Crohn’s Disease is an inflammatory conditions of the GI tract, which usually affects people aged 20-40 years. It can be caused by a number of factors, including dysregulation of immune cells or interruption of the mucus barrier which lines the intestine. Pro-inflammatory substances called cytokines are present in high concentrations in the intestine, while there is a shortage of anti-inflammatory cytokines. This imbalance can lead to diseases such as Crohn’s.
Integrins are a specialised family of receptors present on many cell types. The α4β7 integrin is present on T lymphocytes, and allows them to bind to cells of the intestine. The T lymphocytes can then become activated and subsequently release pro-inflammatory cytokines, leading to inflammation. This integrin is a drug target for Crohn’s disease treatments, in order to prevent the infiltration of inflammatory T lymphocytes to the intestine. The drug is called natalizumab and is a monoclonal antibody which can block the α4β7 integrin – specifically, natalizumab binds to the α4 part of the integrin molecule, thereby preventing T lymphocyte binding and activation.
Natalizumab was shown to be a successful treatment for Crohn’s disease, due to reduced T lymphocyte-mediated inflammation in the intestine. However, the specificity of natalizumab for all α4 molecules resulted in significant and serious side effects. The drug was also found to block the binding of the T cell ligand VCAM-1 for its receptor in the brain; VLα4. T lymphocytes were therefore unable to infiltrate the brain tissue; a finding which led to the trial of the drug for multiple sclerosis (MS). MS is a degenerative condition resulting from the destruction of brain cells. By blocking T lymphocyte entry to the brain, natalizumab functioned as a successful treatment for MS.
However, T lymphocytes are supposed to migrate to the brain for a reason. In the case of viral infection of the central nervous system or brain, T lymphocytes are vital to infiltrate the infected area; some T lymphocytes directly kill infected cells by delivering toxic granules, while others flag up infection and subsequently recruit other immune cells. Natalizumab prevents T lymphocytes from entering the brain, so was found to cause opportunistic infections of the brain and nervous system – some of which, such as the Epstein Barr virus, can be life threatening.
Natalizumab is an illustration of how drugs which can seem like a solution to one disease can have applications elsewhere – as well as having the potential to cause serious side effects.
Ghosh et al (2003) “Natalizumab for active Crohn’s disease” New England Journal of Medicine Volume 348 No 1 p. 24-32.
Miller et al (2003) “A controlled trial of Natalizumab for relapsing multiple sclerosis” New England Journal of Medicine Volume 348 No 1 p. 15-23.