Session Title: Rheumatoid Arthritis - Animal Models II
Session Type: Abstract Submissions (ACR)
Dendritic cells (DCs) are a heterogeneous cell population that plays an important role for the initiation of protective and pathogenic immunity. Flt3L is a growth factor that drives DC development from bone marrow (BM) progenitors and it is crucial for maintenance of DCs in the steady-state. The objective of this study was to address the role of Flt3L-dependent DCs in the initiation of collagen-induced arthritis (CIA).
CIA was induced in Flt3L-/- and WT C57/BL6 littermates. In vitro and in vivo uptake and migration was performed using BM-DCs and dermal DCs. Antigen presentation was studied in vivo by adoptive transfer of CFSE-labeled OT-I or OT-II T cells + OVA in Flt3L-/- and WT mice and in vitro by culturing BM-DCs with OT-I and OT-II cells. T cell proliferation was analyzed by CFSE dilution. To study BM-DC function qPCR array (Dendritic and Antigen Presenting Cell PCR Array- Qiagen) for 84 genes was performed. To test the potential of a Flt3 inhibitor (CEP701) in the prevention of CIA, an in vivo study was performed injecting CEP701 before the onset of disease in DBA-1 mice.
We showed that Flt3L-/- mice are protected from CIA. In Flt3L-/- mice CD103+ DCs are almost absent. The amount of DCs carrying antigen reaching the LN in Flt3L-/- mice was reduced compared with WT. Uptake and migratory capacity was similar in Flt3L-/- BM-DCs compared to WT BM-DCs. Adoptive transfer of OT-I and OT-II T cells + OVA in Flt3L-/- mice resulted in a dramatic reduction of total cell proliferation and more importantly less divisions compared with WT animals. No intrinsic defects on DC function were observed by qPCR array. Mice treated with CEP701 before the onset of disease were protected from CIA and that correlated with the disappearance of CD103+ migratory DCs. Synovial T cells were reduced and correlated with disease severity.
Antigen presentation in Flt3L-/- mice is impaired. As CD103+ DCs are absent in Flt3L-/- mice and are important in (cross)-presenting antigens our data reveals a crucial role for CD103+ DCs in the induction of CIA. As a consequence of CD103+ DC absence Flt3L-/- mice showed a reduction in T cell activation in particularly reduced CD8 T cell responses. Targeting this DC subset might be of interest in individuals at risk of developing autoimmune disorders.
M. I. Ramos,
K. A. Reedquist,
Hoffmann-La Roche, Inc.; MedImmune/AstraZeneca; Five Prime Therapeutics, Inc.; GlaxoSmithKline,
P. P. Tak,
M. C. Lebre,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fms-like-tyrosine-kinase-3-ligand-dependent-cd103dc-are-crucial-for-the-initiation-of-collagen-induced-arthritis/