The inflammatory response is indispensable for protective immunity, but microbial pathogens often trigger an excessive response called cytokine storm that is harmful to the host. Despite recent advances in our understanding of inflammatory signaling, how to prevent a cytokine storm remains a challenge.
Now, a “groundbreaking” study at the Faculty of Medicine of the Hebrew University of Jerusalem (HU) has uncovered exciting possibilities for treating inflammatory disorders and preventing cytokine storms that can be damaging to the body and even kill patients.
The research was published in the Journal of Biomedical Science under the title “The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling.”
What conditions could be helped?
Among the numerous inflammatory disorders are fatty liver disease. fatty liver disease, obesity, endometriosis, type-1 and type-2 diabetes, inflammatory bowel disease, asthma and rheumatoid arthritis.
The scientists have discovered that particular domains within key mediators of our immune response – called B7 and CD28 receptors – have a vital role in enabling the inflammatory response and can be targeted with man-made molecules to manage immune responses and inflammation, saving lives. These findings bring us one step closer to developing effective treatments for inflammatory diseases.
How does the immune system work and why?
The team of researchers conducted this study with the aim of understanding how our immune system works and why it sometimes goes into overdrive during severe infections and autoimmune diseases. They created small copies of specific domains within the B7 and CD28 receptors, called mimetic peptides, to investigate how these affect the production of inflammatory molecules.
The results showed that these mimetic peptides successfully reduced the interaction between B7 and CD28 receptor proteins and thereby lowered the production of inflammatory molecules in human immune cells. This suggests that they could be used to develop treatments for inflammatory disorders, for example, in bacterial infections, severe sepsis and viral infections involving lung injury such as influenza and COVID-19.
When tested on mice, these mimetic peptides provided significant protection against lethal toxic shock caused by a harmful bacterial toxin that kills by eliciting an inflammatory cytokine storm. Even at exceedingly low doses, the specific B7-1 and CD28 mimetic peptides showed remarkable effectiveness in preventing the harmful effects of the toxin and protecting from death.
“Our findings show for the first time the critical role played by these B7 and CD28 receptor domains in controlling immune responses and inflammation,” said biochemistry and molecular biologist Prof. Raymond Kaempfer. “By selectively reducing inflammation yet without completely stopping it, we may be able to protect against cytokine storms associated with severe infections and autoimmune diseases.”
This research opens up new possibilities for developing targeted therapies that can balance immune activation needed to protect from pathogens yet prevent excessive inflammation. By regulating the interaction between B7 and CD28 receptors, he concluded, the team may be able to fine-tune the immune response and prevent harmful inflammatory reactions.
