As reported by The Hartford Courant, March 1, 2005.

One Vaccine, Many Diseases

By William Hathaway

About five years ago, Dr. Rajiv Chandawarkar, a reconstructive plastic surgeon and researcher at the UConn Health Center, and UConn cancer researcher Pramod Srivastava decided to investigate further how heat shock proteins affect immune-system responses.

Srivastava had extracted such proteins from a variety of cancer tumors and reintroduced them in low doses into the cancer patients, a technique that rallied a vigorous and targeted immune response to the tumors. Phase III trials for the cancer vaccine are now being completed.

Chandawarkar wondered whether heat shock proteins could help promote wound repair. As part of that research, the two men injected heat shock proteins into mice at higher doses than those used in the cancer vaccine.

To their surprise, the high doses of heat shock proteins had the opposite effect of what occurred at lower doses: They suppressed rather than triggered the immune system.

The researchers later found that high doses of heat shock proteins protected mice from developing both multiple sclerosis and Type 1 diabetes.

"It is a very strange paradox," Chandawarkar said. "The fact is that these are challenging diseases, and there are multiple approaches to understanding them. But there are also some general principles that are as important, if not more important, than the differences."

The research is part of a larger scientific effort to find common links among diseases like Type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Collectively, autoimmune diseases affect millions of people; three out of four patients are women.

Autoimmune researchers, who receive a fraction of the grants cancer researchers do, are cautiously optimistic that they may be able to find therapies that can treat at least a few autoimmune diseases.

"There's still a lot of skepticism, but there is also hope," said Dr. Noel R. Rose, director of the Center for Autoimmune Disease Research at Johns Hopkins University. "There might be a universal treatment out there, but we are still far, far from that."

Rose, who is chairman of the Autoimmune Diseases Coordinating Committee of the National Institutes of Health, has been charged with coordinating autoimmune research grants originating at several NIH agencies.

Autoimmune research has been hampered because research efforts traditionally have been spearheaded by specialists from different academic areas. For instance, endocrinologists study insulin-deficiency in type 1 diabetes, rheumatologists the joint pain of rheumatoid arthritis, and neurologists the damage to nerves caused by multiple sclerosis. And there is good reason for scientists to be pessimistic about universal treatments.

Autoimmune diseases each produce a unique molecular flag on specific organs that triggers an immune-system attack.

However, while signals that cause the diseases may be unique, the immune-system response to different diseases may be similar.

Already, scientists have had some success using those similarities in developing drugs that can treat multiple autoimmune diseases. For instance, the cancer drug Rituxan, which targets the immune system's B cells, has shown promise in treating rheumatoid arthritis and lupus, an autoimmune disease that afflicts a variety of organs.

Also, drugs that target a protein involved in inflammation - tumor necrosis factor alpha, or TNF-a - have been used to treat rheumatoid arthritis, psoriasis and Crohn's disease, Rose said.

Clinical trials are the next step in determining whether the paradoxical behavior of heat shock proteins can be harnessed to treat multiple autoimmune diseases. A trial at UConn could begin next year, perhaps to treat rheumatoid arthritis, Srivastava said. He acknowledged, however, that more work needs to be done to assess potential dangers of the treatment.

"We do not as yet have a clear understanding of the mechanisms involved," Srivastava said.

While the rewards are great from pursuing treatments powerful enough to work in many different diseases, so are the risks that the treatments will adversely affect health, Chandawarkar said.

But that won't stop scientists from searching for simple ways to intervene in complex diseases, whether they are cancer or autoimmune diseases, said Dr. Ira Mellman, an immunobiologist and scientific director at the Yale Cancer Center.

"If physicists can look for a unified theory, why can't biologists?" Mellman asked. "Sure, it is complicated, but there are general principles at work. These are not random events."