Eliot Kristan's Blog

I came across a description of how the new Multiple Sclerosis drug Tysabri works while reading Debra Niehoff’s book The Language of Life. Niehoff uses a very well-composed description of Tysabri to exemplify the process of biochemical communication as well as a real-world consequence of manipulating our cellular social world. Here it is in full:

Axons, like wires, conduct electricity more effectively if they’re surrounded with a layer of insulation. To that end, many nerves are enveloped by supporting cells known as Schwann cells (in the peripheral nervous system) or oligodendrocytes (in the central nervous system), which wrap themselves around the nerve to create a layer of insulating material called myelin. Myelin contains both lipids and proteins, the best known of which are myelin proteolipid protein, mylein-oligodendrocyte gylcoprotein, and a complex of seven closely related proteins known collectively as myelin basic protein.

So-called autoreactive T cells that recognize myelin proteins, particularly myelin basic protein, can be found in the blood of even normal healthy people, part of the contingent of malcontents that the body has chosen to ignore. As long as they remain innocent, they cause no problems. And innocent they are likely to stay, for the myelin of the brain is shielded behind the highly selective barrier formed by the brain vasculature, which limits the transit of naive lymphocytes, along with all but the smallest, most lipid-loving molecules.

Occasionally, however, a perverse twist of fate – infection with a virus containing a protein that’s a dead ringer for myelin basic protein is one popular candidate – activates myelin-reactive T cells. Quiescent, autoreactive T cells were excluded from the central nervous system. But these active “autoaggressive” T cells are at liberty to ignore all barriers. “Step aside! Might be an infection!” they roar as they push their way, armed and spoiling for a fight, into the brain or spinal cord. Instead of microbes, however, they find myelin. Spewing cytokines and chemokines that bring ravenous macrophages and more autoreactive-turned-autoaggressive T cells running, they precipitate an inflammatory immune reaction that annihilates the cells responsible for myelin production in the brain, spinal cord, and optic nerves. Without myelin, nerve conduction slows to a crawl. Weakness, numbess, or loss of vision in one eye are often the first symptoms of the destruction, followed by a pattern of alternating remission and relapse and progressive disability. Dubbed sclerose en plaques disseminees - multiple sclerosis – by Jean Martin Charcot, the French neurologist who first described this autoimmune catastrophe in 1868, MS, as it’s known colloquially, affects nearly 1 million people worldwide, the majority women, two-thirds between the ages of 20 and 40.

Antigen recognition in multiple sclerosis skews the helper T cell ratio in the Th1 direction. Instead of defusing the conflict by dousing the participants with anti-inflammatory cytokines, like any socially responsible Th2 cell would do, Th1 cells shout incendiary words certain to feed the fire and increase the damage to innocent cells: the inflammatory cytokines interleukin (IL)-2; interferongamma; and the proinflammation, proproliferation, prodeath signal TNF-a. The release of these signals heralds the beginning of an acute inflammatory episode; in fact, it may actually precede the attack by several weeks. TNF-a is an especially baleful word, a synonym for “disability”: the higher the level of TNF-a in the cerebrospinal fluid, the more impaired an MS patient is likely to be. What’s more, it’s a bad sign for the future – one study has found that the higher TNF levels over a two-year period, the more rapid the rate of disease progression.

In addition to its other meanings – “Drop dead,” for example or “come here” – TNF-a says “knock, knock” to the endothelial cells lining brain blood vessels. In response, endothelial cells don adhesive molecules (just as they do to capture macrophages) that cure bloodborne aggressive T cells to slow down and roll, looking for a door to the inside of the brain. A gaggle of chemokines then show them where to find the friendliest integrins, and they stop to chat. Talk leads to more intimate relations with endothelial cells, so smitten they go slack-jawed allowing T cells to squeeze through the blood vessel. “Charge!” shout the chemokines, and the T cells fall on the hapless oligodendrocytes. Half-chewed myelin generated by the attack provides a fresh infusion of myelin antigens, while the relentless battle cries of T cells draw even more recruits to the site of the damage, perpetuating or exacerbating the autoimmne response.

Once scientists learned the secret words traded by cytokine-inspired T cells and endothelial cells willing to pull them out of the bloodstream, they could interrupt the conversation with a word of their own – “natalizumab.” An antibody to the integrin receptor VFA-4, found on the surface of active myelin-reactive T cells, “natalizumab” sounds so much like “V-CAM1,” the endothelial cell adhesion molecule that matches VFA-4, it’s no wonder T cells confuse the two. By the time they realize “natalizumab” is actually a nonsense word, not a handhold on the blood vessel wall, they’ve been swept downstream, far from the myelin-bearing cells they were intent on attacking.

Neurologists had high hopes for natalizumab, after a 2-year clinical trial in more than 900 MS patients showed that its ability to block the passage of myelin-reactive T cells from blood to brain reduced the relapse rate by 66 percent compared to patients receiving a placebo. But luring T cells away from their jobs also undermines the alliance between adaptive and innate immune mechanisms that has proven so effective in the fight against crafty pathogens, tamping down autoimmune reactions at the risk of increasing susceptibility to infection. Just three months after natalizumab -Tysabri, as it was known in the marketplace – was approved by the Food and Drug Administration under a new policy designed to expedite the introduction of drugs to treat potentially life-threatening conditions like MS, sales were suspended in response to reports that two patients had developed a rare viral infection typically seen only in severely immunocompromised patients. “I’m shocked that it happened so soon,” said one expert, Lawrence Steinman, in an interview with The New York Times. “But I knew it was going to happen sooner or later.”

Niehoff concludes the chapter with a philosophical romp:

Paul Ehrlich, whose ideas about the interactions between antibodies and hypothetical “side chains” on the surfaces of pathogens helped frame the concept of receptors, called the ravages of a confused immune system horror autotoxicus. Expanding the reach of the immune system, to ensure it can deal with the pathogens of tomorrow as well as those long familiar to the human race, carries with it the implicit risk of debilitating or even, as Ehrlich noted, horrific results. Like memory, immunity can overreact to the wrong information. Yet “survival is impossible without vigilant defense against attack and injury,” and that vigilance can be had only at the price of accepting the perils it entails.

“Change is suffering’ was the insight that founded Buddhism,” writes Stewart Brand. “We hate change. Ever since the big easy chair was reupholstered it’s not as comfortable anymore. And we love change. Let’s just redo the kitchen! To change is to lose identity; yet to change is to be alive.”