FRI0295 Inhibition of cathepsin s leads to suppression of antigen specific t cells from patients with primary sjÖgren syndrome

Background Primary Sjogren syndrome (pSS) is an autoimmune disease characterised by an infiltration of T and B cells into exocrine gland tissue and its subsequent destruction 1 . Antigen presenting cells, including B cells, foster T cell activation and anti-SS-A/SS-B producing plasma cells, eventually leading to disease progression and systemic complications 2 . Objectives Cathepsin S (CatS) is crucially involved in MHCII processing in pSS mouse models 3 and patients 4 . In this translational study we investigated the ex vivo effects of the CatS inhibitor RO5459072 in different bio-compartments, including specific T cells, of pSS patients and healthy controls. Methods Ex vivo CatS activity was assessed in different bio-compartments of 15 pSS patients and 13 healthy controls and in presence or absence of RO5459072 using commercial activity and quantification assays. In addition, antigen (5 µg/mL SS-A, 5 µg/mL SS-B, 5 µg/mL Influenza H 3 N 2 ; 2 µg/mL Tetanus Toxoid and 100 ng/mL SEB) specific T cell responses were examined using 2 × 10 5  PBMC/well IFN-g/IL-17 Dual ELISPOT (48 hour incubation) and 5 × 10 4  PBMC/well BrdU proliferation assays after (72 hour incubation) in presence or absence of RO5459072. Results pSS patients showed significantly higher CatS activity in tear fluid than healthy controls (two-tailed t-test p ex vivo derived pSS patient cells in Elispot and BrdU assays (table 1). Table 1 Suppression of antigen specific T cell responses (Elispot) and suppression of cell proliferation (BrdU) in the absence or presence of RO5450972 (0–100 µM). One-tailed t-test: *p Conclusions CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. RO5459072 is a potent inhibitor of CatS and the pSS associated relevant antigen specific T cell responses. References [1] Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjogren’s syndrome. Nat. Rev. 2010;6:529–537. [2] Brito-Zeron P, Baldini C, Bootsma H, et al. Sjogren syndrome. Nat Rev Dis Primers 2016;2:16047. [3] Saegusa K, Ishimaru N, Yanagi K, et al. Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J Clin Invest2002;110(3):361–9. [4] Hamm-Alvarez SF, Janga SR, Edman MC, et al. Tear cathepsin S as a candidate biomarker for Sjogren’s syndrome. Arthritis Rheumatol 2014;66(7):1872–81. Acknowledgements We would like to thank Ms. Evelyn Fischer and Dr. Bettina Bannert for their valuable contribution of patient samples, technical assistance and clinical information. Disclosure of Interest P. Hargreaves Grant/research support from: Roche, M. Theron Employee of: Roche, F. Kolb Employee of: Roche, M. Manchester Employee of: Roche, B. Reis Employee of: Roche, A. Tiaden: None declared, D. Kyburz Grant/research support from: Roche, T. Manigold Grant/research support from: Roche