Searching for hidden chinks in the immune system's armor

For Dr. Keith Jerome, the most intriguing question about cancer is not what causes it but why our bodies fail to defend us from the disease after it strikes.

"Infection with a cold virus brings on a very noticeable immune response — congestion, nasal swelling — all of which is part of the infection-fighting process to clear the virus from the body," said Jerome, an immunologist in the Clinical Research Division. "Yet for many cancers, there are no obvious signs of an immune reaction, despite the fact that cancer cells clearly don't look normal."

That paradox first struck Jerome while he was a graduate student at Duke University about 15 years ago, where he made a surprising discovery in women with breast cancer. When he extracted their lymph — a clear fluid that carries infection-fighting cells through the body — Jerome found immune cells that reacted against a substance found on breast-cancer cells.

The immune cells he identified are known as T cells, infection-fighters that destroy virus-infected and other unhealthy cells.

"It had been thought previously that the immune system couldn't see tumors," Jerome said. "So the question then turned to, 'why isn't the immune system working to recognize and kill tumors when they arise in the body?'"

Today in his own laboratory at the center, Jerome's research is yielding insight into this and other immune-system shortcomings that cause serious human health problems. Understanding how some diseases evade our body's defense system may help explain the incomplete control of chronic viral infections by the immune system, the lack of success of current vaccination approaches to many viruses as well as the inability of the immune system to control many tumors.

Jerome's research primarily focuses on the human herpes virus, one of nature's wiliest — and most common — infections. He uses the microbe as a model system to probe for chinks in the immune-system armor that may be common to many types of immune failure.

"As I was setting up my own lab, I realized that another example where you see immune failure is with viral infections," he said. "We see that a lot with our transplant patients, whose immune systems are compromised. And even among healthy individuals, some of us control some infections, while others don't."

That's particularly true with herpes virus infections, which span an enormous clinical spectrum, Jerome said.

"A lot of people infected with herpes virus never know it, yet others have obvious symptoms and frequent recurrences," he said. "It's clear that the virus has ways to deal with immune system."

Viruses are so highly skilled at escaping immune capture because they have evolved together with humans over millions of years, Jerome said.

"They've had plenty of time to probe for our weak spots," he said. "If we can learn why we can't completely control viral infections, we will likely learn many things about ourselves. We expect that what we learn about viral immune evasion will be relevant to other examples of immune failure, including cancer."

Cellular suicide

In the last few years, Jerome's lab has discovered two tricks used by the herpes virus to elude immune system capture. One is to throw a monkey wrench into the system that enables an unhealthy cell to commit suicide, a process called apoptosis. Cellular suicide is one way for the body to rid itself of virus-infected or other diseased cells.

"It's been clear for years that at least some viruses can inhibit cell death, which is advantageous for the virus because it needs to be inside a living cell in order to make copies of itself," Jerome said. "We found that herpes virus inhibits cell death by interfering with the signal from the immune system that tells an infected cell to die."

The finding also has implications for cancer-cell immune evasion. Tumors are generally defective in the cell-suicide process, which is one reason why chemotherapy often fails.

A second evasion tactic enables a herpes-infected cell to halt certain disease-fighting T cells, called cytotoxic T lymphocytes (CTL), dead in their tracks.

"When CTLs come in contact with a herpes-infected cell, they become completely dysfunctional," Jerome said. They aren't dead, but they can't do any of their normal functions."

The discovery is especially exciting, Jerome said, because there have been reports that CTLs in the vicinity of tumors are also inactive. "It's been very hard to study this directly because there are only small samples of cancer-inactivated cells," he said. "With the herpes virus, we have a very experimentally tractable system for studying the mechanism behind this inactivation."

The ultimate goal is to use this knowledge to create therapies that overcome immune failure in cancer and viral infections or that dampen the hyperactive immune response that causes autoimmune diseases such as lupus or rheumatoid arthritis.

"When we understand how a virus shuts off an immune cell, we may be able to develop therapies that block the shutoff signal or mimic the inactivation to deliberately turn off hyperactive cells," he said.

Viral PCR laboratory at the Seattle Cancer Care Alliance

Jerome also confronts immune-system evasion in his clinical practice at the Seattle Cancer Care Alliance, where he diagnoses infections in patients undergoing bone-marrow and stem-cell transplants for blood cancers. Transplant patients, as well as those who receive high-dose chemotherapy for solid cancers, have weakened immune systems unable to cope with a variety of viral, bacterial and fungal infections.

Jerome heads the clinic's Viral PCR lab, which provides same-day testing for viral infections that most commonly plague patients with compromised immune systems.

"For a lot of the viruses, we need to catch infections at the earliest whiff of viral activation," Jerome said. "If you wait even a week with patients in this immunocompromised state, a simple infection can become an almost untreatable malignancy."

Almost all of the lab's tests — which are based on highly sensitive techniques for detecting tiny amounts of viral genetic material — were developed by the laboratory, which processes samples sent from all over the country.

"Part of the lab's function is service work, but we are also on the lookout for the new diseases that may be likely to affect our patient population," he said. "For example, when the West Nile virus surfaced, we developed a test in record time — about a month."

The lab detected only one case of West Nile virus in a patient visiting from Colorado, where the disease is common.