"Triple punch" immunotherapy puts Crohn's disease into remission in mice
Crohn’s disease is an inflammatory bowel condition, and one suspected cause is the immune system launching an overly-strong response to gut microbes. Now researchers have developed a new kind of immunotherapy for Crohn’s that delivers a “triple punch” by tweaking the responses of different immune cells.
In some people, the immune system’s foot soldiers – T effector cells – can overreact to certain microbial proteins, causing them to launch a widespread attack that inadvertently hurts the human cells as well. That leads to the bowel inflammation, pain, colitis and other gastrointestinal symptoms that Crohn’s patients are all too familiar with.
So for the new study, researchers at the University of Alabama at Birmingham set out to find a way to calm down these overzealous T cells. They managed to develop a treatment that prevents colitis flareups in mouse models of Crohn’s, by reducing the numbers of T memory (Tm) cells and increasing the numbers of T regulatory (Treg) cells.
T memory cells act like sentinels, keeping watch for resurgences of prior infections. They lay low until they detect an antigen that they “remember” encountering, then quickly spring into action, producing huge numbers of the soldier-like T effector cells. Normally it’s an important function – but in Crohn’s patients, these Tm cells can develop a memory for harmless microbial antigens and trigger an unnecessary immune reaction.
For this study, the team focused on flagellins, a type of protein often found in harmless gut bacteria, but which is a common colitis trigger. In Tm cells that were sensitive to flagellin, the researchers blocked a signaling protein called mTOR, which is vital for producing T effector cells. Then, the scientists activated these Tm cells – but with mTOR blocked, they’re unable to mount their attack and die off instead.
The third prong of the attack is to induce a larger response from Treg cells, which keep the troublemakers in check. The team tested the new method in mice with Crohn’s, and found that it prevented colitis flareups. Similar results were found in tests on immune cells taken from human Crohn’s patients.
For now, the researchers admit that targeting one specific flagellin is unlikely to be too useful for treating Crohn’s, but future versions of the therapy may have more luck by widening their net to other flagellins. Eventually, the hope is that the treatment could be used to help keep Crohn’s patients in remission from symptoms. In the longer run, it could potentially be adapted to help treat other autoimmune diseases like type 1 diabetes or multiple sclerosis.
The research was published in the journal Science Immunology.
Update (Dec. 23, 2020): This article has been updated to reflect the fact that the cause of Crohn's disease is not definitively known.