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here comes a day in the early careers of many professionals--a singular defining moment that both shows their strengths and sets the stage for the rest of their careers. Think North Carolina Freshman Michael Jordan's winning jumper in the waning seconds of the 1982 NCAA championship game.

For Professor Argyrios Theofilopoulos, M.D., of the Department of Immunology at The Scripps Research Institute (TSRI), that event occurred when he was a young doctor in the Greek army--fulfilling his mandatory service after completing medical school in the late 1960s.

This was a transitional time for Theofilopoulos.A few years earlier, he had graduated at the top of his medical school class at the University of Athens, and a few years later, he would be leaving Greece to come to the United States and begin a lifelong career as an immunologist. But in 1968, Theofilopoulos was an army doctor stationed near the Bulgarian and Turkish borders.

"I was taking care of not only soldiers, but also people in remote villages," says Theofilopoulos, recalling how he would make his rounds--sometimes in a jeep and sometimes on the back of a horse--in all sorts of weather and difficult circumstances, often until late in the evening. "I was the only doctor in this area."

When Theofilopoulos arrived, the old man's blood pressure was very low, and after examining him, Theofilopoulos found a hemorrhage in the back of the man's nose, which, if left unchecked, would surely lead to the man's death. Stopping the bleeding might well save the man's life, but that was easier said than done 100 miles from nowhere in the remote border region between Greece and Bulgaria.

Theofilopoulos had practically no medical supplies. "I had nothing to work with," he says.

He did, however, have a box stuffed with some random medical surplus donated by the United States Army. He quickly opened the box, dumped its contents out on a table, rifled through, and found a urethral catheter. This thin tube was hope.

Theofilopoulos grabbed the urethral catheter, pushed it up the man's nostril, and pulled it out through the man's mouth. He then attached a cotton ball to the end of the catheter, pulled it back up the nostril, pushed it behind the pharynx where the hemorrhage was, and stopped the bleeding. Outside the tiny building, the villagers and the soldiers cheered, and Theofilopoulos became something of a hero in that region.

"After that," says Theofilopoulos, "The old man was bringing me chickens and nuts and other gifts, and my fame exploded to all the surrounding villages."

AFTER THE ARMY, A CAREER IN RESEARCH

Although he eventually gave up clinical practice to focus on basic science, Theofilopoulos's experience as a clinician has driven his subsequent career, where he has endeavored for many years to address some of the basic concepts of autoimmune diseases. Throughout this distinguished career, he has never forgotten that moment, decades ago, in that small village.

"I have always had great concern for the patients," he says. "This has been the guiding force in my life."

As a researcher, he has sought answers that could alleviate suffering--a journey that began in 1970, soon after he was discharged from the Greek army.

Theofilopoulos came first to the University of Texas Southwestern Medical School in Dallas, on a Rotary Fellowship to study rheumatic diseases in the laboratory of Professor Morris Ziff. It was the first time Theofilopoulos had ever been outside of Greece.

In 1972, he felt ready to move on and had a desire to expand his knowledge in immunology, so he came to Scripps to work as a postdoctoral fellow under the guidance of world-renowned immunopathologist Frank Dixon, who was director of the institute and chair of the Department of Experimental Pathology.

Theofilopoulos settled down, both in La Jolla and at TSRI, and raised a family while he pursued basic research. His wife, Ellie, obtained a master's degree in psychology and is involved in cultural events and volunteer work. His three children, now grown, were all born and raised in La Jolla. Aliki, his daughter and the oldest, is an animator. Dimitri, the middle child, is just finishing law school, and his youngest son, Andreas, is a computer programmer and was recently married.

Soon after Theofilopoulos began to put down roots at TSRI, he turned his attention to a disease known as lupus that he and Dixon had been interested in for some time. For the next two decades, he contributed an extraordinary amount to our knowledge of this disease--work for which he has received a number of scientific awards and honors. These include, most recently, two honorary doctorates from the University of Athens, Theofilopoulos's alma mater, and the University of Patras, in the town where he grew up.

ONCE THOUGHT TO BE FROM WOLF BITE

Lupus is a chronic, inflammatory autoimmune disease caused by multiple genetic, environmental, and other factors, most of which are unknown. It is a complicated disease that affects women ten times more often than men, and it can appear a thousand different ways in a thousand different people. The Lupus Foundation of America estimates that approximately 1.4 million Americans have a form of lupus, a disease that ranges widely case by case, has a long list of symptoms, and affects a wide variety of tissues--especially the skin, joints, blood, and kidneys.

The diversity of symptoms means that lupus is often misdiagnosed. In fact, even the name "lupus," which means "wolf" in Latin, is a mischaracterization of sorts. The word lupus was first used in the Middle Ages to describe a chronic rash on the skin. The name may have been chosen because the rash on the skin resembled the effects of a bite from one of these wild animals. Or, some believe the name arises from the fact that the rash was common about the cheeks, giving lupus victims a werewolf-like appearance.

Lupus was rigorously described and defined as a medical condition in the early 1800s, but it was not until the latter half of that century that real progress was made in defining the full clinical spectrum of this disease. The first positive step was when doctors recognized that the disease could be systemic and could cause damage to the kidneys and other internal organs distinct from and sometimes in the absence of its defining rashes.

Today we know that the disease is not the bite of a Canis lupus, but the bite of a person's own immune system.

Lupus occurs when a person's own B cells are directed against "self" molecules. B cells are one of the immune system's front-line fighters and are responsible for producing antibodies that target infected cells or foreign pathogens in the bloodstream and help the body control and clear infections.

But in lupus, these antibodies target the body's own molecules instead. For instance, many people who have lupus produce an antibody that targets red blood cells, which are a vital oxygen-transporting component of blood. The antibodies coat the red blood cells, which are then taken up and destroyed by macrophages. This can lead to a deficit of red blood cells and anemia. Since a person's own immune system causes lupus, it is categorized as one of the "autoimmune" diseases.

In the early years of his research, Theofilopoulos worked with a mouse model discovered in New Zealand that develops symptoms resembling lupus. Theofilopoulos spent several years analyzing this model, describing lupus's basic characteristics. He wrote some of the first detailed descriptions of the molecular and cellular characteristics of the disease, including its relationship to T cells, B cells, organs like the thymus, and antibodies.

"Then," says Theofilopoulos, "when molecular cloning began, we started defining the structural characteristics of the autoantibodies and other immune system-related genes that were implicated in lupus."

He and his colleagues sequenced a monoclonal anti-DNA antibody that is a major factor in lupus, and he discovered that the genes that encode these pathogenic antibodies are not very different from those encoding regular antibodies against foreign antigens. He also cloned and characterized several T cell receptor genes and studied the mechanism by which self-reactive T cells are eliminated in mice and humans with systemic autoimmunity.

INVESTIGATING CAUSES AND POSSIBLE INTERVENTIONS

More recently, Theofilopoulos has focused on identifying the genetic components of lupus, and he has been working for the last several years with his TSRI colleague Dwight Kono towards this end. Reaching this goal is no simple task, and even though scientists know that some genes play a big part in lupus, they do not yet know all the players.

Furthermore, no one gene is the culprit. Lupus, like many autoimmune disorders, seems to be caused by a multiplicity of genes interacting with unknown environmental factors and unknown biological mechanisms that trigger it.

"In [lupus], you have not only multiple genes but environmental and other stochastic influences," says Theofilopoulos. "Knowing one of them may not be sufficient to change the disease process. Yet some genes may have a greater effect than others, and if we can identify them, we may be able to intervene." Evidence in mouse models, he adds, indicates that deleting chromosomal segments that carry such genes significantly reduces the severity of the disease.

For instance, Theofilopoulos has identified one possible target for therapy, an inhibitor of cyclin-dependent kinases that is overexpressed in T cells during lupus that may be responsible for one symptom of advanced lupus-- a flood of helper T cells, a type of immune cell resistant to proliferation and apoptosis (programmed cell death). Targeting this inhibitor is likely to lead to the elimination of these helper T cells and a reduction in the severity of the disease.

Other types of genes that have been found to contri-bute to lupus are those encoding for Type 1 and Type 2 interferons, pro-inflammatory molecules referred to as IFN-a/b and IFN-g, respectively. Based on these findings, Theofilopoulos has reported using cDNA that encodes the receptor for IFN-g to block the activity of the IFN-g and cure lupus in animal models.

Similar beneficial effects have been observed in lupus mice that lack the IFN-a/b receptor.

Use of recombinant receptors for IFN-a/b and IFN-g should provide a better means to reduce the severity of the disease.

NEW TREATMENTS NEEDED

However sophisticated and promising all this might sound, it does not mean that a cure is anywhere near. In fact, one single cure may not be possible because of the heterogeneous nature of the disease.

"For lupus, there is considerable variation--possibly hundreds of phenotypes," says Theofilopoulos. "This makes it difficult to find one answer and one panacea."

Instead of viewing maladies like lupus as one disease, one might be able to identify a sub-group of patients with a particular genetic defect that contributes to their particular form of the disease.

"Then we would be much better off designing treatments," says Theofilopoulos. Knowledge of the subtypes of the disease might enable doctors to direct specific treatments to specific individuals.

No significant new treatments for lupus have been found since the 1950s, when doctors began using corticosteroids to treat it. Prior to that, at the turn of the 20th century, doctors discovered the effectivenessof anti-inflammatory and anti-malaria drugs. Although a few other treatments have been developed in the last 50 years, corticosteroids, anti-inflammatories, and anti-malarials are still the main therapies for the disease today, despite a high incidence of side effects.

The hope is that instead of giving these non-specific drugs, one could design drugs to treat a specific form of lupus. Theofilopoulos believes that this is the future, and his will to realize it is what drives him forward.

"I have a strong desire to make a breakthrough to help somebody--even a single individual," he says. "Then I will feel like I have accomplished something."

AUTOIMMUNITY AND CANCER

His work in autoimmunity has also recently led Theofilopoulos and his colleagues Wolfgang Dummer, M.D., Andreas Niethammer, M.D., and Ralph Reisfeld, Ph.D., to suggest a new, potentially more effective way to battle cancer--hit the immune system with cancer vaccines or cancer cells when it's down and it will bounce back swinging harder than ever against those cancer cells.

The technique involves administering an injection of fresh immune cells to replace the ones that die immediately after chemotherapy or irradiation. An injection of cancer cells at the same time serves as a form of "immunotherapy," which induces a person's immune system to attack existing colonies of those cancer cells. In the technique, the fresh immune cells immediately begin to multiply through a mechanism involving recognition of self-molecules and, because they see the cancer cells, they are rapidly and preferentially activated to kill them.

"In this case, autoimmunity can be beneficial to the patient, and the treatment has utility on the basis of its simplicity," says Theofilopoulos.