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AB0169 Trichostatin a induces CD8A positive tolerogenic dendritic cells and regulatory T cells in SKG mice, and ameliorates the severe arthritis
  1. K. Misaki1,
  2. A. Morinobu2,
  3. J. Saegusa2,
  4. K. Nishimura2,
  5. S. Kumagai3
  1. 1Rheumatology, Kurashiki Central Hospital, Kurashiki
  2. 2Clinical pathology and Immunology, Kobe University
  3. 3Rheumatology, Shinko Hospital, Kobe, Japan

Abstract

Background Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by cellular infiltration of and proliferation in the synovium, leading to the progressive destruction of the joints. Dendritic cells (DC) play a pivotal role by triggering the immune responses in RA pathogenesis. Trichostatin A (TSA) plays a significant role of controlling gene transcription as a histone deacetylase inhibitor, and has been reported to regulate immune responses.

Objectives We examined to elucidate the effects of TSA on the phenotype and function of DC and on arthritis in SKG mice.

Methods Arthritis was induced in SKG mice by Zymosan A (ZyA) injection. TSA was administered and its effects on arthritis were evaluated by joint swelling and histological evaluation. IL-17A production in lymph node cells was determined by ELISA. Foxp3 expression in lymph node cells and the phenotypes of splenic conventional DC (cDC) were examined by flow cytometry. Bone marrow-derived DC (BM-DC) were generated with granulocyte macrophage colony-stimulating factor. The effects of TSA on cytokine production, cell surface molecules, indoleamine 2,3-dioxygenase (IDO) expression and T cell stimulatory capacity of BM-DC were examined by flow cytometry, ELISA, quantitative real-time polymerase chain reaction and Western blot, and the allo-mixed lymphocyte reaction, respectively.

Results TSA, when administered before the onset of arthritis, prevented SKG mice from arthritis. TSA treatment also showed therapeutic effects on arthritis in SKG mice, when administered after the onset of arthritis (daily treatment and twice-a- week treatment). TSA treatment reduced IL-17A production and increased in the ratio of CD4+CD25+Foxp3+ cells among CD4+ cells in lymph node, suggesting that regulatory T cells are involved in the prevention of arthritis in SKG mice with TSA. In the CD8α+ splenic cDC subset, the expressions of CD86, CD80, and CD40 were significantly decreased in the TSA-treated group compared to the control group. In contrast, there were no significant differences in the expression of these molecules in the CD8α- cDC subset. Thus, TSA predominantly affects CD8α+ cDC in vivo. In vitro, TSA markedly suppressed ZyA-induced IL-12 and IL-6 productions, cell surface molecules by BM-DC and up-regulated IDO expression at mRNA and protein levels. TSA-treated BM-DC also showed less T cell stimulatory capacity.

Conclusions TSA changes DC to a tolerogenic phenotype, induces regulatory T cells and ameliorates arthritis in SKG mice.

Disclosure of Interest None Declared

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