Our objective is to harness the power offered by new single-cell technologies to deconvolute immunopathogenic responses and their heterogeneity in tissues of patients affected by immune-mediated inflammatory diseases (IMIDs) in order enhance the rational for future drug and biomarker discovery. Immune-mediated inflammatory diseases (IMIDs) encompass a group of chronic disorders of the immune system with unknown etiologies and a continuously rising incidence in western countries over the past 70 years (Bach, 2002). IMIDs can severely impacts the quality of life of patients. Pain and discomfort, which can complicate daily activities and lower performance at work, are frequently observed in most IMIDs. Besides, patients suffering from IMIDs are prone to develop severe cardiovascular, metabolic and psychological comorbidities. By affecting about 70 million people, IMIDs represent a major public health issue in Europe (Cooper et al., 2009). Despite important success, however, the clinical benefit of targeted immunotherapy in polygenic IMIDs has remained limited to a subset of patients and the use of standard of care imaging and/or histological diagnostic assays has failed to stratify potential responders from non-responders. Immunopathological heterogeneity across clinically and histologically identical lesions has long been recognized and it is now clear that clinical and histological diagnoses are not sufficient to predict the clinical response to most immunotherapies. Accordingly, none of the targeted immunotherapy approved to treat patients affected by polygenic IMIDs are provided with decision algorithms to maximize therapeutic responses. Diseases are caused by dysfunctional cell types that populate the organ affected. Yet there is little understanding of the cellular diversity in normal or diseased organs. There is therefore an urgent need to gain a better understanding of the cellular programs in normal and lesional human tissues, as the poor understanding of disease pathophysiology significantly limits the identification of relevant targets.
Our current project aims at characterizing the pathogenic role of mononuclear phagocytes(MNP) in Crohn’s disease. In a previous study, we optimized a pipeline for the analysis of gut tissue resections and endoscopic biopsies with high-resolution single cell technologies(scRNAseq, high-dimensional cytometry, multiplex imaging). We identified a cellular module,which we named the GIMATS module (IgG-plasma cells, inflammatory MNP, activated T andstromal cells). The GIMATS organization appeared driven by a unique MNP-dependent cytokine/chemokine network. The GIMATS module was present in inflamed ileums of a subsetof patients and its presence at diagnosis correlated with failure to achieve durable corticosteroid free clinical remission upon anti-TNF therapy (Martin JC, Cell, 2019). We now want to better characterize the cellular and molecular drivers of the MNP-driven GIMATS module to identify new therapeutic targets tailored to non-responders to anti-TNF therapy. To this end we apply state-of-the-art technologies to the characterization of MNP and interacting partners in normal and inflamed tissues of CD patients. This allows the generation of patient-driven hypotheses that we test in optimized pre-clinical reductionist approaches including in-vitro culture systems and rodent colitis models.
Significance for Crohn’s disease:
CD represents a major burden that impacts negatively the patients’ quality of life and progressively leads to high disability altering daily life and work productivity. Besides, the incidence of CD has dramatically increased worldwide over the past 50 years and, with 505 per100,000 inhabitants, Europe has the highest prevalence rate of CD. CD cumulative relapse rateis 90 % within the first ten years of the disease and 40% of the patients experience a first surgery within ten years after diagnosis. While new therapeutic strategies have decreased the need for surgery as compared to older cohorts, the rate of second surgery has remained unchanged.Incomplete control of mucosal inflammation in CD lesions represents a significant risk factor for progressive bowel damage and surgical resection (Pariente et al., 2011). However, up to 40% of CD patients never respond to anti-TNF antibodies and despite enormous dedication to researchand development, the pharmaceutical industry continues to struggle to identify novel drug targets that ultimately meet clinical endpoints in IBD trials. These failures represent an enormous economic burden and a distraction for physicians and scientists that adversely impact clinical care. With this project, we will provide a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade as well as novel therapeutic opportunities tailored for combination with anti-TNF antibody blockade.