Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.
A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.
Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.
“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.
Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1+-activated endothelial cells.
This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.
“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.
The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.
Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.
They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.
“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”
They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.
“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.
The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.
SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.