More MS news articles for September 2000

Cracking the code of immunity Research on T cells may lead to vaccines against cancer, AIDS

By Steve Sternberg

Actor William Hurt hadn't heard from former high school classmate Ellis Reinherz in at least a year. Then, one day, Hurt's phone rang. It was Reinherz, brash and confident as ever.

He told Hurt that he had an idea that could someday revolutionize medicine, by enabling doctors to vaccinate newborns against cancer, AIDS and other deadly diseases that defy ordinary vaccines. He wondered whether Hurt could help him raise $150 million to get the project off the ground.

Hurt listened attentively as Reinherz outlined his approach. It hinged on a remarkable type of white blood cell known as the helper T cell. Helper T cells might be thought of as the conductor that orchestrates human immunity.

Learn how to manipulate them, and you can manipulate the entire immune system -- so that it targets cancer cells and germs it might have ignored.

What's more, Reinherz had achieved this in mice, proving in principle that the approach works. Hurt was captivated. "Ellis all of a sudden pops up and has this brilliant idea," he says, realizing this was an entirely new way of thinking about vaccination.

The actor was one of several friends who have rallied to help Reinherz raise money for the Molecular Immunology Foundation he established to fund the research. "He's got some talented, experienced people gathered into a potent work team that will make this happen," Hurt says.

Reinherz isn't a theorist, pondering interesting questions for their own sake. He is an experimentalist, searching for practical answers. He wants to crack the code governing the regulation of the human immune system, and he wants to do this in a decade or two.

Reinherz is convinced that the method he calls "thymic vaccination" offers a unique opportunity to prevent AIDS, hepatitis, prostate cancer, leukemia, multiple sclerosis and other autoimmune diseases. "The real acid test," he says, "will be manipulating the immune response to prevent human disease."

A two-decade quest

A professor of medicine at Harvard University and chief of immunobiology at Dana-Farber Cancer Research Institute in Boston, Reinherz has spent two decades exploring the basics of human immunity. He has made some critically important discoveries.

In the early 1980s, Reinherz and a mentor, Stuart Schlossman, created the immune suppressive medicine OKT3, which helped make organ transplants routine and less risky. About the same time, the two led a team that recognized an immune-system workhorse, the helper T cell.

Anyone who doubts the importance of helper T cells to human health might consider AIDS -- which kills people by killing off their T cells. Kill off too many helper T cells, and people fall prey to a host of infections and cancer.

To understand how you can manipulate the immune system, researchers say, it helps to know something about how the immune system works -- and how helper T cells do their job. In theory at least, only two things matter to the helper T cell: self and non-self.

Self refers to the body's proteins. Non-self covers proteins found in viruses, bacteria, toxins and tissues transplanted from someone else.

Central to the T cells' ability to recognize foreign proteins are molecules known as MHCs. MHCs poke through the surface of certain white blood cells.

These white blood cells literally engulf any proteins they might encounter in blood and tissues. The cells digest the proteins and display snippets of them, called peptides, in the MHC molecules protruding from the cell's surface.

Each patrolling helper T cell has more than 10,000 receptors that are capable of docking with MHC molecules. This cellular handshake lies at the core of human immunological defense, just as a human handshake once served to determine whether a stranger was armed.

Short peptides displayed by the MHC molecule are the key to immune recognition. They are all the T cell receptor needs to determine whether the encounter will end in a friendly handshake or immune activation, an invisible Armageddon in which T cells multiply wildly and send off distress signals that rally the body's defenses.

The thymus' crucial role

These insights have taken decades to emerge. One key set of experiments took place in the 1960s, when two researchers revealed for the first time where the T cell learns to distinguish peptides that cause illness from those that do not. The organ is called the thymus, and it lies just above the heart.

The thymus is a school for T cells. But how T cells are educated -- and why 99% of them flunk out shortly after birth, dying in the thymus -- remains a mystery.

Researchers have since shown that the T cell's education hinges on the handshake between the T cell receptor and the peptide locked in the MHC. The T cell's training takes place within an infant's first year of life, when thymic school is in full session.

During that year, the infant is bombarded with microbes of every kind; those microbes are chewed up by white blood cells, which flaunt snippets of the microbes' proteins on their surface. The intensity of the T cells' interaction with these peptides governs whether the cells will live or die.

Cells that react too powerfully trigger their own suicide, a brutal way of clearing the blood of renegade T cells that might attack the body's own tissues. Cells that respond too weakly flunk out because they are unable to mount a potent enough immune response.

Reinherz proposes that the T cell's fate is determined not by the components that make up the peptide, but by its structure. Last year, Reinherz and one of his colleagues, Jia-Huai Wang, set out to show this by producing an X-ray crystallographic snapshot of the T-cell's handshake with the MHC molecule.

Wang's image, published in December in the journal Science, looks festive, like a collection of colorful, interlocking ribbons. But it reveals a critical fact about T cell recognition; it is a function of the peptide's shape.

A peptide that puts pressure on a certain point in the T cell receptor will trigger an immune response--and prime the body to reproduce a similar response if the peptide should reappear.

If the peptide puts too much pressure on the receptor, or binds too strongly, it sets in motion biochemical events that cause the T cell to commit suicide.

Reinherz envisions influencing this learning process with vaccines, formulated from peptides, which supply all the information T cells need to arm themselves against future calamities like cancer or AIDS. That will involve painstakingly testing one peptide after another to determine which ones will properly arm a T cell and which ones will prompt it to commit suicide.

Unlike ordinary vaccines, which influence only the 1% of T cells that graduate from the thymus, Reinherz says, thymic vaccination will "exploit the 99% of T cells that now go to waste," populating the blood with T cells armed to take on many of mankind's deadliest diseases.

Immunologists intrigued

Some of the nation's leading immunologists are intrigued by Reinherz's theory but remain skeptical about its future. Bruce Scharschmidt, the vice president of research for the biotech firm Chiron, says Reinherz is "probably right," but he adds, "It will never happen in my lifetime."

Says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases: "It's a brilliant idea, but it's unclear whether it can be translated into reality."

Next month, Fauci's institute will decide whether to take a leap of faith and back Reinherz's foundation with a hefty grant of $6.3 million over 3 years. Both Harvard University and MIT have expressed interest. The Bill & Melinda Gates Foundation has deemed the work too preliminary, Reinherz says.

Actor Hurt is betting on Reinherz. "He never lets up," Hurt says. "I hope he gets someone to support him."

Reinherz acknowledges that he doesn't have all the answers, but he's convinced he's on the right track.

"If I'm 100% right, we're going to look back and say, 'Ye gods, the face of medicine has changed. If I'm just 50% right, we'll still look back and say the face of medicine has changed.' In my mind, the chance of my being totally wrong is zero."