Not for MDs Only: Stanford PhD directs the body's defenses
Immune Traffic Controller
By Amy Adams
When Tom Schall began working toward his Stanford PhD in 1984, the molecules that would become his life's work existed only by evidence of their effects -- they were the invisible hand that directed the immune cells in their disease-fighting job. Since that time, Schall has not only discovered many of the 50 known human chemokines but he's putting these small proteins to work making pumped-up, fast-acting vaccines and discovering drugs to prevent immune diseases.
Schall was among the first to discover chemokines when he isolated a gene he called RANTES from cultured immune cells. At the time, he was a graduate student in Stanford's cancer biology program working in the lab of professor Alan Krensky, PhD. "It had been known for almost 100 years that something was guiding the trafficking of immune cells in the body," Schall says. He intended to find out what that something was. "What attracted me was the pioneering spirit," he says.
During his career, Schall has gone from pioneer to settler, working on chemokines at Genentech for seven years, DNAX for four years and finally starting his own company, ChemoCentryx, in 1997 to use chemokine research to develop drugs. San Carlos, Calif.-based ChemoCentryx has drugs in early stages of development to treat autoimmune disease, cancer, heart disease and transplant rejection. Researchers there are also making headway with chemokine-enhanced vaccines.
What's the big deal about chemokines? They play the role of director for the body's immune system, explains Schall. These molecules, which all share the same basic structure, summon immune cells to the site of infections, induce immune cells to release disease-fighting compounds and guide the development of immune cells once they form. They do their work by binding to receptors lodged on the surface of some immune cells, triggering changes within that cell.
Their roles are so complicated, sometimes they get "messed up," Schall adds. In autoimmune disease, for example, chemokines summon immune cells to the body's own tissues -- such as joints in rheumatoid arthritis -- where the immune cells use their might against the wrong targets.
Some wily disease-causing viruses and bacteria have also learned how to use chemokines against us. They release a "go away" chemokine that causes the immune system to turn a blind eye. In both cases, Schall sees potential to meddle with the chemokine response in order to treat the diseases.
Chemokine Defense Shield
In addition to treating conditions where the immune system has already gone awry, Schall sees a role for chemokines in preventing diseases from occurring. It turns out that with a dose of the appropriate chemokines, regular vaccines can become uber-vaccines with larger, faster responses.
The vaccine work, dubbed ProDendryx after the dendritic cells it targets, hinges on recruiting immune cells to the site of a vaccination. In a normal vaccination, the doctor injects a liquid containing either a dead variant of the virus or bacteria or small particles taken from these potential sources of infection. Immune cells called dendritic cells travel through the bloodstream and bump into the foreign bodies, gobble up the putative invaders and display the cellular bits on their cell surface.
Thus decorated, the dendritic cells continue their travels through the bloodstream where they bump into a class of disease-fighting immune cells called T cells. When a T cell recognizes a particular molecular chunk latched onto the dendritic cell, it multiplies and goes on the offensive. If any complete virus or bacteria works its way into the body, it encounters an army of T cells that can attack and fend off the disease.
Where a regular vaccination relies on nearby dendritic cells bumping into the target molecules, Schall's chemokine-enhanced vaccines would lure dendritic cells to exactly where they are needed. "What we have found is that certain highly specific chemokines target these dendritic cells," Schall says -- target them and summon them in huge numbers. Schall sees ProDendryx as beefing up the dendritic cell school system for the T cells.
Studies using mice show that including chemokines in the vaccination strengthens the initial response as well as the response months later when the animals are exposed to the virus or bacteria in question. Such a good response from the first shot could mean the end of multiple vaccination regimens. "Using this, you might not have to come back for three hepatitis B or childhood vaccinations," Schall says.
In addition to a response with more oomph, the immune response is faster when a vaccine contains chemokines, Schall says. This speed raises the possibility of a post-exposure vaccination. "If you were exposed today, wouldn't it be great if you could go to the clinic tomorrow to get a shot?" he asks. The U.S. government answers a resounding yes: The Defense Advanced Research Projects Agency has awarded ChemoCentryx two grants to develop these after-exposure vaccines.
The idea is that the military would not need to vaccinate all personnel against all possible forms of biological attack. Instead, troops who suspected they had been exposed to smallpox or any other agent could march straight to the medic for a vaccine/chemokine cocktail. If Schall's research pans out, the vaccine could ramp up the immune system in just a few days, slightly ahead of the agent's assault on the body.
Schall says these vaccination programs represent just a glimpse of the role chemokines will play in medicine of the future. "Ten years from now drugs that regulate chemokine action will be standard in pharmaceuticals." With any luck, ChemoCentryx will be part of that standard, he adds.
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