Scientists have developed a potentially transformative new technique that could help in the discovery and development of new therapies for a number of globally prevalent autoimmune diseases.
Conditions such as lupus, rheumatoid arthritis and inflammatory bowel disease (IBD) – as well as malfunctions in transplanted cells – are all caused by altered cytokine secretion from immune cells in the human body.
To find treatments for such diseases, experts must identify the genetic regulators of secretion so they can explore the most effective ways to inhibit them.
An international team of researchers has developed a new method called Secretion-Enabled Cell Ranking and Enrichment (SECRE), which is detailed in a study published in Nature Biomedical Technology.
They have shown that the method is accurate in sorting hundreds of millions of CRISPR-edited cells based on their secretion patterns, and in identifying the genetic regulators of cytokine secretion in an autoimmune disease. In addition, the method takes into account the detailed profiles of approved treatments and treatments in development to determine whether pre-existing therapies can be repurposed in new ways.
In the study, the researchers describe how they validated their approach against the cells known to play an essential role in the development and severity of IBD, and how they proved that this approach has the potential to find new ways to treat conditions that affect millions of people worldwide. .
The research is the result of a project lasting about four years between scientists from Great Britain, the United States and Canada, leading experts in the field of developing new tools for the diagnosis and treatment of diseases, led by Professor Shana Kelley, chairman of the Chan-Zuckerberg Institute and professor at Northwestern University.
This is an incredibly new approach that has the potential to deliver enormous benefits to patients, doctors and pharmaceutical companies working to develop new treatments. It gives us the opportunity to sort large numbers of cells based on their secretion patterns and identify therapeutic targets that can be applied to help people with conditions for which few therapeutic options currently exist. “Through our existing work we have shown that it has the potential to help identify ways to treat various autoimmune diseases, but my work is now also expanding to types of cancer, including some of the most aggressive types of brain tumors.”
Dr. Mahmoud Labib, a lecturer at the Peninsula Medical School of the University of Plymouth, and the key inventor of the approach
A possible treatment for inflammatory bowel disease?
Inflammatory bowel disease (IBD) is a long-term health condition estimated to affect approximately 7 million people worldwide. It is characterized by chronic inflammation of the digestive tract, which can result in severe abdominal pain and diarrhea, and there is currently no known cure.
As part of their work to validate their approach, the researchers examined the effect of various kinase inhibitors on CD4+ T cells, which are known to produce interferon-gamma, a protein widely implicated in several autoimmune diseases, including IBD. The inhibitors studied included XMU-MP1, a small molecule previously studied as a treatment for heart failure, hair loss and a number of other medical conditions.
In this case, the researchers used XMU-MP1 to treat mice with a form of colitis that has a similar cell secretion profile to that in people with IBD. They found that the mice experienced significantly less weight loss and reduced symptoms of colitis, while their colons appeared almost normal and showed no significant loss of intestinal stem cells.
Based on these findings, the researchers say their results suggest that using XMU-MP1 as a means to inhibit the production of interferon-gamma in the intestines may be an ideal means of controlling IBD. They also say it offers a promising future strategy for the therapeutic molecular targeting of the condition, although extensive clinical trials would be needed before it could be considered as a treatment.
How the SECRE technique works
The Secretion-Enabled Cell Ranking and Enrichment (SECRE) technique captures the secreted cytokine on the surface of the cell. These cytokines are then labeled with magnetic nanoparticles and sorted at high resolution in a microfluidic device fabricated using scaled three-dimensional printing.
The SECRE technique allows rapid and rapid sorting of cells based on their secretion patterns, making it amenable to large-scale functional genetic screening. This approach also links the functional signature of the cell to its phenotype, allowing selective sorting of specific subsets of immune cells based on specific cell surface markers and the secretion-specific factors.
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Magazine reference:
Labib, M., et al. (2023). Identification of druggable regulators of cell secretion via a kinome-wide screen and high-throughput immunomagnetic cell sorting. Nature Biomedical Technology. doi.org/10.1038/s41551-023-01135-w.
This article was adapted from khn.org, a national newsroom that produces in-depth journalism on health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling and journalism.
