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.
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 antigensin 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.
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Paulina A
PA
García-González
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Katina
K
Schinnerling
Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile , Santiago , Chile.
Alejandro
A
Sepúlveda-Gutiérrez
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Jaxaira
J
Maggi
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Lorena
L
Hoyos
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Rodrigo A
RA
Morales
Translational Research Institute, University of Queensland Diamantina Institute , Woolloongabba, QLD , Australia.
Ahmed M
AM
Mehdi
Translational Research Institute, University of Queensland Diamantina Institute , Woolloongabba, QLD , Australia.
Hendrik J
HJ
Nel
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Unidad de Dolor, Hospital Clínico de la Universidad de Chile, Santiago, Chile.
Lilian
L
Soto
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Bárbara
B
Pesce
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile , Santiago , Chile.
María Carmen
MC
Molina
Departamento de Medicina, Hospital Clínico de la Universidad de Chile , Santiago , Chile.
Miguel
M
Cuchacovich
Banco de Sangre, Hospital Clínico de la Universidad de Chile , Santiago , Chile.
Milton L
ML
Larrondo
Sección de Reumatología, Hospital del Salvador , Santiago , Chile.
Óscar
Ó
Neira
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Diego Francisco
DF
Catalán
Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK.
Catharien M
CM
Hilkens
Translational Research Institute, University of Queensland Diamantina Institute , Woolloongabba, QLD , Australia.
Ranjeny
R
Thomas
Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile , Santiago , Chile.
Ricardo A
RA
Verdugo
Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
Juan C
JC
Aguillón
cell-based therapy; dendritic cells; rheumatoid arthritis; tolerance; transcriptome