immune system


LIKE MANY PHARMACEUTICAL RESEARCHERS, DR. ARTHUR KRIEG is working on a cure for cancer. He also hopes to eradicate AIDS, lupus, hepatitis C, even allergies. And he hopes to do all this with a single kind of drug. He’s no mad scientist. His company, Coley Pharmaceuticals, focuses on the innate immune system, the body’s defense mechanism against thousands of vastly different pathogens . Colev’s dream is to control that system, manipulating its response so precisely that bacteria, viruses and even tumor cells won’t have a chance.

The innate system is the body’s main line of defense against bad guys —a burglar alarm and ---- a police force all in one. Until recently, doctors have essentially treated it as the Rodney Dangerficld of the body. “When I was in medical school, the innate immune system didn’t get much respect, says Kricg. What changed all that was the discovery in the late ‘90s of ‘toll-like receptors— primitive yet powerful micro-scopic structures (named after the German word for “amazing”) that are at the heart of the innate immune response.

When the body is invaded by germs, the innate immune system figures out whether it’s dealing with bacteria or viruses, then immediately turns on its toll-like receptors. The receptors direct a cascade of defenses, telling the body to either eat the germs (via phagocytic cells), kill them (by sacrificing infiltrated bodily cells) or generally make life difficult for them (via inflammation). The innate immune system can also warn other parts of the body to buck up their own cellular defenses. If none of that works, the innate immune system tries yet another strategy, calling its adaptive counterpart into action. The adaptive immune system is the one most people are familiar with, the system of T cells and B cells that remembers how to fight specific germs the body has been exposed to before. Without the innate system, the adaptive system doesn’t know when to work. In other words, the innate system is the master controller that makes immunity possible.

When drugmakers hear the phrase “master controller” they get excited. That principle especially applies to Krieg’s cancer treatments, which manipulate the body into attacking something that’s not even one of its usual targets (i.e., a bacterium or virus). “We can trick the body into thinking a cancer is a kind of viral infection,” he says. Coley Pharmaceuticals started Phase III trials, in conjunction with Pfizer, last month, injecting lung-cancer patients with synthetic DNA that mimics a virus but doesn’t cause symptoms.   The cancer treatment is Coley’s most successful drug so far, hut it’s by far not the only one. The company also has a hepatitis C drug in the Phase lB stage. Last month it announced that treatment for just four weeks had decreased the viral load in hep C patients’ bloodstreams. Then there’s Coley’s approach to HIV/AIDS. Vaccines against the virus haven’t worked so far, but Krieg says that in a few small trials, he’s used his synthetic DNA to boost their effectiveness, resulting in “a highly significant improvement in the immune response.

Vaccines have been a popular focus of study fbr other companies, too. The way most conventional vaccines work, says immunologist Alan Alderam of the Institute for Systems Biology, is that “you take a bug and you crush it up or kill it, you shove it into the person and you hope for the best.” For diseases like polio, of course, that does the trick . “But in the case of HIV and TB” in which the immune system can’t function properly, says Alderam, “you’re stuck.” Vaccines admin-istered with an innate-immune booster might kick-start the immune rcsponse that otherwise stays dormant. Furthermore, innate-immune boosters could help doctors vaccinate people against a wide variety of pathogens all at once an idea that’s particularly valuable in an age of biotcrrorism. NovaScreen, a firm that screens existing drugs for new uses, is working on such a booster with funding from the Dcfcnse Department. Boosting the innate immune system, of course, has risks, chief among them the possibility that doctors might overdo it. “The inflammatory system is a two-edged sword,” says Alderam. “It’s there for a reason—you absol-utely need it to fight infection—but too much of it is really, really bad.” Doctors already know what happens when the immune system is over-activated: the patient gets an autoimmune disease. Some of the mechanisms the innate immune system uses to fight pathogens particularly inflammation—arc responsible for a host of health problems of their own. “There’s definitely a potential downside,” says Krieg. He has seen it firsthand: some of the participants in his trials have reacted badly, developing flu-like symptoms and inflammation or blistering at the site of the injection.

Of course, “controlling” the immune system means being able to turn it down, as well as up . If autoimmune diseases result from an overactive system, the thinking goes, why not just reverse the direction of the system? In lupus, for instance, the body essentially turns on itself making antibodies to its own RNA or DNA. Or take allergies, in which the immune system mistakes everyday substances for pathogens. If doctors could use the innate system to stop the body from reacting in those cases, they could essentially eliminate the illnesses. The treatment would come with its own risk: turning the immune system down too much. “You’d expect people to become a little more susceptible to infections in those cases,” says Aldcram. Doctors would then have to treat those infections with antibiotics. And they’d be happy to get far enough down the road to face that problem.



December 12, 2005 (pgs. 56-58)

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