Study Charts Course for Next Generation of Drug Targets in Autoimmune Diseases

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.”