Can we treat inflammatory bowel disease by holding the cells of the immune system captive?

Teachable moment in classrooms:

1. cellular basis of life chapter – cell membrane proteins can function as receptors
2. digestive system chapter – anatomy of the digestive system, location of large intestine
3. digestive system chapter – layers of the gastrointestinal tract, location of mucosa
4. immune system chapter – cell-based immunity depends on cytotoxic T-lymphocytes

The news item:  Recently the following article appeared online:

New drug for IBD, ulcerative colitis wins FDA approval: ‘Amazing results’

“We’re seeing pretty amazing results” with newer treatments, said one expert. “If you look over the last few years, it’s been game-changing.”

The article states that inflammatory bowel disease and ulcerative colitis are diseases of the lining of the large intestine and rectum where open sores develop, and while the precise cause is unknown, we consider this a consequence of the improper functioning of the immune system. The article describes the symptoms as diarrhea, abdominal pain, fatigue, and rectal bleeding. The article states that the current steroid and other injectable treatments are effective, but patients could be treated easier with oral medication.

So, Why Do I Care??  Each year over 70,000 people in the US are diagnosed with inflammatory bowel disease; currently about 2.1 million people are treated for the disease. Because the symptoms are debilitating, and treatment options have been limited to injectable drugs, the significance of Etrasimod (Velsipity) is that it provides a treatment option using oral medication instead of injections.

Plain English, Please!!!   First, let’s talk about what inflammatory bowel disease is. This disorder happens when the immune system overreacts to viruses or bacteria in the gastrointestinal tract (GI-tract), the tube-shaped part of the digestive system going from the mouth to the anus. Most of the time the large intestine and the rectum are the location for inflammation. The overactive immune system sends a large number of cytotoxic T-lymphocytes to the inner lining, the mucosa, of the GI-tract. Once there, those T-lymphocytes release inflammatory mediators that cause vasodilation, and eventually tissue damage. The damaged mucosa prevents absorption of nutrients and causes bleeding and diarrhea.

Second, let’s talk about how the immune system becomes overactive during the disease. Normally most of the T-lymphocytes reside in the lymph nodes limiting the number of T-lymphocytes released into circulation as there are few invaders to defeat. Imagine a parking lot (the lymph node) with cars (T-lymphocytes) with engines running. A molecular signal allows the cars to shift into drive and move out of the parking lot. Normally only a few of the cars react to that molecular signal which is a molecule called sphingosine 1-phosphate (S1P). T-lymphocytes detect the S1P signal through proteins called receptors. Imagine S1P molecule as a baseball, that fits into the receptor, the baseball mitt on top of the car. Once the baseball mitt catches the baseball, the car is put into drive and moves. For some reason, in inflammatory bowel disease the receptor has a higher-than-normal activity, and it makes large numbers of T-lymphocytes move out of the lymph node. That means that an abnormally high number of T-lymphocytes are moving to the large intestine. That abnormally high number of T-lymphocytes lead to inflammation and subsequent tissue damage.

Third, let’s talk about how Etrasimod acts. It makes sense that if the higher activity of the S1P receptor is responsible for the release of large number of T-lymphocytes from the lymph node, then a drug that reduces the receptor activity would prevent the T-lymphocytes from exiting the lymph node. Etrasimod is such a drug, as it sticks to the baseball mitt, the receptor, and lowers its activity. With normalized lower speed of the receptor most the T-lymphocytes are held captive in the lymph node, and there will be fewer T-lymphocytes in the large intestine, so inflammation will be reduced, and symptoms of inflammatory bowel disease will be moderated.