Pathogenetic mechanisms and therapeutic target discovery in chronic immune-mediated inflammatory diseases Insights into the role of the lymphatic system and drug repurposing strategies

The aim of this thesis was to unravel pathogenetic mechanisms and identify novel therapeutic strategies in immune-mediated inflammatory diseases (IMIDs), with a focus on the lymphatic system in inflammatory bowel disease (IBD) and on transcriptomics-driven drug repurposing across IMIDs.
In the first part of this thesis, we investigated the role of lymphoid structures in IBD pathogenesis, treatment response, and immunogenicity to biologics. We showed that mesenteric lymph nodes and lymphatic vessels actively shape immune priming, antigen presentation, and lymphocyte trafficking. Using cytometry-based profiling, we found that anti-drug antibody formation against anti-TNF therapies was associated with elevated B-cell and dendritic cell frequencies within lymph nodes. Furthermore, we demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators, such as etrasimod, profoundly alter T-cell migration, highlighting lymphocyte trafficking as a tractable therapeutic axis in IBD.
In the second part, we applied transcriptome-guided drug repurposing pipelines to identify novel therapeutic candidates. In systemic lupus erythematosus, we uncovered compounds, which could potentially restore monocyte-derived pathologic gene signatures, including heat shock protein-90 and inflammasome inhibitors. In individuals at risk for rheumatoid arthritis, we identified agents targeting the PI3K kinase and matrix metalloproteinase-9 pathways that could reverse preclinical synovial signatures, thus offering preventive potential. In Crohn’s disease–associated intestinal fibrosis, we discovered that dual blockade of PI3K and histone deacetylases synergistically attenuated fibroblast activation, proposing a new anti-fibrotic strategy.
We conclude that the lymphatic system function is a central determinant of IBD pathogenesis and treatment outcomes, while omics-based drug repurposing provides promising, cost-efficient avenues for precision therapy across IMIDs. These insights pave the way for mechanism-driven interventions to improve outcomes in autoimmunity.