Mtor Blockade By Rapamycin Decreases Arthritis And Spondylitis Development And Severity In Hla-B27 Transgenic Rats

Background HLA-B27 misfolding is thought to play an important role in the pathogenesis of spondyloarthritis (SpA), possibly through triggering of ER stress and the unfolded protein response. One of the mechanisms that regulates the unfolded protein response is autophagy. Autophagy is a process that degrades proteins, cytoplasmic particles and organelles in lysosomes and is regulated by protein kinases, mechanistic target of rapamycin (mTOR) and AMP activated protein kinase. Objectives To study whether blockade of mTOR will affect spondyloarthritis development and/or severity in the Mycobacterium tuberculosis ( M. tub ) induced disease HLA-B27 tg rat model. Methods 6 weeks old, female or orchiectomized male HLA-B27/Huβ2m transgenic rats were immunised with 60–90 µg heat-inactivated M. tub in IFA. Rats were prophylactically or therapeutically treated three times a week intra-peritoneally with 1.5 mg/kg rapamycin or vehicle. Clinical measurements included weight, clinical scores for spondylitis and arthritis, and hind paw swelling measured by plethysmometry. After 5 weeks of treatment rats were sacrificed; axial and peripheral joints were isolated for histology and metacarpophalangeal joints, spleen and lymph nodes were isolated for RNA isolation. Results In the prophylactic experiment 72.7% (8/11) and 18.2% (2/11) rapamycin treated rats developed arthritis and spondylitis compared to respectively 100% (13/13; p=0.0225) and 92.3% (12/13; p Conclusions mTOR blockade significantly suppressed arthritis and spondylitis in the M. tub induced disease HLA-B27 transgenic rat model of SpA. Disclosure of Interest S. Chen: None declared, M. van Tok: None declared, D. Pots: None declared, J. Taurog: None declared, M. van de Sande: None declared, D. Baeten Employee of: UCB Pharma, L. van Duivenvoorde: None declared