Current issue
Working the (immune) system
How four Rockefeller labs are joining forces to cultivate
treatments for autoimmune disease
BY LYNN LOVE
As far as Ralph
Steinman is concerned, we are
alive right now because — among other reasons — our
immune systems are allowing it.
As you read this newsletter, your T cells, B
cells, natural killer cells — each of the immune
system’s warriors that circulate in your bloodstream —
are allowing your body’s heart, brain, pancreas, joints and
other tissues to exist and function without harassment or
interference. This remarkable process is called tolerance.
But in autoimmune disease, that’s not
the case. The legendary German scientist Paul Ehrlich described the
body’s capacity to turn on itself as “horror
autotoxicus.” Ever since Ehrlich’s observations at the
turn of the 20th century, scientists have tried to figure out what
causes the biological system designed to protect your body from
disease to revolt against it or break immune tolerance.
Now, for the first time, several Rockefeller
University scientists are devising novel and specific
ways of treating lupus, type 1 diabetes, multiple sclerosis,
rheumatoid arthritis, psoriasis and other autoimmune diseases by
unraveling and exploiting the biological mechanisms of tolerance
and autoimmunity.
The progress is not only an example of how
science, creatively practiced, can shed light on the body’s
most complex and mysterious workings — it’s also a
model of how collaboration among Rockefeller labs can solve
problems that might be too big for a single lab to tackle.
Four of the university’s seven
immunology labs, headed by Steinman, Jeffrey Ravetch, Michel Nussenzweig and Alexander
Tarakhovsky, all part of the
university’s Christopher H. Browne Center for Immunology and
Immune Diseases, are tackling different but related pieces of the
autoimmunity puzzle. The interactions are a testament to how
Rockefeller’s small size and flat administrative structure can make the best use of limited resources to
answer big questions. The labs have formed a de facto working group:
what’s revealed in one lab is often incubated in the next.
A key element of the understanding they are
developing is one of active maintenance of tolerance on a daily
basis, in the “steady state.” As long as the immune
system’s killer cells tolerate the body’s tissues,
health is preserved.
“This tolerance is literally what keeps
us alive,” says Steinman, head of the Laboratory of Cellular
Physiology and Immunology. “Studies in immunology have most
often emphasized the immune system’s role in defense against
infections and tumors, but tolerance is just as critical, even in
the steady state. If one could learn how to induce authentic immune
silencing, or tolerance, to the causes of autoimmune disease and
allergy, it would constitute a revolution.”
The spiny dendritic cell, discovered by
Steinman and colleagues in 1973, is a nexus for clues about
how the immune system functions: the specialized cell carries out
both the protective work of the immune system and its preventative
work of maintaining tolerance. This is because the dendritic cell
is what’s known as an antigen-presenting cell. It picks up
foreign molecules — bits of the invading bacteria, for
example — then evaluates them and relays messages about how
best to respond to other immune system cells such as T and B cells
that then carry out the dirty work. Through this biologically
didactic process, dendritic cells can recognize an enormous variety
of antigens and either encourage or subdue an immune system attack.
The scientific community was not prepared to
consider a new cell type in the immune system when Steinman made
his famous discovery 30 years ago. “We discovered the
dendritic cell because we had new microscopes and other cell
biological methods to pursue things we saw that did not fit into
accepted categories,” says Steinman, who is the
university’s Henry G. Kunkel Professor. “When we
discovered it, we could not envisage how important the dendritic
cell would be in understanding both the immunity and tolerance
aspects of the immune system.” It wasn’t until the
1990s that the dual role of the dendritic cell was fully
appreciated.
Soon after the dendritic cell discovery,
Michel Nussenzweig, now Rockefeller’s Sherman Fairchild
Professor and head of the Laboratory of Molecular Immunology, came
as a graduate student to the laboratory then headed by Steinman and
the late Zanvil Cohn. “It was a perfect time for me, a
curious young medical student, to enter the field. The dendritic
cell seemed like the most exciting and natural project to devote
myself to,” says Nussenzweig.
Nussenzweig has since emerged as a leader in
his own right in the field of autoimmunity. In 2001, for example,
he and graduate student Daniel Hawiger proved that the dendritic
cell is as responsible for establishing tolerance to the body as it
is to getting the body to eradicate pathogens — a finding
that cleared the way for dendritic cells to be exploited in the
treatment of autoimmune disease.
However, the dendritic cell alone does not
tell the whole story. In fact, it’s just one of several
checkpoints the immune system has developed to ensure that its
force isn’t unleashed on the wrong target.
Think of it as an electric circuit: In order
for a circuit to be completed, a series of switches need to be
closed. “At a basic level, the immune system is a checkpoint
system,” says Jeffrey Ravetch, Theresa and Eugene Lang
Professor and head of Rockefeller’s Laboratory of Molecular
Genetics and Immunology. “From the earliest days of B cells
to the way that T cells are informed by dendritic cells in the
periphery, health is maintained in a series of tolerance
checkpoints along the way.”
An additional checkpoint was discovered by
Nussenzweig and postdoc Hedda Wardeman in 2003. Their research
found that a majority of early immune system B cells — which
are important to antibody production during infection — are
self-reactive. If allowed to mature, these misguided B cells would
predispose the body to severe autoimmune disease, most likely,
lupus. Yet because of an immune system checkpoint, these
self-reactive B cells are killed off before they fully mature in
the bone marrow.
Another series of checkpoints, identified by
Rockefeller’s Alexander Tarakhovsky, head of the Laboratory
of Lymphocyte Signaling, are signaling proteins, such as one
discovered by Tarakhovsky and postdoc Ingrid Mecklenbrauker called
protein kinase C delta, which can establish or foil the steady
state of tolerance.
“We can almost think of the immune
system as a symphony, or a cascade, of signaling, which brings
about certain changes to individual cells and their ability to
recognize antigens,” says Tarakhovsky. “When that
signaling fails to maintain tolerance, the symphony takes on a
dissonance that it normally avoids.”
Understanding the checkpoints — and
being able to hear the symphony — will eventually lead to new
ways of corralling the immune system when it misfires and may
eventually help combat some of our most perplexing diseases.
Tolerance in the face of diversity
In the case of autoimmune diseases like type 1 diabetes and lupus, scientists know that the checkpoint system has failed. Rockefeller University researchers are now studying how to prevent autoimmunity from occurring in the first place.
BY LYNN LOVE
Eluding lupus
In the case of lupus, the immune system attacks not a
single organ but the skin, joints, blood and kidneys. As many as 1.5
million Americans have been diagnosed with lupus.
The problem is antibodies. Antibodies, Y-shaped
proteins that lead the immune system to specific invaders, start forming in
humans from infancy and hang out inside the body. When appropriate, they
bind to microbes and other foreign material, called antigens. This
connection between an existing antibody and an antigen starts a process
called clonal expansion, in which the body’s B cells produce great
numbers of antibodies. Some of these new antibodies will have a tighter fit
with the existing antigens than the original antibody did.
With bacteria or other invaders, a tight fit with an
antibody makes the pathogen easier for other immune cells to identify and
destroy. But during clonal expansion, antibodies are also created that bind
to the body’s own cells (see illustration, below). These antibodies
are known as autoreactive antibodies. Ideally, the body’s immune
system tolerates these autoreactive antibodies. But when it doesn’t,
the results are disastrous.
“Autoreactivity is not the exception, it’s
the rule,” Ravetch says. Yet the body maintains tolerance and
autoimmunity is held off. Why?
One of the immune system’s antibodies, known as
immunoglobulin G or IgG, actually controls the activities of other
antibodies that are prone to autoreactivity. In most cases, IgG inhibits
the potential onset of the autoimmune cascade we know as lupus and it
performs this role via the Fc receptor that forms its, and every other
antibody’s, Y shape.
But not always: In 2000, Ravetch, who is an expert on
the Fc receptor, and postdoc Silvia Bolland discovered that a defect in the
IgG Fc receptor will cause spontaneous autoimmunity in mice that are
genetically predisposed to lupus.
“Many people who could develop lupus never
do,” says Ravetch. “But the animals we studied broke tolerance
and developed full-blown lupus. So we immediately wanted to know how this
inhibitory receptor contributes to the maintenance of tolerance.”
Once Ravetch and his colleagues further characterize
IgG’s inhibiting role in lupus, they may be able to develop a means
of repairing faulty Fc receptors that lead to the onset of the disease.
Halting diabetes
When an out-of-balance immune system attacks
the pancreas, the result is type 1 diabetes. Over 5 million people
worldwide rely on insulin injections to metabolize the sugars that
their own bodies can no longer process.
But remarkable new research from
Steinman’s lab now shows that it may be an imbalance of
immune system T regulatory cells that triggers the onslaught. These
cells work as suppressors: they turn off the body’s immune
response. Steinman’s study in mice, reported in the June 7
issue of the Journal of Experimental
Medicine, shows that dendritic cells
can be used to expand functional T regulatory cells, which can
actually reverse the course of type 1 diabetes in mice.
“Instead of silencing the attackers
directly, we learned how to generate another type of cell, a
suppressor cell, which essentially turns off the attackers,”
says Kristin Tarbell, a postdoctoral associate in Steinman’s
lab. “At that point, it’s basically a numbers
game.” At the onset of the disease there are not enough of
the regulatory cells to suppress the immune response against the
body’s insulin-producing pancreatic islet cells. By putting
the right number (in the case of mice, 5,000 to 50,000 regulatory T
cells) in the right place, the researchers arrested the process
(see illustration, below).
Steinman and Tarbell’s study used mice
that were genetically predisposed so that their suppressor T cells,
once activated, would home in directly on the pancreatic islet
cells. Now, the scientists need to run the same experiment in mice
with normal T cells. This critical next step will determine whether
the research can be moved to clinical studies in humans.
Even now, the findings prove an important
biological principle that could lead to prevention of type 1
diabetes in humans: autoimmunity can be reversed if the immune system’s
mechanisms for tolerance — recognition and acceptance of the
body’s own cells — can be repaired, and dendritic cells
mediate this repair
Take it a step further, and the research could
have implications beyond prevention of the disease. Islet cell
transplantation, for example, a still experimental technology, is
far from foolproof. “At the moment, the problem with islet
cell transplants is that the same process that destroyed the first
set will destroy the second,” Tarbell explains. But with the ability to restore
balance in the immune system, islet cell transplant could succeed.
July 16, 2004
