Counter Attack

Bellur Prabhakar, PhD, is developing a potential breakthrough therapy for autoimmune disease.

Autoimmune diseases, which occur when the body’s immune system turns on itself, are as fascinating to researchers as they are destructive to the people who suffer from them. From rheumatoid arthritis, which attacks joints, to type I diabetes, where the immune system destroys insulin-producing cells, autoimmunity is mysterious, dangerous and difficult to treat.

But in 1999, Bellur S. Prabhakar, PhD, made a significant discovery in his laboratory at UIC. After 18 years of studying the proteins and cell behaviors that trigger autoimmune activity, Prabhakar, head of UIC’s department of microbiology and immunology, succeeded in tracing autoimmune function back to its root the dendritic cells that initiate autoimmune response. By altering the properties of those dendritic cells, Prabhakar and his colleagues reversed the spread of autoimmune disease in laboratory mice. Though the technology still is about a year away from clinical testing on humans, it has the potential to be an enormously important medical breakthrough.

According to the National Institutes of Health, 23.5 million Americans suffer from autoimmune diseases such as multiple sclerosis and lupus. Symptoms range from chronic fatigue to the muscular dysfunction caused by MS, and the diseases can be fatal: Autoimmune diseases, collectively, are one of the nation’s top 10 causes of death among children and women younger than 65. Common treatments, such as corticosteroids and immunosuppressant drugs, decrease immune system function and leave the body open to attack from outside by viruses and bacteria.

At the core of Prabhakar’s work is a strategy for altering only the parts of the immune system that are functioning incorrectly. Because the destructive work of autoimmune diseases is done by T cells or antibodies, he focuses on the dendritic cells that trigger autoimmune behavior by presenting proteins called antigens to the T cells. A T-cell response is required for antibody production as well, so by altering the interaction between the dendritic cell and the T cell, Prabhakar can short-circuit most autoimmune activity.

“People have always tried to treat the symptoms and developed all sorts of technologies to prevent immune responses by turning off T cells once they’ve been turned on,” Prabhakar says. “What we’ve done is fundamentally different. Our technology attacks the very first step in the autoimmune process, which is how the antigen presentation is perceived by the immune system. You can’t go earlier than this in a treatment protocol.”

His team has developed two related treatments. The first consists of treating with a protein called granulocyte macrophage colony-stimulating factor, which the body produces and that also is used in cancer treatments. When dendritic cells encounter GM-CSF, the dendritic cells are activated but do not fully mature. Only a mature dendritic cell is capable of inducing an autoimmune response in T cells, so there’s no attack. Better yet, GM-CSF induces the T cells to become “regulatory T cells” and to shut down any pathogenic T cell activity present.

“It’s a yin-yang effect,” Prabhakar says. “GM-CSF restores the balance that was skewed by the autoimmune disease.”

The second treatment focuses on T cells that already have been activated. When dendritic cells approach T cells, they present two types of antigens to allow for a stronger bond with the T cell. Prabhakar, along with Chenthamarakshan Vasu, PhD, assistant professor of surgery and Mark Holterman, MD, PhD, associate professor of surgery and chief of the division of pediatric surgery, found that they can introduce a bispecific antibody (a synthetic antibody that recognizes more than one protein on a cell surface) that can bind to dendritic or target cells with one of its arms and to a pathogenic T cell with the second arm and shut it down.

Prabhakar had administered GM-CSF to laboratory mice possessing two autoimmune diseases: Hashimoto’s thyroiditis (HT), which often leads to hypothyroidism, where the body doesn’t produce enough thyroid hormone; and type I diabetes. At his time, Matthew Meriggioli, MD, director of neuromuscular disease; joined forces with Prabhakar and applied this method of treatment for myasthenia gravis (MG), which weakens muscles. In mice that were close to dying from HT or MG, the treatment reversed the course of the disease. When mice showed symptoms of type I diabetes, the treatment suppressed the disease indefinitely.

Prabhakar says that one of the keys to developing the new treatment was assembling a team of multidisciplinary researchers at UIC. The team includes Holterman, Meriggioli, and Vasu. The doctors’ clinical focus helped Prabhakar move toward clinical applications.

Prabhakar often would be at work in his lab late in the evening when Holterman would arrive.

“We’d just be shooting the breeze,” Prabhakar remembers. “If he came from a transplant surgery, he’d say, ‘It’d be great if we could use this in transplant.’ I’d say, ‘That’s an interesting idea, how could we make it work?’ That’s how we got started. It’s a great example of how academic intellectual environments can create new knowledge.”

Meriggioli, who specializes in myasthenia gravis and was frustrated by the shortcomings of the available treatments, relished the opportunity to search for new solutions.

“I think our work carries a very good potential to lead to better treatment for myasthenia patients,” says Meriggioli, who did little research on this topic before coming to UIC in 2004. “I couldn’t ask for a better science mentor than Dr. Prabhakar, and I’m fortunate that he’s so interested in forging these kinds of collaborations.”

Prabhakar, Holterman, Vasu and Meriggioli are now business partners as well. The research team, along with UIC and the technology investment firm IllinoisVentures, already has founded a company to begin developing the two treatments for commercial application. The company is called Tolerogenics, after the “tolerogenic” state of the dendritic cells once the treatment is administered.

So far, most of the company’s work has focused on studying the competitive landscape, preparing for the regulatory approval process, and making sure that the intellectual property involved in the treatments is unique. Because GM-CSF is already an approved cancer treatment, Prabhakar speculates the regulatory process could be smoother than usual for a new treatment.

With those steps nearly complete, the firm is calculating the costs of development and potential return on investment; it will use those figures to attract seed-level investors to fund clinical testing. Once the treatment is closer to approval, Tolerogenics plans to sell its technology to a larger biotech firm.

First, though, there’s the matter of determining dosages for humans and then testing the treatment on patients. Even after clinical testing is begun, the treatments will be at least another five years from going to market, according to Katherine Hyer, director of life sciences at IllinoisVentures.

“It’s hard to explain the product development industry to someone creative, because it’s boring,” she says. “You’re proving the same thing over and over again, doing the same experiments, making something more durable.”

So Prabhakar will try to be patient with his breakthrough. But it’s difficult not to think about the potential impact of the treatment.

“If we have a successful product, that means I’m curing autoimmune diseases,” he says. “What more satisfaction can I have?”