Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Histone Deacetylase Inhibitor (HDAi) Ameliorates Chronic Arthritis in SKG Mice by Altering Conventional Dendritic Cells (cDCs) Phenotype into Tolerogenic DCs.
Misaki2, Kenta, Morinobu2, Akio, Saegusa2, Jun, Miyamoto2, Yoshiaki, Kasagi2, Shinpei, Kumagai1, Shunichi
Background & Purpose:
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis, leading to joint destruction. CDCs contribute to pathogenesis of RA by triggering the immune responses. HDAi plays a significant role of controlling gene transcription, and has been reported to regulate immune responses. Here we examined the therapeutic effects of HDAi (Trichostatin A: TSA) on the RA model mice and cDCs.
SKG mice were injected with Zymosan A (ZyA) to induce chronic arthritis. DMSO or TSA was daily administrated to SKG mice. Cell surface molecules and cytokine production in splenic cDCs, clinical arthritis scores, histological arthritis scores were evaluated in each group. The effects of TSA on bone marrow cells-derived cDCs treated with ZyA (BMcDCs-ZyA) were assessed by flow cytometry, ELISA, real-time PCR (RT-PCR) and the allo-mixed lymphocyte reaction (allo-MLR) in vitro.
Clinical arthritis scores and histological arthritis scores in SKG mice treated with TSA were significantly lower than those with DMSO. CD80 and CD86 expression of splenic cDCs in TSA group were notably down-regulated compared to those in DMSO group. IL-17A production in CD4 positive splenocytes was also decreased in TSA group. In vitro, IL-12p70, IL-12p40, IL-6 secretions and CD80, CD40 levels of BMcDC-ZyA were reduced in BMcDC-ZyA with TSA by flow cytometry and ELISA, respectively. Indoleamine 2,3-dioxygenase (IDO) expression in BMcDC-ZyA with TSA was much higher than those in BM-cDC-ZyA determined by RT-PCR. Pretreatment of BMcDCs with ZyA+TSA resulted in significantly reduced naïve CD4 positive T cell proliferation compared to that with BMcDCs-ZyA in allo-MLR.
TSA has notable anti-arthritis effects on SKG mice by modulating functions of cDCs. TSA alters DC function into tolerogenic DC, such as decreased expression of co-stimulatory molecules and pro-inflammatory cytokines, increased IDO expression, and reduced T cell proliferation. This is the first report that HDAi ameliorates the disease activity of SKG mice.
To cite this abstract, please use the following information:
Misaki, Kenta, Morinobu, Akio, Saegusa, Jun, Miyamoto, Yoshiaki, Kasagi, Shinpei, Kumagai, Shunichi; Histone Deacetylase Inhibitor (HDAi) Ameliorates Chronic Arthritis in SKG Mice by Altering Conventional Dendritic Cells (cDCs) Phenotype into Tolerogenic DCs. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1715