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Introduction Tertiary lymphoid structures (TLS) often develop in target tissues of autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis, and Sjogren’s syndrome (SS). These structures consist of aggregates of B and T cells with varying degree of organisation and are proposed to promote the generation of autoreactive effector cells and autoantibody production. Modulation of the S1P1 receptor inhibits egress of pathogenic lymphocytes from lymphoid organs and reduces their availability in circulation. This has proven to be an effective target for the treatment of AID including MS and is currently being considered for early phase clinical trials in SLE and SS. Objectives To investigate the functional targeting of the S1P1 receptor in a murine model of SS. Methods Cenerimod, an orally active, selective S1P1 receptor modulator, was administered either preventively (early in inflammation) or therapeutically (established inflammation) in an inducible model of SS to evaluate the efficacy of cenerimod in vivo. Histology, flow cytometry and qPCR were used to analyse the tissue samples. Results Cenerimod induced disaggregation of the lymphocytic structures and resolution of salivary gland (SG) inflammation with a concomitant decrease in focus score, lymphoid structure size and T/B-cell follicular organisation. Mice treated with cenerimod displayed significantly decreased T (naive, central memory and effector) and B (including CD138 +plasma cells) lymphocyte infiltration in cannulated SG, relative to vehicle treated mice. Interestingly, the lymphocytes from cenerimod treated mice exhibited significantly reduced proliferation as well as reduction in pro-inflammatory cytokine RNAs such as IL-17, IL-21, and IL-6. Furthermore, the gene expression profile associated with TLS formation (LTα, LTβ, TNFα, CXCL13, CCL19) was less pronounced in cenerimod treated samples. The cervical lymph nodes draining the salivary glands showed a slight reduction in T lymphocytes, but no significant defects were observed in structure, organisation and production of lymphoid chemokine/cytokines, suggesting that homeostatic regulation of tertiary and physiological lymphoid organs differentially relies on lymphocyte/stromal cell cross-talk during inflammation. Conclusions Together, these data demonstrate that the S1P1 receptor modulator cenerimod regulates TLS in mice and might therefore be a potential treatment option in AID with TLS formation such as SS and SLE. The data also unveil differential requirements for the establishment and maintenance of secondary versus tertiary lymphoid structures. Acknowledgements This research is funded by Idorsia Pharmaceuticals Ltd. Disclosure of interest S. Nayar: None declared, J. Campos: None declared, C. Smith: None declared, C. Buckley: None declared, S. Froidevaux Employee of: Idorsia, K. Wartha Employee of: Idorsia, C. Seemayer Employee of: Idorsia, F. Barone: None declared |
