Not for MDs Only: Stanford PhD directs the body's defenses
Immune Traffic Controller
By Amy Adams
Photography by Bryce Duffy
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.
Comments? Contact Stanford Medicine at
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