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RESEARCH PRODUCT

FRI0150 Mtor blockade by rapamycin decreases arthritis and spondylitis development and severity in hla-b27 transgenic rats

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Career situation of first and presenting author Student for a master or a PhD. Introduction TNF and IL-17A have been demonstrated as key inflammatory cytokines in Spondyloarthritis (SpA), whereas targeting bone remodeling remains an unmet clinical need in SpA. The mammalian target of rapamycin (mTOR) regulates IL-17 expression and osteogenesis and could therefore be a promising therapeutic target in SpA. Objectives To investigate if blockade of mTOR with rapamycin inhibits the pathological processes in inflammation and bone in SpA. Methods Cytokines were measured by ELISA in the supernatant from SpA patient PBMCs stimulated with anti-CD3/CD28, with various concentrations of rapamycin. SpA FLS were cultured in osteogenesis conditions with rapamycin, supplemented with TNF, IL-17A or both cytokines and stained for alkaline phosphatase (ALP) and Alizarin red. 6-weeks-old HLA-B27/Huβ2m transgenic rats were immunized with 60–90 µg heat-inactivated M. tub in IFA. Rats were treated with 1.5 mg/kg rapamycin or vehicle intraperitoneally (3x a week) in prophylactic and therapeutic settings and monitored for spondylitis and arthritis incidence and severity. Inflammation, bone destruction and formation were evaluated by histology after 5 weeks of treatment. IL-17A, IL-17F and TNF mRNA expression were tested in the metacarpophalangeal (MCP) joints. Results TNF and IL-17A protein production by SpA PBMCs after stimulation were decreased in the presence of 1 nM rapamycin (p Conclusions mTOR blockade decreases IL-17A and TNF production in vitro in Spa PBMCs and reduces osteoblastic differentiation of human SpA FLS. In the M. tub induced HLA-B27 transgenic rat model of SpA, mTOR blockade reduces arthritis and spondylitis development and severity by targeting inflammation and bone remodeling. Disclosure of Interest None declared.