Study charts course for next generation of drug targets in autoimmune diseases

In a world first, researchers in Oxford and Birmingham 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 led by researchers at the University of Oxford and involving a team from the University of Birmingham’s Department of Inflammation and Ageing 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 researchers followed patients before and after treatment with the most commonly used advanced therapy for IBD, anti-tumour necrosis factor (anti-TNF). 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.

“This study dissects regulation of response to the most commonly used biological anti-TNF therapy in inflammatory bowel disease by applying single cell and advanced spatial analytics to tissue samples taken before and during therapy in both responders and non-responders, revealing fundamental understanding of how therapies work at the tissue level.”

Professor Andrew Filer

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.

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 Andrew Filer, co-author of the study, Professor of Translational Rheumatology at the University of Birmingham and co-theme lead of the NIHR Birmingham BRC Inflammatory Arthritis research theme, added: “This study dissects regulation of response to the most commonly used biological anti-TNF therapy in inflammatory bowel disease by applying single cell and advanced spatial analytics to tissue samples taken before and during therapy in both responders and non-responders, revealing fundamental understanding of how therapies work at the tissue level.

“The same analytics were applied to a preliminary cohort of patients with Rheumatoid Arthritis which is treated with an identical therapy, yielding intriguing insights. It is a powerful illustration of the power of collaboration between NIHR Biomedical Research Centres in Oxford and Birmingham with aligned programmes of work.”

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.”