymph node homing capacity and stability. These cells, herein termed Dex-modulated and MPLA-activated DCs (DM-DCs), expressed low levels of CD83, CD86, and CD40, secreted high levels of IL-10 and TGF-β and low levels of IL-12, and stimulated T-cell proliferation and cytokine production at low levels in allogeneic and autologous cultures ( 20 , 22 ).…”

Characteristics of dendritic cells from patients with rheumatoid arthritis and different type of drug therapy

“…Согласно данным литературы, используемые в терапии РА препараты способ-ны индуцировать толерогенный потенциал ДК. В частности показано, что глюкокортикоиды угне-тают созревание генерируемых из моноцитов ДК [11,12,24]. Терапия больных РА моноклональ-ными антителами к TNF-α сопровождается ко-личественным снижением в циркуляции миелоид-ных и в меньшей степени плазмоцитоидных ДК и снижением ýкспрессии СD83 [25].…”