< Terug naar vorige pagina
Publicatie
The role of Innate Lymphoid Cells in Chronic Intestinal Inflammation and Fibrosis
Boek - Dissertatie
Intestinal tissue damage and remodeling is a hallmark of inflammatory bowel disease (IBD) progression and severity. Developments in the field of immunosuppressive agents and biologicals have resulted in higher remission rates in IBD patients. However, progress in the prevention and treatment of intestinal fibrosis has been limited. Therefore, new insights in the pathogenesis of intestinal fibrosis are required to identify new pathways for intervention. The main objective of this doctoral thesis was to unravel the role of innate lymphoid cells (ILC) in chronic intestinal inflammation and remodeling in mice and men. In a chronic murine model of inflammatory colitis, we showed that the adaptive immune system is activated with progressive induction of T helper (Th)1 and Th17 cells in mesenteric lymph nodes with increasing number of cycles of administration of dextran sulfate sodium (DSS). Inhibition of T helper cell associated cytokines or regulatory T cells did not alter the deposition of collagen. Next, we showed that fibrosis can still be induced in the absence of the adaptive immune system. Identification of innate lymphoid cells (ILC) as mucosal, resident, cytokine-producing cells and players in liver and lung fibrosis, led us to the study of these cells in our murine model of chronic intestinal inflammation and fibrosis. In both wild type and RAG1-/- mice we observed an enrichment of interleukin (IL)-13 producing ILC2 with increasing numbers of DSS administration. However, upon antibody-mediated depletion of all ILC, no attenuation of fibrosis could be observed. These results were validated in ILC deficient mice. However, in these mice we found that in absence of ILC, recovery after withdrawal of DSS is impaired and associated with a higher mortality. To identify essential alternative innate immune players responsible for the induction of fibrosis in the absence of both ILC and the adaptive immune system, we targeted neutrophils, eosinophils and mast cells. However, our preliminary data did not illustrate a major role of these cells in our model.
In the inflamed gut tissue of patients with IBD we found an increase in pro-inflammatory ILC1 and in immature NKp44- ILC3, while there was a decrease of mature NKp44+ ILC3 when compared to healthy controls. Similar but less pronounced changes in ILC1 were observed in blood, while circulating NKp44- ILC3 were decreased. Changes in mucosal and peripheral ILC subpopulations could not differentiate between Crohn's disease (CD) and ulcerative colitis (UC). In fifteen % of CD patients we observed NKp44+ ILC3 in blood, and these cells were not detected in blood of healthy 206 controls or UC patients. We were able to show that current biological therapy (ustekinumab targeting the IL-12/23 cytokines, anti-tumor necrosis factor and vedolizumab) can partly restore intestinal ILC subset equilibrium with a decrease in ILC1 (except for ustekinumab) and an increase in NKp44+ ILC3. Furthermore anti-TNF therapy was also able to mobilize more NKp44+ ILC3 in circulation. In order to translate the findings of the murine model to human disease, we characterized the cells of both the innate and adaptive immune system in the mucosa and the deeper layers of intestinal resection tissues of patients with fibrostenosing CD. In the inflamed ileum, no differences were observed between mucosa and deeper layers, reflecting the transmural nature of CD. In contrast, in the fibrotic ileum, B cells, eosinophils, mature dendritic cells and M2 macrophages were enriched. These results argue that inflammation in the deeper intestinal layers is different from the inflammatory signature seen in inflamed regions. Overall we were able to show that ILC are not essential for the induction of fibrosis in a murine model, arguing for redundancy of ILC in intestinal remodelling. However, both in mice and CD patients with intestinal remodelling, an enrichment of other innate immunity cells including neutrophils, eosinophils and monocytes point to a major role of the myeloid cell lineage in intestinal fibrosis.
In the inflamed gut tissue of patients with IBD we found an increase in pro-inflammatory ILC1 and in immature NKp44- ILC3, while there was a decrease of mature NKp44+ ILC3 when compared to healthy controls. Similar but less pronounced changes in ILC1 were observed in blood, while circulating NKp44- ILC3 were decreased. Changes in mucosal and peripheral ILC subpopulations could not differentiate between Crohn's disease (CD) and ulcerative colitis (UC). In fifteen % of CD patients we observed NKp44+ ILC3 in blood, and these cells were not detected in blood of healthy 206 controls or UC patients. We were able to show that current biological therapy (ustekinumab targeting the IL-12/23 cytokines, anti-tumor necrosis factor and vedolizumab) can partly restore intestinal ILC subset equilibrium with a decrease in ILC1 (except for ustekinumab) and an increase in NKp44+ ILC3. Furthermore anti-TNF therapy was also able to mobilize more NKp44+ ILC3 in circulation. In order to translate the findings of the murine model to human disease, we characterized the cells of both the innate and adaptive immune system in the mucosa and the deeper layers of intestinal resection tissues of patients with fibrostenosing CD. In the inflamed ileum, no differences were observed between mucosa and deeper layers, reflecting the transmural nature of CD. In contrast, in the fibrotic ileum, B cells, eosinophils, mature dendritic cells and M2 macrophages were enriched. These results argue that inflammation in the deeper intestinal layers is different from the inflammatory signature seen in inflamed regions. Overall we were able to show that ILC are not essential for the induction of fibrosis in a murine model, arguing for redundancy of ILC in intestinal remodelling. However, both in mice and CD patients with intestinal remodelling, an enrichment of other innate immunity cells including neutrophils, eosinophils and monocytes point to a major role of the myeloid cell lineage in intestinal fibrosis.
Jaar van publicatie:2020
Toegankelijkheid:Open