Education: How does Fingolimod (Gilenya) work.

You (Matt) Wrote : It seems like stopping white blood cells from entering the blood would be very very dangerous..... I don't understand how people on Gilenya don't just get sick....."

The blood flows round the body to deliver nutrients to the cells of the body. Fluid (plasma) can leave the body from capillaries (smallest blood vessel between an artery (vessel comming from the heart) and a vein (blood vessel going to the heart). This fluid (now called lymph) bathes the cells and drain into lymph glands via lymphatic vessels. Some white blood cells (dendritic cells) move from skin to lymph glands via these lymphatics and a current idea is that these cells transport information to the lymph glands that there is a infection to deal with. In the brain the dogma is that there is no lymphatic drainage, others suggest there is some limited drainage to the cervical lymph gland. In the lymph gland these dendritic cells and the lymph encounter lymphocytes (white blood cells T and B cells)
White blood cells circulate round the blood and can enter lymph glands via specilalised blood vessels called high endothelial venules (small vein) blood vessels using a molecule called CD62L which binds to a sugar molecule on the high endothelial cells.

The NAIVE cells made in the bone marrow and moved via the blood and then into lymph glands. There they encounter lymph and dendritic cells and if they are NAIVE lymphocytes cells (that have never seen their target before) they multiply when dendritic and macrophages show the naive lymphocytes their intended target (e.g. virus, bacteria or in case of autoimmunity- a protein or lipid derived from the body). So where you had one cell you know have lots. These cells also change their coat (differentiate) and put up markers (such as CD44 and CD49d = protein that tysabri blocks) that allow these cells called EFFECTOR cells to enter tissues to seek out and destroy the infection. These cells may sometimes down regulate CD62L so they do not go back into lymph nodes (EFFECTOR MEMORY CELLS). Other cells become MEMORY cells so that when they see the target (e.g infection) again the they respond quicker and more vigourously to produce effector cells. Some of these memory cells (CENTRAL MEMORY CELLS) travel through the lymph glands. The white blood cells then exit the lymph gland, possibly traveling to the next lymph gland via the Efferent lymphatics (lymph vessel that leaves the lymph gland). This eventually drains back into the blood and from there the white blood cells circulate round the body.

In cases of MS the thought is that these white blood cells then enter the brain and thinking that oligodendrocytes and myelin are infections they cause damage that leads to demyelination and symptoms of MS. Now Gilenya works by blocking the action of a molecule (Sphinosine-1-phosphate receptor) that is a gatekeeper of the efferent lymphatics that stops the white blood cells exiting the lymph gland.

However only the naive and central memory populations, which are thought to be involved in MS, use this molecule to exit the lymph cells, whereas effector memory cells that fight infection do not. Therefore whilst Gilenya is a potent immunosuppressive and can inhibit relapsing disease the hope is that it does not stop one from fighting off infections.
Another way to think of this is to imagine a racing track (blood system) and the pitstop (lymph gland) and the racing cars (white blood cell). Cars have to go into the pitstop to change their tyres and then off they go back to the blood. The team managers can call in the cars by perhaps putting out a flag so the cars come in. The naive (yellow) and central memory (green) cars run on Goodyear tyres whereas the red car (effector memeory) cars run on Pirelli tyres. Now gilenya blocks the Goodyear truck from delivering tryes and so when the cars come into the pits for a tyre change there are no spare tyres and so the yellow and red cars get stuck in the pitstop and have to retire from the race. However, the red car can just keep going and protect against infection.

For those of you interested, below is a video infomercial for Doctors made by Novaritis, which indicates how fingolimod may works. The first half talks about what we have said above.