## Tysabri woes

Tysabri (Natalizumab) is a promising new drug for the treatment of multiple sclerosis. It is supposed to act by preventing immune cells from entering the brain via the blood-brain barrier. A loss of integrity of the blood-brain barrier is associated with relapses in MS and helping to seal this barrier is one of the mechanisms presumed to underly the beneficial effects of interferon $\beta$ as a therapy for MS. In clinical trials Tysabri seems to compare very well with interferon $\beta$ which is now widespread in the treatment of MS. It is not surprising that this has led to enthusiasm in the medical world and hope among patients. Unfortunately there is a catch. In 2005 two patients being treated with Natalizumab and interferon developed the dangerous disease PML (progressive multifocal leukoencephalopathy), with one of them dying. There was also a fatality in a patient being treated for Crohn’s disease with Natalizumab in combination with other drugs. The suspicion of a causal connection between the therapy and the deaths arose. The drug was removed voluntarily from the market by the manufacturers but later reapproved by the authorities with certain restrictions after an inquiry. Now two new cases of PML in patients receiving Tysabri have been reported. The share prices of the manufacturers plummeted.

It remains to be seen what these unfortunate events will mean for the future of this drug. There is another aspect of the story which I find interesting. If this substance has such powerful effects, positive or negative, can it tell us more about the normal mechanisms of multiple sclerosis or other autoimmune diseases? In particular, what can it tell us about the role of the blood-brain barrier? PML is caused by the JC virus, which is extremely widespread in the human population but usually harmless, causing no symptoms. PML occurs most frequently in patients with AIDS and transplant recipients being treated with drugs which suppress the activity of the immune system. This suggests that under normal circumstances the immune system successfully keeps the virus in check but that when the immune system is suitably impaired the virus can multiply in an uncontrolled way, causing a deadly disease. From this point on it is not hard to imagine a possible connection between drugs which seal the blood-brain barrier and PML. In this scenario the immune system would have been denied sufficient access to the central nervous system to control the virus population.

Natalizumab is a monoclonal antibody against the adhesion molecule VLA-4 (very late antigen 4), also known as CD49, which belongs to the family of integrins and occurs on the surface of leucocytes.

I have not encountered any mathematical models for the function of the blood-brain barrier, despite its importance for many medical issues.