OP0194 HISTONE DEACETYLASE 1 (HDAC1): A KEY MEDIATOR OF T CELLS FOR THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

Background Despite enormous efforts to develop new therapeutic strategies for treatment of rheumatoid arthritis (RA), the large number of non responding patients to currently available drugs underlies the unmet need to identify new therapeutic targets. Certain CD4+T cell subsets, especially those polarized toward the T helper (Th) subsets Th1 andTh17, have been shown to be major drivers of inflammation in patients with RA. The expression of their key transcription factors is controlled by histone modifications which includes acetylation of lysine residues mediated by histone deacetylases (HDAC). Indeed, pan HDAC inhibitors have been shown to be a potential therapeutic strategy. However, major side effects limited the clinical use and underline the need of more specific HDAC inhibitors. Objectives We addressed the individual role of HDAC1 on the development of collagen-induced arthritis model (CIA), which partially reflects human RA. Methods Mice with a T cell specific deletion of HDAC1 (HDAC1 cKO) were generated by using the CD4Cre/LoxP system. At week 8 of age arthritis was induced in wild type (WT) and HDAC1 cKO mice by immunizing with chicken collagen II (CII), emulsified in complete Freund’s adjuvant. After 21 days mice received a booster injection of CII. The animals were 3 times per week scored for paw swelling and grip strength. Anti-CII antibody levels were determined by ELISA. Various cell subsets, including Th cells, where detected in the blood, the spleen and the draining lymph node by FACS analysis. To test antigen-specific T cell activation we performed in vitro restimulation of spleen and lymph node cells with collagen II followed by assessment of cytokine production and quantification of the proliferation rate using 3Hthymidine incorporation. After 4 and after 10 weeks mice were sacrificed and paraffin sections of the affected joints were analyzed for histomorphologic signs of inflammation, cartilage and bone destruction. Results Eighty percent of the animals developed serum anti-CII anibodies (IgM and IgG) whereby the antibody levels were a day 21 of disease similar between the HDAC1 cKO and the WT mice. Furthermore, no differences in the production of antibody subclasses, especially of pathogenic IgG2c antibodies, were observed. Enhanced percentages of Th1 and Th17 cells among HDAC1-null CD4+T cells were detected after immunization in the HDAC1 cKO mice. Nonetheless and unexpectedly, these mice did not develop any signs of disease at the clinical level while WT mice developed pronounced paw swelling and loss of grip strength. In accordance with the clinical data, histological analysis revealed no signs of inflammation, no bone erosion and no appearance of osteoclasts in the joints of HDAC1 cKO mice. This appeared to be mainly caused by an impaired migratory capacity of HDAC1 cKO CD4+ T cells, so that they were unable to invade the joints. Conclusion Our data show the importance of HDAC1 as a key immune regulator in the pathogenesis of T cell driven collagen induced arthritis. Therefore it might be considered as an interesting novel therapeutic target in RA. Disclosure of Interests None declared