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Working the (immune) system
How four Rockefeller labs are joining forces to cultivate treatments for autoimmune disease
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.
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



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