In this full-length doctor’s interview, Jeffrey Bluestone, Ph.D., explains how diabetes research may offer a way to stop type 1 diabetes from progressing.
Dr. Bluestone: It’s an antibody that bonds to and changes T-cells. T-cells are the white blood cells in the body that are responsible for your immune system recognizing bacteria and viruses and anything to protect you from the common cold. Unfortunately, at times, the antibody recognizes things it shouldn’t, like your own pancreas or your own brain, for multiple sclerosis or your joints in rheumatoid arthritis. We made this antibody that attacks the T-cells and prevents them from destroying the tissues that they would normally destroy.
Dr. Bluestone: In type 1diabetes, your immune system inappropriately attacks your own beta cells and destroys them. Beta cells are the cells that make insulin and are essential for controlling your blood sugar. T-cells are responsible for recognizing a lot of different proteins, proteins that are not just on the beta cells. Sometimes it recognizes proteins, for instance, in your brain, and that’s why people get multiple sclerosis. When it recognizes proteins in your gut you get Crohn’s disease or inflammatory bowel disease, or in your joints and you get rheumatoid arthritis. Different T-cells see different things. You can never predict what’s going to happen.
Dr. Bluestone: In essence, we’re trying to block the T cell — we’re trying to block the cell that destroys the insulin producing cells. Each T cell has a protein on its cell surface — a receptor that recognizes the different proteins on viruses or bacteria and the antibody blocks that interaction. It’s like putting the wrong password into a computer program. Not only can you not log on to the computer, but it actually shuts you out so you can’t put in the right password. Once the antibody interacts with the T-cell, it actually turns it off and prevents it from ever attacking the beta cell again.
Dr. Bluestone: There were 24 patients in the trial. Twelve patients got the drug over a two-week period. We injected it every day intravenously so that the T-cells would be coated with the antibody and the antibody would signal those T-cells and turn it off. The other 12 patients didn’t get any treatment for the duration of the trial.
Dr. Bluestone: After two weeks, we monitored the patients for how much insulin they’re able to make. We also monitored them for how well they can control their blood sugar. We monitored their immune response and how that functions. What we found, is after a year, the majority of patients, nine out of 12, who were treated with the antibody ended up making equal and more insulin than they made at the time we started the trial. The majority of the patients not treated, 10 out of 12, now made much less insulin than they made at the time that they first enrolled in the trial.
Dr. Bluestone: Type 1 diabetes you start actually having the disease probably close to birth. It’s based on genetics, there probably are some environmental impacts, but what happens is very soon after birth your immune system starts inappropriately attacking your own pancreas. Slowly but surely, it’s killing off beta cells. At first you lose 10 percent of your beta cells, and then, 20 percent of your beta cells, and 30 percent.
It turns out, that most of us can survive absolutely fine on 10 or 15 percent of our beta cells. We have a lot of access. Most type 1diabetics are working — walking around for many years having the disease, but it’s not clinically manifested because they don’t have any need for all of that extra islet producing capability. Then something happens. They usually get below this threshold, below this 10-percent reservoir and all of a sudden, they have trouble controlling their blood sugar. We do our treatment as soon as we can after that diagnosis. That way we catch whatever islet beta cells are left before they’ve all been destroyed. We can’t replenish the 90-percent that’s already been lost. The best we can do is stabilize the disease at this point.
There are two ways that you might expand the therapy, one is if you could get in earlier. Getting to people before they’re actually clinically diabetic. There are trials going on that have been quite successful in being able to predict with some certainty, kids who are going to become diabetic. We hope to start treating those kids before they become diabetic and preserve 40 percent of their islets or 50 percent of islets and maybe they would never have to go on insulin. We can also try to replace the insulin producing cells by transplant, where we put islets back into people who already have no more of their own islet function. Then treat them with the drug at the time that we put new islets in, so that they would hopefully be able to maintain their own blood sugar without needing shots of insulin.
Dr. Bluestone: As I said, you’re constantly destroying your cells, so it’s just a question of when you’re going in. Some people get diagnosed very early on, others get diagnosed later on. The earlier you can get in, the better off you’re going to be. If we could do it five months earlier, we might be able to preserve a few more percent of the islet cells. If we can go two years earlier that would be even better. There is a question of whether it pays off at all, once you’re already diabetic, to go in and preserve, even the 5 percent or 10 percent of the islets you have left — we believe it is. The reason is there has been a good amount of clinical data that shows if you can preserve even a little bit of your own insulin producing capability rather than having to take shots for every bit of your insulin it actually has a long-term impact on your ability to control your blood sugar and the complications that you get from the disease. It’s why the pump, which a lot of people use now to deliver insulin, has been so much more successful than taking shots. Even a little bit of insulin given every minute is going to be better than five shots a day, where your level of insulin goes way up and way down. What we hope is that this drug by preserving even if it’s 5 percent or 10 percent of the insulin producing cells, will give you at least a baseline of your own insulin production. It will help you in controlling your blood sugar, even though it doesn’t get you off of insulin, it’s not a cure.
Dr. Bluestone: I think what we’ve done is prolonged what’s called, the honeymoon period. The period in which they have the remotest chance of making their own insulin. We hope that years down the road that has an implication for the complications. I think as much as anything else, it’s a proof of principle that we can get into these patients, we can delay at least the disease manifestation long term. It gives a lot of hope, that either we’ll come up with even better drugs, or, as I said, be able to get in earlier, or, using other insulin producing cells, really cure the disease. Right now, we’ve mostly shown we can slow down the progression in a majority of patients that can continue to make it you’re right, don’t take about 20-percent less insulin than they would take otherwise. The long-term challenge here is to figure out a way to do this much earlier or to do it under the cover of other islets, insulin-producing cells, so that they won’t need to take any insulin at all.
Dr. Bluestone: Because it’s a drug that attacks T-cells and T-cells are important for immunity, virus infections and bacteria, there’s always a risk that during the course of the treatment, you’ll be somewhat more susceptible to an infection. In fact, drugs like this have been shown in other settings to have a slight increase in susceptibility to both infections and cancer in some patients, when given very large doses over a long period of time. We’re giving smaller doses, we’ve giving them over a short period of time. But there’s always a risk that you’re going to have some immunosuppression, because that two-week period you’re getting the drug. The other complication, such as it is, is you get some small side effects. Some people get some headaches, a little bit of fever and most of the patients get a rash on their fingertips or toes. That’s actually a good thing, because we know one of the ways the drug works is by tricking the immune response and one of the tricks, the manifestation of the trick is you get kind of an allergic reaction. It’s a rash and so we know when a patient gets a rash that the antibody has done what it’s supposed to do.
Dr. Bluestone: I think there are two potential implications. One is, of course, the drug itself, and hopefully it will be a drug that has some usefulness and tested, then tested in a larger cohort of patients, and will continue to show efficacy. But I think there’s actually a larger implication. Up until this trial, there was a lot of resistance in the community, the diabetes community, to treat kids just when they get the disease with drugs to try to alter the disease. In fact, over the last five or six years, there have been few, if any trials, done in this population. What the drug actually did, in some ways, is suggest that you can have an impact in some patients early on after the disease is diagnosed. I think it’s invigorated, or re-invigorated the community to think about immune modulation coming in and changing the immune system just after diagnosis. Now there are all kinds of trials that are being planned with numerous drugs, some of which may work better than this drug, to try to see if you can alter the immune system right after diagnosis. I think that’s the biggest implication — it’s opening up now a whole field of research that otherwise didn’t exist.
Dr. Bluestone: We are starting a trial now. This is a trial sponsored by something called the Immune Tolerance Network, which I oversee. That trial is going to give three courses of the drug. One at the exact time they’re giving now, six weeks. Another course, at six months, and then the last course, at one year. The idea is, by giving it three times, perhaps we can wipe out every last T-cell that’s causing the problem and prolong the therapy even longer. You wouldn’t want to give this drug constantly just like you wouldn’t want to give any immunosuppressive drug constantly. It will make you much more susceptible to infections and other things if you are constantly immunosuppressed. It’s one of the problems that patients who get kidney transplants or liver transplants have. They are always taking an immunosuppressive drug, and they are therefore much more susceptible to these things.
Dr. Bluestone: We don’t know all the answers to that. Again, the analogy I use is that of a computer program or a bank vault lock. It’s what immunosuppressant drugs do; they block your ability to put in a password or put in a bank code. But then as soon as the next person comes along they can put it in. What this drug does is it changes the wiring inside the cell. So where that cell normally would be stimulated and activated and kill the beta cells after the antibody interacts with it, it’s sort of a mimic, and it changes the wiring in the cell. You can’t come back in later and signal that cell anymore, it kind of becomes anergasia, nonfunctional. The reason it seems to last a long time, is because it causes permanent changes, where most immunosuppressive drugs are more of a cloaking, rather than actually changing the cell.
Dr. Bluestone: There are several challenges in islet cell transplants, some of which this drug or any drug, does in effect, is getting enough islets to be able to do this stuff. But I think that the biggest challenge from an immunologic side is you’ve got a setting in which patients have an autoimmune disease. Their own immune system is attacking their pancreas, plus you’re putting in islet cells in a transplant from somebody else. So you have the immune response trying to get rid of somebody else’s islets as well. There’s a powerful immune system at work that’s sole function, is to try to eliminate those cells you’ve just put in.
What we’re doing now to solve that problem is, as you pointed out, give these very potent sledge hammer immunosuppressant drugs for the rest of your life. Thirty pills a day is very serious stuff. In order to make this a viable and long-term successful therapy, we need to induce what we call tolerance, immune tolerance. We need to be able to re-educate the immune system so that you can take a drug, or whatever, for a very short period of time, and then for the rest of your life you’ll keep the graft without rejecting it. That’s what drugs like this are focused on doing — causing permanent changes in the immune system so you don’t have to take these drugs forever. Whether we’re talking islet transplant or any other kind of transplant, or even autoimmune diseases like multiple sclerosis or diabetes, we want to be able to come in with a therapy that can be done for a short period of time, can be as specific as possible to only deal with the cells that are causing the disease, and then not have to take lifelong drugs.
Dr. Bluestone: Right and if you were a mouse we could do that with you tomorrow. Because we can get it to work in mice, the challenge is to get it to work in people. Which is where you can put back the cells, treat with a drug long enough to re-educate the immune system, take you off the drugs and then you make your own insulin from these cells you’ve put in forever.
Dr. Bluestone: If you’re a mouse we’re very close. You know it’s always hard to predict these things. I think we’ve learned a tremendous amount in the last 10 years. We know better now how the immune system works and how to try to deal with this. The fact that in the last two years we have been able to go from virtually no success in doing islet transplants to now having 80-percent success, and having no way to treat a new onset diabetic, to now, having ways where three-quarters of them prolong their insulin production, is very exciting and very hopeful. I think the next step of getting to the state of immune intolerance is a challenge and we’re working very hard.
Dr. Bluestone: I’ve been an immunologist for 25 years. I’ve been in diabetes research very actively probably over half of that time, since the early 90s. It’s a long, hard road.
Dr. Bluestone: There is no reason why type 1diabetes shouldn’t be cured relatively soon. We know the rules, we know what the problems are, we know what we have to deal with and how to deal with it.
Dr. Bluestone: I am a very big fan of islet transplants. We have a program here we’re very committed to. I think it’s the one way that we know today that we can get people off insulin, and cure them of their disease without a terribly invasive operation, like a pancreas transplant. We can do this. One of the biggest challenges are the immunosuppressive drugs. We need to be able to change them, we need to be able to induce tolerance and that’s what I do, and hope will do successfully. But of course there are great challenges out there as well because there are only about 2,000 to 4,000 pancreases available each year. There are a million people out there with type 1diabetes and if this is going to be a broadly useful technology, we’ve got to come up with a better way of getting islets. That either means we’re going to have to figure out ways to use other animals, like pigs. I’m skeptical it’s going to happen in the near future, or we’re going to have to be able to grow them. Whether we’re allowed to stem cells, whether it be from embryonic or adult stem cells, and learn ways to grow islets so that we can transplant all these people who will need it.
I’m very optimistic about islet transplant. I think, in some ways, it’s already successful, but that success comes at a price, and the price of these drugs. We have to get people off these drugs. But even tomorrow, if I could guarantee we could take you off the drug and you’d be fine, there are few patients we could treat with this therapy. We are challenged now to figure out new sources of islets and how to get enough of them to be able to treat all the patients.
Dr. Bluestone: I’m not a patient, but what I hear is interesting. First of all, I think it’s important to set up that question. We’re not talking about taking shots of insulin versus taking immunosuppressive drugs. Because if that were simply what we were talking about, then to me, the answer is simple. The shots of insulin are much easier and better. What we’re talking about is 20 years from now, the risk of amputation, the risk of blindness, the risk of kidney disease that you would have if you’re stuck taking insulin for the next 20 to 50 years of your life. It’s the immunosuppressive drugs, which have some increase in infection and cancer risk.
But that question is a much more difficult one, because if you could predict with a crystal ball that I was going to get complications from diabetes, I would take an islet transplant tomorrow given the risk of the immunosuppressive drugs. In fact, what’s an interesting ethical challenge right now, is when you give patients these transplants, if we’re thinking of taking them off their drug — that’s what tolerance is going to need, is taking them off their drug. Will a patient want to come off their drugs? The challenge is they may have to go back on insulin if they reject their graft right, or they may stay on the drugs. Most people we’ve talked to would rather stay on the drugs and not go back to insulin. This tells you something about most patients — that they really hate the idea of having to take insulin. They don’t like what it does to their lives, they don’t like their future if the complications come in. So I think right now it’s a difficult choice and hopefully if we get better at this, it will become an easy choice. The transplant and the drugs are much better than staying on insulin.