The development of anti-TNF drugs like infliximab (RemicadeTM) and adulimumab (HumiraTM ) has transformed the way Crohn’s disease and Ulcerative Colitis are treated — and for many people, the drugs gave them their lives back. We previously discussed how these drugs are made. Now let’s ask: how do they work?
Here’s the thing: we don’t really know. In 2013, a research review pointed out: “the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown.” But that’s not to say we don’t know anything about anti-TNF. We just don’t know everything.
At the most basic level, anti-TNF drugs block TNF, which is short for ‘Tumor Necrosis Factor’. TNF is a kind of cytokine, or signalling chemical, made by white blood cells. One thing TNF can do is kill certain kinds of tumor cells — hence its name.
More important for IBD patients is that it can drive inflammation and kill epithelium cells — that is, the cells lining the gut. It also signals the body to produce other cytokines that cause inflammation and tissue damage. Because of TNF’s key role in IBD, turning off the signal is an obvious way to treat the disease.
It turns out that where the drug turns off TNF is an important part of its effect. Researchers first thought that anti-TNF drugs like infliximab treated IBD by blocking TNF outside of cells, or sTNF. Then it was discovered that other drugs that block sTNF do not help IBD. Researchers then focused on infliximab’s effect on TNF bound to cell membranes, or mTNF. By binding to mTNF, infliximab can drive a number of changes in the immune response.
More specifically, we know that infliximab, has the following effects:
- slows down inflammatory signals in the immune system
- deactivates certain white blood cells
- activates anti-inflammatory cells
- protects the cells lining the gut
- limits blood vessel proliferation in mucosal-producing gut tissue
- helps heal mucosal-producing gut tissue
- inhibits the signals that activate genes that drive inflammation
All of this helps reverse the process driving IBD, but we don’t know which is most important. If we did, pharmaceutical makers could target more directly only the most important processes. Drugs like infliximab remain a relatively blunt instrument — but effective, nonetheless.
However, up to 40% of Crohn’s patients and up to 70% of UC patients do not respond to anti-TNF drugs. There is some evidence to think that a genetic factor plays a role in determining whether or not a patient responds to the drug, but the genes have not been identified with any certainty.
Along similar lines, recent mouse studies have shown that in some kinds of intestinal inflammation, TNF actually helps promote healing. The science is very complex, but it boils down to the fact that cells can have two kinds of TNF receptors, called TNF Receptor 1 and TNF Receptor 2. The kind of inflammation seen in IBD patients is associated with TNFR1, so blocking that receptor as beneficial effects. This is probably how infliximab works for patients who see a positive response.
However, TNFR2 is associated with healing in the gut, so blocking that receptor can actually create IBD-like symptoms. This may be why some of the anti-TNF drugs that are ineffective in IBD can actually trigger the disease.
Infliximab and other TNF inhibitors are an important innovation in IBD treatment. Yet even as they help millions of people, there is still much more research to be done on the exact mechanism by which the drugs work. With that research will come a better understanding of IBD, and the potential for still more effective treatments.
Articles used in this post include:
Guo, Y; Lu, N; & Bai, A. “Clinical Use And Mechanisms Of Infliximab Treatment On Inflammatory Bowel Disease: A Recent Update“. Biomedical Research International 2013. Available free on PubMed.
Oikomopoulos, A; W.K. van Deen; & D.W. Hommes. “Anti-TNF antibodies in inflammatory bowel disease: do we finally know how it works?” Current Drug Targets 14:12 (November 2013). Accessed via Sci-hub.io.
Dube, P.E.; S. Punit; & D.B. Polk. “Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease“. American Journal of Physiology 308:3 (February 2015) Available free online.
Image used under ‘fair use’ doctrine from Nielsen, O.H. and M.A. Ainsworth, “Tumor Necrosis Factor Inhibitors For Inflammatory Bowel Disease“. New England Journal of Medicine 369:8 (Aug 22, 2013). Accessed through Sci-hub.io.