Rebooting your immune system
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.
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.”
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