In a world first, researchers in Oxford have mapped the cellular dynamics following treatment with the most commonly used advanced therapy in autoimmune diseases. They have discovered why some patients benefit from this therapy while others do not, potentially paving the way for new therapies.
Autoimmune diseases such as inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, affect five percent of the global population. A major problem faced by the IBD community is that current drugs do not work for every patient. Given that we do not know why these drugs don’t work, the development of new treatments has been hindered.
A new approach by researchers at the University of Oxford’s Kennedy Institute of Rheumatology puts patients at the centre of the research question. The findings of their research, which was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC and the Kennedy Trust for Rheumatology Research, was published in Nature Immunology.
The interdisciplinary research team also included scientists and clinicians from Oxford’s Translational Gastroenterology and Liver Unit, the University of Birmingham and academic and industry colleagues from Australia and the United States.
The researchers followed patients before and after treatment with the most commonly used advanced therapy for IBD, anti-tumour necrosis factor (anti-TNF). The beneficial effect of anti-TNF in autoimmune diseases was first discovered at the Kennedy Institute of Rheumatology in the 1990s and revolutionised patient care. However, this treatment does not work in four out of ten patients.
For the first time, clinicians and scientists used a technology called ‘single-cell RNA-sequencing’ to characterise gut samples collected before and after anti-TNF treatment, one cell at a time – creating the largest cell atlas of IBD to date. They discovered the cellular basis for why some patients benefit from anti-TNF whilst others do not.
The study generated around 1 million single-cell transcriptomes – the full range of messenger RNA molecules – from 216 gut biopsies of 38 patients – some in remission and others not. The transcriptomes revealed disease-specific cellular differences and mapped potential treatment responses for Crohn’s and colitis.
The first author of the paper, Dr Tom Thomas of the Kennedy Institute of Rheumatology, said: “Thus far, single-cell RNA-sequencing has generally been used to study IBD, a dynamic chronic disease, at a single time point. We embedded this technology in the patient journey to investigate a critical translational question and learn directly from the patient.”
The team found that epithelial and myeloid cells were key in determining the success of treatment. Epithelial cells line the surface of the gut, and certain epithelial cells, known as goblet cells, produce gel-like mucin to protect the body from gut bacteria. The team discovered that patients who benefitted from anti-TNF had more goblet cells and these exhibited higher levels of mucin expression.
Professor Calliope Dendrou, bioinformatics lead and co-senior author, said: “Conversations about anti-TNF outcome in IBD have been historically centred around non-response. We are shifting the paradigm by demonstrating that treatment benefit is determined by the balance between factors that drive remission versus inflammation.”
A specific group of myeloid cells, called monocytes, were distinct in patients with different treatment outcomes. In patients who did not benefit from anti-TNF treatment, these monocytes had higher levels of factors that attract and activate immune cells. But in patients who did benefit, these cells had higher levels of an immune regulator that may act as a brake on the inflammatory process.
Professor Christopher Buckley, co-senior author and Director of Clinical Research at the Kennedy Institute of Rheumatology, said: “Understanding the cellular basis for treatment failure will act as a navigational aid for drug developers in designing the next generation of therapeutic agents, and will help clinicians to best position existing therapies. This first ‘longitudinal’ therapeutic atlas provides a foundational resource for scientists to compare against other treatments and across the many other autoimmune diseases.”
Professor Sir Ravinder Maini and Professor Sir Marc Feldmann, who last month jointly received The Royal Society’s Royal Medal for discovering the anti-inflammatory effects of anti-TNF therapy in rheumatoid arthritis, said: “Finding the cellular basis for anti-TNF treatment outcome is an important conceptual advance for the field, and coming from scientists at the Kennedy Institute where we first described the clinical utility of anti-TNF therapy, is particularly gratifying. “This ‘patient-centred’ study identifies cell-specific signatures of gene expression in the gut and joint tissues and explains how immune-inflammatory pathways are regulated. This approach illuminates how drugs work and lays the foundation for future drug discovery in a wide range of inflammatory diseases”.