Session Title: Rheumatoid Arthritis: Animal Models
Session Type: Abstract Submissions (ACR)
Autoimmune diseases often result from inappropriate or unregulated activation of autoreactive T cells. The induction and maintenance of T cell tolerance to tissue antigens is essential to prevent autoimmunity. 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. Traditional approaches to treatment of autoimmune diseases through immunosuppression have focused on direct inhibition of T cells. 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.
Collagen-induced arthritis (CIA) was induced in mice lacking Flt3L (Flt3L-/-) and WT littermates (C57/BL6 background, 9–10 weeks old). The arthritis severity was assessed using an established semiquantitative scoring system (0–4). After 60 days (chronic phase) phenotypical and functional analysis of spleen and lymph nodes was performed: T and B cell markers, FoxP3 expression, activation markers, co-stimulatory markers and cytokine production. Collagen type II specific antibodies and a panel of inflammatory cytokines were measured in the serum. Histological markers for cellular infiltration, cartilage destruction and peptidoglican loss were performed, as well as immunohistochemistry stainings for cellular markers.
In CIA abrogation of Flt3 signaling led to decreased disease incidence (area under the curve p<0.0005) and severity (p<0.005). CIA Flt3L-/- mice showed reduced spleen and lymph node cellularity (p< 0.0001) and reduced percentage of activated CD4+CD25+ T cells compared with WT (p=0.03). Flt3L-/- CD4+ T cells also produce significantly less IL-17 (p=0.016) and TNF-a (p=0.010), and CD8+ T cells less IFN-g (p=0.029) compared to WT. We also observed less infiltration of inflammatory cells and less peptidoglican loss.
Conclusion: Mice lacking Flt3L are protected from CIA. We observed that Flt3L deletion influences the magnitude (cell numbers) and quality (CD25 expression and cytokine expression) of T cell responses. Stimulation of lymphocytes by different types of DC, DC at different stages of maturity and producing and responding to different growth factors might contribute for this change in T cell numbers and/or effector functions in Flt3L-/- mice. Targeting this signaling pathway might be considered as a good therapeutic strategy in RA.
M. I. Martins Ramos,
K. O. N. Karpus,
P. P. Tak,
Employee of GlaxoSmithKline,
M. C. Lebre,
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/orchestrating-the-orchestrators-blockade-of-flt3l-signaling-dependent-dendritic-cells-protects-against-collagen-induced-arthritis/