Tested: A Reboot for the Immune System
The ability to reprogram the immune system is one of the most sought-after goals in medicine. Now researchers are closer than ever to pulling it off in patients with Type 1 diabetes, one of whom happens to be our correspondent
A sign rests on the windowsill in the office of Jeffrey Bluestone, director of the Immune Tolerance Network and the Diabetes Center at the University of California at San Francisco. Measuring nearly three feet across, it reads “Club Bluestone” in pink and blue neon. It’s the sort of artifact you’d expect to find in a bar. But Bluestone is a world-renowned immunobiologist; his father-in-law had the sign made for him in the late 1980s when Bluestone was working long hours in his lab at the University of Chicago. As the night wore on and their energy faded, he and his colleagues would turn out the lights, turn on the sign and, propelled by the power of Bruce Springsteen, push forward with their research. “It was our version of partying,” he says.
Bluestone has worked in that lab and ones like it for almost 30 years, wrestling with one of the most vexing problems in medicine: how to keep the immune system from attacking the body itself. It’s been a challenging three decades. Immune researchers work on a biological defense system that’s comparable to the world’s greatest military. This military has millions of potential enemies but no clear leader; instead its members are on constant patrol, a hair trigger away from launching an attack. It’s a recipe for anarchy. Yet the majority of the time, the immune system knows when to hold back. Using processes we still don’t fully understand, a healthy person’s immune system is able to draw a clear line between the body’s own tissues, which it leaves untouched, and invaders, which it identifies and destroys.
The immune system can also be devastatingly destructive. The body’s tendency to reject organ transplants, attacking them as if they were dangerous foreign invaders, is well known. But more prevalent are autoimmune diseases, in which your immune cells attack your own tissues and organs. Left unchecked, these malfunctions can result in one of more than 80 known conditions, including Type 1 diabetes, rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease and psoriasis. According to the Autoimmune Related Diseases Association, conditions like these affect more than 50 million Americans.
The perfect immune-modulating drug would target only the part of the system causing the problem. As of now, however, most immunosuppressive drugs work by dampening the entire immune system, which leaves the patient susceptible to short-term problems like infections and long-term afflictions as severe as cancer.
Bluestone, who is now 56, has devoted most of his career to improving on this crude, brute-force approach. In the early days of his “club,” he spent many of those long nights tweaking an organ-transplant drug called OKT3, which he and other researchers thought might also be useful for autoimmune diseases like multiple sclerosis and Type 1 diabetes. The problem was, the drug had severe side effects, including cases in which it sent recipients’ immune systems into a kind of overdrive that could be fatal. Eventually, though, working in mice, Bluestone and his colleagues succeeded in changing the drug’s structure to eliminate these side effects. Then he began investigating what else the drug could do.
In 1987 he joined forces with Kevan Herold, an endocrinologist and researcher who was then a colleague of Bluestone’s at the University of Chicago, and the two began exploring the drug’s effects in mice with Type 1 diabetes, an autoimmune disease caused when a class of white blood cells called T cells mistakenly destroys the cells in the pancreas that produce insulin. As their research progressed, they were thrilled to find that the drug halted the progression of Type 1 diabetes in the mice. Second, the new version appeared to act like a guided missile, targeting problematic cells in the immune system without handicapping the rest of it. Bluestone and Herold began to think it might be possible to use it and other, similar drugs as short-term therapies to “reprogram” the immune system, permanently coaxing it back to its original, balanced state. In the world of immunology, this is referred to as immune tolerance. According to Herold, it is the field’s most sought-after goal. And now, thanks to a number of breakthroughs in targeted immune therapy, that goal seems closer than it has ever been. Jordan Pober, the director of the Human and Translational Immunology program at Yale University, is openly enthusiastic about the state of the science: “We’re in the midst of a revolution in our ability to manipulate the immune system.”
By 1995, Bluestone and Herold were eager to move from mouse to man. They wanted to see if the drug could also have a positive effect on Type 1 diabetes in humans. It wouldn’t be a total cure, but if the drug could stop the normal course of the disease—which usually gets progressively worse over the course of a person’s life as the body finishes killing off the cells that produce insulin—it would be a major breakthrough. So in 2000, they launched a trial of the modified drug.
That’s where I came in.
Jeff Bluestone and Lab Members
In the winter of 2001, my senior year of college, strange things started to happen to me. I was insatiably hungry. I was so thirsty that I had dreams about Italian sodas and crept out of bed at night to slurp water from our bathroom faucet. Yet despite my near-constant eating and drinking, I lost 15 pounds. My eyesight became blurry; I was dizzy and tired. One afternoon in February, after eating a plateful of food, I began throwing up, and when I didn’t feel better after a day in bed, my roommate insisted I go to the student health center. There, a doctor took one look at my list of symptoms and ordered a blood-glucose test. When my blood-sugar levels came back at more than 400 milligrams per deciliter (normal is between 80 and 100), the diagnosis was immediate: I had Type 1 diabetes.
No one fully understands what triggers Type 1 diabetes—maybe a virus, maybe an environmental toxin. Whatever the cause, the result is life-threatening. Insulin is a hormone that unlocks your cells so they can access the glucose in your blood, which provides them with fuel. Left untreated, you essentially starve, no matter how much you eat. Until insulin was discovered in 1922, a diagnosis of Type 1 diabetes was a death sentence.
I was diagnosed on a Saturday morning, and no diabetes educators were on duty at the student health center where I’d been admitted. So a friend bought me a stack of books on Type 1 diabetes, and I spent the weekend learning as much as I could. I was relieved to learn that Type 1 was no longer terminal but less excited to find out that, unless I rigorously controlled my blood sugars, the disease could destroy my kidneys, cause me to go blind, lead to heart disease and—in addition to a litany of even more complications, including foot amputation—reduce my life expectancy by seven to 10 years.
I also had to correct my own misunderstandings about diabetes. For example, I learned that Type 1, which may affect as many as three million Americans and can be controlled only by multiple daily injections of artificial insulin, differs from the much more prevalent Type 2, which can often be managed with a combination of diet, exercise and oral medications. And how Type 1 diabetes, which most people think is diagnosed just in children (thanks in part to its former name, juvenile-onset diabetes), can occur at any age.
More challenging was learning to live with the disease. For although artificial insulin keeps me alive, it’s not a cure. Controlling Type 1 is a constant balancing act, requiring me to carefully measure food and insulin doses so that my blood-glucose levels don’t go too high and trigger the long-term complications mentioned earlier, which occur when chronic high glucose levels damage blood vessels. Conversely, if my glucose levels fall too low, starving my brain of its only source of energy, it could cause seizures or a coma or even kill me. Making things trickier still, everything from stress to illness to time of day affects glucose levels. Managing diabetes is exhausting and constant, and as your immune system kills off your remaining insulin-producing cells, it becomes even more difficult to control.
I was desperate to go a different route. As soon as I was diagnosed, my mother, a registered nurse, began looking for possible clinical trials and stumbled upon a reference to Herold and Bluestone’s work. And so on a cold February afternoon a week after being diagnosed, my parents and I traveled to the Naomi Berrie Diabetes Center at Columbia University Medical Center to meet with Kevan Herold and learn more about his study. My father was hesitant—the immune system is not something one usually wants to mess around with—and asked Herold whether he thought the potential benefits of the drug were great enough, compared with its possible side effects, that he’d give it to his own children if they had diabetes. “Yes,” said Herold, who is the father of three girls and has Type 1 diabetes himself.
That was it. I signed the liability waivers, did a series of preliminary blood tests, and held my breath as Herold drew a slip of paper to determine whether I’d be in the drug group or the control. Much to my relief, the paper said “drug.” (The trial wasn’t blind.) Several days later, I began 12 days of daily injections of a mysterious, clear fluid so cold that I could feel it as it entered my veins. (The control group took diagnostic tests every six months, just like the drug group, but they didn’t receive an actual placebo.) After the first dose, my blood pressure dropped briefly; soon the skin on my palms began to peel. Other than that, I saw no external evidence of what the drug was doing. I didn’t care. For the first time since my diagnosis, I felt like I had an opportunity to take back control of my system.
Researchers are always careful not to assume that a drug will act the same in humans as it does in mice, but in this case, it did. Even though I couldn’t feel the drug working, profound changes soon began taking place inside my body’s immune system, changes that researchers are still trying to understand. In short, my immune system stopped killing off the cells that make insulin.
Why this happens, Bluestone and Herold are not exactly sure. The latest theory is that the drug has two important effects in Type 1 diabetes. First, it inhibits the malfunctioning T cells that attack the pancreas, preventing them from killing the rest of the insulin-producing cells. The drug also appears to increase the number of a different population of immune cells called regulatory T cells, which are thought to act like sentinels, patrolling the body and calming down their hyperactive cousins before anything gets out of hand. The theory is that after the drug regimen is finished and the problematic T cells start to recover, the newly beefed-up population of regulatory T cells is better able to hold them in check.
As I later found out, Bluestone’s drug is what is known as an anti-CD3 monoclonal antibody. By binding to CD3 receptors on the surface of the T cells, the drug changes the way the cells function—and, in a convenient, unexpected twist, it seems to be more active against the T cells that are misbehaving.
I returned to the clinic every few months for follow-up testing, and whereas most people in the control group slowly lost their remaining ability to produce insulin, my level of production didn’t just stay steady—it increased. This didn’t mean I was cured; then, as now, I pay fastidious attention to my meals, activities and insulin doses. But the fact that I have any ability to make insulin means that my disease is probably easier for me to control than it would have been had I not participated in the trial. In 2002 Herold and Bluestone published a paper in the New England Journal of Medicine announcing that one year out, insulin production had been preserved in nine out of the 12 drug recipients, compared with two out of 12 people in the control group. What’s more, several other subjects were actually making more insulin than they were when they were diagnosed. The success of anti-CD3 represented the first one-time treatment with minimal side effects that had been shown to stop the progression of Type 1 diabetes in humans.
The research community welcomed the news. “There was a lot of enthusiasm about the findings and their implications,” says Teodora Staeva, the director of the Immune Therapies program at the Juvenile Diabetes Research Foundation International. Mario Ehlers, deputy director of the clinical-trials group at the Immune Tolerance Network, concurs. “People finally saw that it was actually possible to make a change to the course of the disease without having to use really toxic immunosuppression,” he says. “Sometimes you don’t know whether something is going to work until you try it, and then when it finally does, you’ve got a road map that other people can also use.”
Use it they did. In 2005 a different group of researchers, led by the French diabetes researcher Lucienne Chatenoud, published a paper in the New England Journal of Medicine demonstrating the successful effects of a second modified anti-CD3 drug in a trial involving 80 people with recent-onset Type 1 diabetes. Meanwhile, Herold and Bluestone continued their research. Last summer Herold began a follow-up study including some of the participants in my trial group, and he’s currently launching a study to see whether anti-CD3 can actually prevent diabetes in high-risk patients. There are now two versions of anti-CD3 monoclonal antibodies in Phase III clinical trials (the second-to-last stage) racing toward FDA approval, helped in part by backing from the pharmaceutical giants Eli Lilly and GlaxoSmithKline, and another one in early development. If everything goes smoothly, an anti-CD3 drug could win FDA approval in as little as two years, making it the first approved treatment ever that targets the cause of Type 1 diabetes.
The advance of targeted immune therapies reaches far beyond the treatment of Type 1 diabetes. After all, anti-CD3 monoclonal antibodies might be more like guided missiles than conventional immunosuppressive drugs, but they can still cause collateral damage. Because they target a receptor that’s found on all T cells—not just the ones that are going after the pancreas—they can have unwanted side effects, such as reducing people’s resistance to opportunistic infections. On the other hand, the fact that anti-CD3 isn’t totally precise means that it can be used for a variety of diseases other than diabetes. Versions of the drug are already being tested for psoriasis, Crohn’s disease and ulcerative colitis, and they’re thought to hold promise for rheumatoid arthritis and multiple sclerosis as well. “The number of diseases potentially affected is huge,” Herold says.
The anti-CD3 monoclonal antibodies have useful relatives, too—different monoclonal antibodies, each of which binds to a different target and therefore can be used to treat a different disorder. Recently, plenty of excitement has focused on rituximab (the “mab” stands for monoclonal antibodies), a drug that affects the surface of a different class of immune cells—known as B cells—and was originally approved in 1997 for non-Hodgkin’s lymphoma. Rituximab was first tested as a cancer drug, but it has since been approved for rheumatoid arthritis and has shown promise in other kinds of autoimmune diseases, including multiple sclerosis. Moreover, in a study on treatments for a type of autoimmune vasculitis (a rare and serious disease in which the body attacks its own blood vessels), rituximab was shown to be just as good as, if not better than, the typical immunosuppressive drugs used to treat the disease. Like many of these precisely targeted treatments, it too had far fewer toxic side effects.
Scientists have discovered immune-programming qualities in other drugs as well. For example, tumor necrosis factor antagonists, which act outside the cells to inhibit inflammation, have not only revolutionized the treatment of rheumatoid arthritis but have also been shown to be effective against a number of other diseases. They’re currently in trials for conditions ranging from eye disease and organ transplantation to osteoarthritis and sepsis.
“The potential that really good drugs which have been developed for one disease might have such efficacy in other diseases is, I think, a very exciting thing,” says Bluestone, who is known for being cautious with his optimism.
Several years after the trial ended, I was asked to share my experience with an audience of people with diabetes at an event sponsored by the University of California at San Francisco. I meant for my story to be inspiring—I’m still making insulin! Look at how great clinical research trials can be!—but instead I ended up feeling like a jerk. Because the drug still hasn’t been approved, I’m one of just a handful of people in the world who have had access to the treatment. And even if the drug were available, it would probably help only people who had been recently diagnosed and still had some insulin-producing cells left, which disqualified most of my audience. It was as if I’d walked into a room full of people who had lost their life savings and bragged about how I’d won the lottery.
But although I’m fortunate to have gotten the drug, my diabetes has not been cured. For that to happen, I’d need replacements for the insulin-producing cells that my immune system knocked off. Since there aren’t enough cadaver-donor pancreases available to cover the millions of Type 1 diabetes patients in America, these replacements would most likely come from stem cells, those malleable creatures that can morph into nearly any cell in the body. The volume of cells I’d need is quite small—a teaspoon’s worth would do—and they could be transplanted via injection in a simple outpatient procedure. Unfortunately, it’s not that easy. First, if you put new insulin-producing cells into my body, whether from a cadaver or stem cells, they would probably be destroyed by the same immune malfunction that caused me to develop diabetes in the first place. And even if you got past that roadblock, there’s another problem, one that arises anytime you try to transplant foreign tissues or cells into the body: rejection. Unless the cells come from your own body or that of an identical twin, the immune system treats the replacement cells as foreign invaders and attacks them just as it would a donor kidney or liver. That means that any treatment derived from stem cells is likely to require some kind of immune-modulating drug to succeed. This, not incidentally, is one of the problems Bluestone is trying to solve at the Immune Tolerance Network.
It’s been nine years since I was diagnosed with Type 1 diabetes. I’ve kept in touch with Herold, who is now director of the Autoimmunity Center of Excellence at Yale University, where he also runs the Yale branch of a network of diabetes researchers called TrialNet. When he received funding last summer to follow up with some of the original study participants to see how long the effects of the anti-CD3 drug might last, I eagerly enlisted. The protocol, known as a mixed-meal tolerance test, was the same thing I’d gone through in the original study. After an overnight fast, I gulped down a glass of Boost nutritional drink, didn’t take any insulin, and then lay in bed for four hours with an IV catheter in my arm so that the nurses could draw multiple blood samples to see how much insulin I was producing. The result? I’m still making a measurable amount, which in the normal course of the disease does not happen.
Unfortunately, my resistance is fading. At nine years out, my insulin levels are roughly half what they were two years after the treatment, and I worry that it’s just a matter of time before my immune system finishes its misguided job of killing off my insulin-producing cells. My hope is that an anti-CD3 drug will gain FDA approval soon so that I can get a second round of treatment, potentially buying me time until researchers like Bluestone and Herold achieve the dream of every person with diabetes: a cure.
Bluestone is just as impatient to see an anti-CD3 monoclonal antibody finally come to market. And although he is reluctant to make assumptions—”Obviously it ain’t over till it’s over”—he’s hopeful that anti-CD3 may soon go into much wider use. “If it does get approved in the next year or two, that would be exciting,” he says. “I would finally feel that what we’ve done would be able to have a real impact on human health.”