As was mentioned in class, most of the treatments for
inflammatory bowel disease that were available around the time the review
articles were published focused on treating the downstream effects of
inflammation, rather than preventing it in the first place. That sparked me to
want to find if there was any more recent research done to try to find a drug
that focused on preventing activation of the inflammatory cascade in the first place.
After some research, I came across a drug called Vedolizumab.
In general, inflammatory bowel disease is characterized by chronic inflammation
in the gut. Therefore, a very simple cure for inflammatory bowel disease would be
to just “turn off” the immune system. Obviously this is not a viable treatment,
as it would cause widespread problems throughout the rest of the body. Vedolizumab
takes advantage of the fact that the body is able to selectively send T cells
to the part of the body they are needed. It has been discovered that one of the
main ways the body directs T cells to the gut is using the glycoprotein α4β7. α4β7 is an integral
membrane protein in T cells and when it binds to a molecule called MAdCAM-1, which is located
in the mucosa, the T cell is able to move through the submucosa into the gut.
From there the T cell can contribute to the immune response needed in the GI
tract. Vedolizumab is a monoclonal antibody that is specific for the α4β7 protein. Vedolizumab
is able to bind to α4β7, preventing it from being able to bind to MADCAM-1, and
therefore inhibiting the movement of T cells into the gut. In this way,
Vedolizumab is able to “shut off” the immune response in the gut, while still
allowing the immune system to function in the rest of the body.
I found this to be a fascinating way to go about treating inflammatory
bowel disease. I feel that too often in medicine the focus is on medicating the
effect rather than the cause. As mentioned above, this was also the case in
inflammatory bowel disease; there were medications to mitigate the effects of
the chronic inflammation, but nothing to inhibit the inflammation from occurring
in the first place. Since it goes to the route of the cause of inflammation, I believe that Vedolizumab shows great promise as a
treatment for inflammatory bowel disease. It will be interesting to follow up
on this drug after it has been more extensively tested.
Sources:
Fedyk, E. R., Wyant, T., Yang, L.-L., Csizmadia, V., Burke,
K., Yang, H. and Kadambi, V. J. (2012), Exclusive antagonism of the α4β7
integrin by vedolizumab confirms the gut-selectivity of this pathway in
primates. Inflamm Bowel Dis, 18: 2107–2119. doi: 10.1002/ibd.22940
Feagan BG, et al. Vedolizumab as induction and maintenance
therapy for ulcerative colitis. The New England Journal of Medicine.
2013;369:699.
Sandborn WJ, et al. Vedolizumab as induction and maintenance
therapy for Crohn's disease. The New England Journal of Medicine. 2013;369:711.
That definitely sounds interesting. Did your research say anything about what stage the drug development is at? I also wonder if a side effect would be preventing T cells from going to a different mucosa of the body that would normally need them or just cause problems there.
ReplyDeleteVery good point about treating the cause rather than the effect. Like you said, Vedolizumab basically inhibits T cell migration to the gut, thus stopping the the inflammatory response from occuring, but may need more testing. I completely agree. Anything that inhibits the inflammatory response needs to be under careful scrutiny, as inflammation is vital to our survival. Questions that need to be addressed could include: "What are the negative effects of stopping T cell migration to the gut? Could there be another important function that is being overlooked in blocking the response all together? What are the long term effects?"
ReplyDeleteAllison, yes it was recently approved by the FDA but I believe we are still waiting on the final approval for use with patients. One of the concerns that have been brought up is that in some patients the drug has been shown to also affect the blood brain barrier. Another of the active ingredients, natalizumab, affects adhesion molecules in the brain as well as the gut. I think that this shows the risk in developing drugs that disrupt normal body functions; although we try our best to make drugs as specific as possible, there is still the chance that it can unintentionally affect other body systems.
ReplyDeleteJohn, you hit the nail on the head. As we've discussed, in autoimmune diseases the immune system/inflammation seem to get a bad reputation, its easy to forget that inflammation has evolved to protect us! Im always a little wary of any treatments that disrupt immune function, although it will help out the specific disease being treated there is always the risk of complications later down the road with subsequent infections.
Joel, in your comment above you mentioned a complication of this treatment that concerned me: subsequent infections. If T cells cannot enter the gut, they cannot protect the body from any pathogens that were eaten or exert much control over the intestinal flora. The studies done so far on Vedolizumab indicate that infections don't seem to occur at a higher rate for those treated with the drug. This seems promising, and I have linked an article that discusses the progress in developing Vedolizumab as well as other treatments that are currently used.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557917/
Jen, thats a very good sign of the effectiveness of the drug, but it also raises some more questions. I wonder if the body is able to adapt somehow to the lack of T cells in the gut or if just having innate immunity is enough to ward off infections in these patients. As we've learned, T cells are an integral part in both their own and B cell function, so not having them could has have drastically negative effects. If anything, I think this shows how resilient the body can be. Even without a huge part of its immune system, it still contains many mechanisms to protect itself.
ReplyDelete