Therapeutic effect of tolerogenic dendritic cells in established collagen-induced arthritis is associated with a reduction in Th17 responses.
OBJECTIVE
Tolerogenic dendritic cells (DCs) are antigen-presenting cells with an immunosuppressive function. They are a promising immunotherapeutic tool for the attenuation of pathogenic T cell responses in autoimmune arthritis. The aims of this study were to determine the therapeutic action of tolerogenic DCs in a type II collagen-induced arthritis model and to investigate their effects on Th17 cells and other T cell subsets in mice with established arthritis.


METHODS
Tolerogenic DCs were generated by treating bone marrow-derived DCs with dexamethasone and vitamin D(3) during lipopolysaccharide-induced maturation. Mice with established arthritis received 3 intravenous injections of tolerogenic DCs, mature DCs, or saline. Arthritis severity was monitored for up to 4 weeks after treatment. Fluorescence-labeled tolerogenic DCs were used for in vivo trafficking studies. The in vivo effect of tolerogenic DCs on splenic T cell populations was determined by intracellular cytokine staining and flow cytometry.


RESULTS
Tolerogenic DCs displayed a semi-mature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen-pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin-10-producing CD4+ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin-17-producing γ/δ T cells.


CONCLUSIONS
Treatment with type II collagen-pulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis.
Stoop
Jeroen N
JN
Newcastle University, Newcastle upon Tyne, UK.
Harry
Rachel A
RA
von Delwig
Alexei
A
Isaacs
John D
JD
Robinson
John H
JH
Hilkens
Catharien M U
CM
D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007167:Immunotherapy; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000473:pathology*; D016896:Treatment Outcome; D014807:Vitamin D / Q000494:pharmacology
D016753:Interleukin-10; D014807:Vitamin D; D003907:Dexamethasone