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Failures
to Communicate April
1997 In 1917 a physician in his 40s named Theodore Janeway, Class of 1892, was enlisted by the military to help solve a medical mystery. The doughboys-in-training, while they were still in the United States, were coming down with a devastating illness and fighting their battles -- sometimes, their last battles -- in hospital beds rather than in the trenches of Europe. This enemy, Dr. Janeway would learn during an abbreviated investigation, was far older than bullets, bayonets, and poison gas -- and just as deadly. "My grandfather got sick and died -- rapidly -- of ordinary pneumonia," says Charles Janeway Jr., a Yale physician and a member of a team of scientists who study the immune system, the body's defense against bacteria, viruses, and other invaders. Janeway's father Charles '30 was a pioneer in this field, and because of his research and that of many others, doctors now have a formidable array of medicines to help the system do its job. Using techniques at the forefront of science, including some similar to those which led to the recent cloning in Scotland of the sheep known as Dolly, Janeway and fellow Yale investigators are attempting to take the next step: improving the sophisticated system that evolved to protect people from infection. "We at last have most of the tools we need to learn how the system works when things are going right or wrong," says Richard Flavell, a molecular biologist who chairs the Medical School's section of immunobiology, an interdisciplinary group of 15 professors whose faculty appointments range from the biology department to the School of Epidemiology and Public Health. "Our hope is that basic immunology research will in time enable us to practice truly preventative medicine." Out of studies underway at Yale may come new drugs and therapies that can be used to fight a host of dreaded diseases, among them AIDS, cancer, multiple sclerosis, diabetes, lupus, and rheumatoid arthritis. Understanding the details of the immunity is also critical to the development of vaccines, such as those that now prevent illnesses like smallpox and polio from ever establishing a beachhead in the human body, and could soon protect us against Lyme disease. There is even hope that it will soon be possible to regulate the immune response, turning it up (in the case of AIDS) or toning it down (in MS and other autoimmune-type ailments in which the system goes awry and attacks parts of the body) to fit the situation. And while no one envisions flocks of cloned sheep grazing on the Cross Campus, researchers here are working with the Alexion Corporation, a local biotechnology company, to develop genetically engineered pigs whose organs might be transplanted into humans without being rejected by the immune system. Research in this high-tech field is moving so rapidly that Janeway's definitive text, Immunobiology: The Immune System in Health and Disease (Garland Publishing), cowritten with London University scientist Paul Travers, has to be revised and reissued every 18 months in order to remain current. Yale scientists are among those most responsible for pushing the pace of discovery, and the unusually comprehensive nature of the investigations underway here means that every part of the process is being watched. Much of the latest work is centered on the white blood cells known as lymphocytes. These get their name from their primary address -- the body's lymph nodes -- and they come in two general varieties -- T-cells and B-cells -- each of which is designed to accomplish a different job. For example, when microbes attempt to invade, T-cells, so called because they mature in the thymus (an organ near the throat), can, to repeat the military analogy, be the foot soldiers and engage in hand-to-hand fighting, or they can be called upon to serve as what researchers term "helpers." In this role, they might aid a cellular vacuum cleaner known as a macrophage by turning on its killing machinery, or they can help guide the artillery of the immune system, the B-cells (these mature in the bone marrow), which fire long-range weapons known as antibodies. These large molecules recognize only one, very specific kind of invader -- or antigen, to use the technical term. Should the antibody fit the antigen, a chain of events is initiated that results in the invader's defeat. The attack is rebuffed, calm is restored, and because the immune system "remembers" the identities of any microbes which put it to the test, the next time that antigen arrives the skirmish may be put down without the person whose body serves as a battlefield ever being aware of the combat. At least, this is how human evolution would like the battle to unfold. But viruses and bacteria are constantly evolving as well, and the result is a cellular arms race. Each side tries to outdo the other, and because the defensive "hardware" sooner or later fails to perform its job, people get sick and die. Immunobiologists are in business to improve the odds that govern human survival, says Flavell, who has been instrumental in developing one of the key tools of the immunobiology trade: a mouse in which a tiny but crucial bit of the genetic program has been eliminated. Flavell explains that researchers -- in part because of the pioneering work of Sterling Professor of Biology Frank Ruddle -- had learned in the 1970s and 1980s how to add genes, and abilities, to mice. These so-called transgenic animals are now a standard part of the scientific arsenal, but in the mid-1980s, investigators learned a new trick: how to "knock out" precisely targeted genes. To researchers studying the gene-directed components of the immune system, "these 'loss of function mutants' have been a real breakthrough," says Flavell. The investigator and his colleagues have created more than 20 different kinds of "knockout mice," including one whose immune system cells have lost the ability to talk with one another. Normally, communication takes place when a molecule called CD40 -- "Everything we study has a romantic name," Flavell says apologetically -- that sits on the cell's surface links, lock and key fashion, to a molecule known as the CD40 ligand on another cell. A similar kind of chemical chat pattern occurs in many of the interactions taking place in the immune system, and the result is that T-cells, B-cells, and macrophages are turned on and sent to work. However, mice in which the genes required to make CD40 ligand were knocked out could not activate the troops -- and neither can people born lacking the genes. "Without the conversation, nothing happens," says Flavell. "It's a very serious defect." Communications failures also figure in the work of Kim Bottomly, professor of immunobiology, who studies a situation in which helper T-cells wind up choosing the wrong vocation. "We're trying to understand how they know what to do," says Bottomly, adding that, like the narrator in the Robert Frost poem "The Road Not Taken," the choice "makes all the difference" -- often, between life and death. Helper T-cells have essentially two job pathways. They can serve as aides de camp to members of the defense forces (often, these are macrophages) that battle bacteria and fungi living inside of cells -- a hallmark of pneumonia and leprosy -- or they can join forces with B-cells to fight against pathogens that are doing damage on the cellular exterior. "Once the cells decide, they're committed to the response, and because they make memory cells, you're stuck with the choice," says Bottomly. Working with transgenic mice, the scientist has learned that the crucial decision is based on chemical signals that come from both inside and outside cells. To explain how the helper T-cell gets the message, Bottomly cites the case of leprosy, a disease in which bacteria specialize in making a living inside the macrophages that have ingested them. The pathogens may be hidden from view, but they are not invisible, for within every cell is a molecule called MHC, and when infection occurs, it's MHC's job to take pieces of the pathogen and display them to the outside world. "The surface of the macrophage becomes a bulletin board that says, 'Help, I'm infected,'" says Bottomly. If all goes according to plan, a helper T-cell that carries the one receptor capable of reading the message will, in the nick of time, pass through the neighborhood, see the note, and help the macrophage turn on its killing machinery. On the other hand, the immune system responds to invading organisms that perform outside jobs with a different set of chemical signals. When the helpers read these, they put out a distress call to the B-cells. A misreading can mean trouble. Bottomly explains that people who have the worst form of leprosy "make a very powerful immune response to the disease -- but it's not the right one." Many allergies also look like cases in which the helper T-cells have gotten the wrong message and chosen the wrong career. Change, however, is possible, and the researcher suspects that allergy shots, in which small amounts of problematic substances are regularly injected into allergy sufferers, are an example of how a malfunctioning system can be retrained. "Unless you live in a sterile bubble, you can't stop pathogens from coming into your body," says Bottomly, "so we need to learn how to deal with the negative aspects of the immune system and figure out how to switch inappropriate responses." One of the most inappropriate is found in arthritis, diabetes, multiple sclerosis, lupus, and other autoimmune diseases in which immune cells attack the body's own tissue. "An immune system is clearly valuable, but it's also potentially dangerous because it can turn on itself," says Charles Janeway, who is studying the natural history of MS, a paralyzing and eventually fatal condition in which T-cells treat the protein that surrounds nerves as if it were a hostile invader. Janeway explains that one of the most surprising discoveries about autoimmune diseases has come from basic research into the generation of the T- and B-cell receptors that must recognize every imaginable antigen the body might encounter over a lifetime. The requisite diversity is truly mind-boggling -- one estimate places the number of possible receptors at one followed by 18 zeroes! -- and because the manufacturing process operates entirely at random, there is plenty of opportunity to create cells that will react against components of the very body they're supposed to protect. Much of this potential havoc is averted, however, because of a winnowing process that takes place early in human development. In essence, every freshly minted cell looks at itself in the mirror. If the reflection it sees looks familiar -- an indication that it will react to self-tissue as if it were foreign -- the cell commits suicide right on the spot. Until recently, scientists believed that this process eliminated self-reactive cells in all but a small percentage of the population who were unlucky enough to be born with a system that somehow went awry. However, it turns out that not only do we make autoreactive T- and B-cells all the time, we also fail to delete a significant number of them. "We're all carrying around the seeds of our own destruction," says Janeway, "but ordinarily, these cells are held in check." While no one has identified the "brake" in humans, the scientist has come up with a candidate substance in mice. "If we get rid of it by gene knockout, all hell breaks loose," he says. In autoimmune disease, that hell can be a long time in coming. For example, lupus, which primarily affects women, often doesn't begin in earnest until a person reaches 35. But long before the ailment causes cells to glow a fluorescent green when they're exposed to a diagnostic procedure, a cascade of events that will eventually prove devastating has already begun. Rheumatologist Mark Mamula, assistant professor of medicine, is trying to figure out where the process starts. While a true autoimmune disease occurs only when the system turns its firepower on a wide variety of self-antigens, Mamula has shown that the trouble can, given both time and the right circumstances, begin with one "humble" mistake. The scientist explains that the autoimmune cascade might start when a mistakenly self-reactive T-cell seeks out a B-cell partner and calls it to arms. Both activated cells then make copies of themselves, and the B-cells, in addition to cranking out antibodies, start doing something else -- something critical. B-cells are highly adept at vacuuming up specific kinds of antigen, notes Mamula. Often, however, antigens travel in mixed company, and like a group of spies armed with a secret password, if one is granted access the rest come along for the ride. Inside the B-cell all these antigens are rendered down to their molecular parts, which are then displayed on the cellular bulletin board. A diverse group of helper T-cells arrive and read the messages for aid, and these troops, in turn, activate a diversity of B-cells. The result is an all-out assault on many components of a person's tissue. Eventually, the battle will wane, but because the immune system is making memory cells -- in effect, remembering something that would be better left forgotten -- there will be new skirmishes, each of which results in more damage: the nerves in MS, the ability to make insulin in diabetes, the joints in arthritis, many tissues in lupus. "By the time we see a patient, the trigger has already been pulled," says Mamula, "so what we're wondering is: can we catch this immune response early and short-circuit it?" The brief answer is "not yet," but I. Nicholas Crispe, associate professor of immunobiology, is optimistic that the day is not far off when immune system research will provide physicians with the ability to fine-tune the system. "It's a matter of tilting the balance," says Crispe, "and we may not have to tilt it very much." Crispe studies an imbalance in a fundamental process known as programmed cell death, the method nature has invented to end an immune response. The scientist explains that instead of calmly reverting to civilian life when the invading microbes have been subdued, "the activated T-cells commit what we call fratricide -- they kill each other. They don't go quietly." Sometimes they don't go at all, and when that happens, there's trouble, particularly when the hangers-on belong to a class of specialists known as killer T-cells. These are called into action to handle virus infections, a situation that results in a killer T-cell causing the demise of its infected counterpart. (The problem in AIDS is that the killer T-cells destroy the helper T-cells, which are infected with HIV, and ultimately disable the immune system.) "Killer T-cells can be very dangerous," Crispe notes. "If they're out of control, there can be lots of 'bystander killing.'" Such a state of affairs may trigger autoimmune diseases, and it may also result in a fatal but thankfully rare syndrome in humans in which the lymph nodes fill up with well-armed killer T-cells that have never been told the battle's over. To prevent such situations, the body has evolved a special method for dealing with these cells. Not only do they meet their ends through conventional means, but Crispe's research has shown that when their work is through, "activated killer T-cells migrate to specific destruction sites in the liver. This organ is the 'elephant's graveyard' of the immune system." Crispe speculates that many tumors set up shop in the liver because it's the one place killer T-cells can't go without being killed themselves, and he suspects that the organ's skill in squelching immune responses is the reason that liver transplants don't require the massive amounts of drugs which are normally needed to prevent rejection of hearts, lungs, kidneys, and the like. To be sure, such boons as rejection-free organs and the ability to selectively increase the lifespan of killer T-cells -- a situation that might result in more people being able to purge the virus that causes AIDS from their bodies -- are currently in the realm of science fiction, says Crispe. But a host of medical miracles, among them the antibiotics that mostly likely would have prevented Theodore Janeway's untimely death 80 years ago, were once in the same realm. The new discoveries that are being revealed every day are the foundation of the next generation of miracles. |
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Yale
Alumni Magazine, PO Box 1905, New Haven, CT 06509-1905. USA.
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