POS1391 UTILITY OF MOUSE MODELS OF LUPUS FOR CLINICAL RESEARCH AND DRUG TESTING
Authors: M. Rivas-Torrubia, M. Morell, Z. Makowska, J. Kageyama, A. Buttgereit, J. Lindblom, P. Cytometry Consortium, I. Parodis, L. Beretta, R. Lesche, F. Mcdonald, M. Alarcon-Riquelme, G. Barturen
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a diverse pathophysiology triggered by the loss of self-tolerance, resulting in inflammation and tissue damage in multiple organs. The use of animal models has been instrumental in advancing our understanding of SLE. The elimination of the requirement for animal models in the FDA's drug approval process prompts a reevaluation of their role. <h3>Objectives:</h3> We aim to define a molecular framework for the future design of preclinical studies in SLE, helping researchers in the selection of mouse models and appropriate time point of study based on the molecular pathways and their relationship with human disease. <h3>Methods:</h3> To address this, a 4 timepoint longitudinal study was conducted using four different spontaneous SLE mouse models: MRL<sup>lpr/lpr</sup>, NZB/W, BXSB.Yaa, and TLR7.Tg6. RNA-Seq from whole-blood, spleen, and kidney, flow-cytometry from spleen, cytokines and autoantibodies in serum were profiled. All data was investigated using both, longitudinal differential expression analysis as well as individual cross-sectional analysis of each time-point. Molecular and flow-cytometry data from blood from SLE patients from the PRECISESADS project was integrated with mouse data using the MEFISTO software, allowing us to integrate direct relationships between human and mouse along the progression of disease. <h3>Results:</h3> Mouse models were extensively characterized at the molecular level. In the spleen, lymphopenia mimicking that occurring in the human and age-associated B cells were in common between mouse models, while neutrophil and cytotoxic lymphocyte expansions differentiated the models. TLR7-involved models showed important transcriptional dysregulation in the spleen as compared to non-TLR7 models, whose dysregulation was primarily in the kidney. Molecular changes were associated with severity across all models, with splenic changes preceding kidney damage and suggesting the ideal moment to study early immune pathogenic processes. Human and mouse molecular integration showed a shared interferon-mediated pathway with MRL<sup>lpr/lpr</sup> and TLR7.Tg6 models associated with hematological and constitutional clinical domains, but at different timepoints. The neutrophil-mediated inflammatory pathway was shared between humans, MRL<sup>lpr/lpr</sup>, BXSB.Yaa and TLR7.Tg6 models and related to renal and cutaneous clinical human domains. <h3>Conclusion:</h3> The findings provide a valuable framework for future experimental design involving SLE mouse models, demonstrating their continued usefulness in investigating the elusive pathogenesis and heterogeneity of SLE. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR). The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under the Grant Agreement Number 115565 (PRECISESADS project), resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007–2013) and EFPIA companies' in-kind contribution. This work was supported in part by the Spanish Ministry of Science and Innovation under grant "Juan de la Cierva" (IJC2020-043364-I). <h3>Disclosure of Interests:</h3> Maria Rivas-Torrubia: None declared, María Morell: None declared, Zuzanna Makowska Bayer Pharma AG, Berlin, Berlin, Germany, Jorge Kageyama Bayer Pharma AG, Berlin, Berlin, Germany, Anne Buttgereit Bayer Pharma AG, Berlin, Berlin, Germany, Julius Lindblom: None declared, PRECISESADS cytometry consortium: None declared, Ioannis Parodis: None declared, Lorenzo Beretta: None declared, Ralf Lesche Bayer Pharma AG, Berlin, Berlin, Germany, Fiona McDonald Bayer Pharma AG, Berlin, Berlin, Germany, Marta Alarcon-Riquelme: None declared, Guillermo Barturen: None declared.