SAT0067 Mice lacking FLT3L are protected from collagen-induced arthritis: Regulating the regulators

Background Autoimmune diseases often result from inappropriate or unregulated activation of autoreactive T cells. Traditional approaches to treat autoimmune diseases have focused on direct inhibition of autoreactive T cells. A key requirement for tolerance is the presentation of antigens in a correct context. Dendritic cells (DCs) are the central antigen-presenting cells (APCs) for the initiation of T cell responses. In this context, stimulation of the Flt3 via Flt3L is known to drive expansion and differentiation of DCs. Moreover, mice lacking Flt3L are have reduced of DC numbers Objectives In the present study, we examined the targeted inhibition of APCs as a mean to downregulate/prevent autoimmune disease in a mouse model for rheumatoid arthritis. Methods Collagen-induced arthritis (CIA) was induced in mice lacking Flt3L (Flt3L-/-) and WT littermates (C57/BL6 background, 9-10 weeks old). The severity of the arthritis was assessed using an established semiquantitative scoring system (0–4). After 60 days, serum, spleen, lymph nodes (LN) and hind paws were collected. Collagen type II (CII) specific antibodies were measured by ELISA. Histological analysis (H&E, Toluidine blue, Safranin O and Trap) was performed on hind paws and phenotypical and functional analysis of spleen and LN was performed: T and B cell markers, FoxP3 expression, activation and co-stimulatory markers and intracellular cytokine staining (after PMA/Ionomycin stimulation). Results Histological analysis of paws showed increased synovial infiltration and joint destruction in WT mice while Flt3L-/- mice showed mild infiltration without inflammation (H&E staining). Cartilage destruction (Safranin O staining) and the number of osteoclast were higher in WT compared with Flt3L-/- mice. Importantly, in steady-state (no CIA induced), Flt3L-/- mice show reduced celularity in both spleen (p=0.007) and LN (p=0.01) and reduced T and B cell numbers compared with WT. CIA induction in Flt3L-/- led to decreased disease incidence and severity (AUC p=0.001) compared with WT littermates. In addition, Flt3L-/- mice showed reduced spleen and LN cellularity (p