UCSF Tolerance Research Featured in JDRF's Countdown Magazine

Therapeutic cures for diabetes may eventually range from regeneration techniques in which islets are produced endogenously, to interventions like the transplantation of islets from donors, animal sources, or engineered sources such as liver or stem cells. Regardless of the technique to replace beta cell mass, therapies won’t result in true cures without the ability to induce tolerance. In type 1 diabetes, there can be several layers of tolerance that need to be in place.

It is the failure of tolerance to recognize cells that belong to the body as “self” that leads to the autoimmune attack that causes type 1 diabetes. The achievement of autoimmune tolerance would make it possible to arrest the development of diabetes and perhaps prevent it altogether. Tolerance is also a state in which the immune system does not reject donated tissue, yet remains effective against other dangers, such as infections, foreign bodies, and cancer. Without tolerance (or immunosuppression), the immune system destroys foreign tissue such as transplanted islets.

For people who have received islet transplants, the most important reason to achieve tolerance is that all the immunosuppressive drugs available so far, while effective at preventing rejection, have serious side effects. Most clinicians believe that except in cases of extreme difficulty with blood glucose control, immunosuppression for an islet cell transplant effectively trades one disease for another that is more serious over the long term. It is especially difficult to justify the risk of potential side effects (including cancer, heart disease, kidney disease) in children, since the risk of complications increases with the length of time the therapy continues.

“Whether or not you need to achieve tolerance really depends on what you think the therapy is going to be,” says Jeffrey A. Bluestone, Ph.D., who directs the Diabetes Center at the University of California at San Francisco, and the Immune Tolerance Network (ITN). “If you’re going to make beta cells out of stem cells or even adult stem cells derived from the patients themselves, you’d better be able to modify the immune system, because diabetes isn’t like other diseases. Cell replacement in diabetes requires modifying the autoimmune disease. So when you put it all together, tolerogenic therapies are the way to go.” 

A COLLABORATIVE RESEARCH NETWORK

The Immune Tolerance Network was formed in 1999 to provide a forum for multidisciplinary research into tolerance, not just for type 1 diabetes but for other autoimmune diseases such as rheumatoid arthritis, as well as allergies and asthma. It is co-funded by the National Institutes of Health (NIH) and JDRF. “We’re currently running about 23 clinical trials, many in type 1 diabetes,” says Dr. Bluestone.

“We’ve learned that good clinical trials take time and are a lot of hard work. Asking the question ‘did the drug work or not’ doesn’t give you the complete picture. What we really need to ask is why the drug worked or didn’t work. Answering these questions requires a wide array of specialized laboratory tests that examine the effects of the drug on the immune system and the disease.

“Of course, we’ve had some real success with the anti-CD3 antibody (see sidebar, “New Antibodies May Prevent Diabetes”) and in some of our allergy trials. We’re all very excited about the prospects for the next five years.”

The ITN model is living up to its promise of tremendous benefits from multidisciplinary collaboration. “It’s been a gigantic insight for us to finally have allergists sitting across the table from the transplant and autoimmune experts, sharing their insights and having a real impact on each other’s work,” says Dr. Bluestone. “We’re really beginning to see that success in one disease can help many of the others.”
In December 2005, JDRF and the ITN announced a $15 million joint funding program to accelerate the pace of tolerance research. The JDRF-ITN Partnership in Immune Tolerance will fund early-stage clinical trials and late-stage preclinical development of potential immune tolerance-inducing treatments for type 1 diabetes.

In particular, the JDRF-ITN Partnership in Immune Tolerance program will support pre-clinical human-oriented studies, phase 1 safety trials, and small efficacy trials that will provide proof-of-principle in well-controlled, safe settings. The program is targeted at both academic and industry investigators, with the goal of fostering new partnerships between the two, and has been organized to respond rapidly to investigators with promising new innovations.

THE CASE FOR ACHIEVING TOLERANCE

It is one thing to cure diabetes by replacing the islets that were destroyed in the original autoimmune attack. It may be quite another to prevent that same autoimmunity from destroying transplanted islets. It is likely, researchers say, that one of the reasons islet transplants become less successful over time is due to recurrence of autoimmune diabetes.

One of the key questions for tolerance researchers is whether or not the autoimmune response can be addressed by the same strategies as the alloimmune response (foreign graft rejection) that occurs in transplantation.

“The immune system is in a very different state in each case,” says Dr. Bluestone. “With transplanted tissue, the immune system is ‘naïve’, because it hasn’t been exposed to the tissue before. In the case of autoimmunity, the immune system is already primed to attack its own beta cells. There may be some mechanistic similarities, but they’re two different tolerance issues. I suspect that there will be a lot of overlapping rules, but there will be some differences to deal with.”

In fact, researchers have found that it is much more difficult to induce tolerance to islet transplants in the presence of autoimmune diabetes. Therefore, it’s possible that the greatest benefit of solving the autoimmunity problem would not be for transplantation, but for prevention of onset of type 1 diabetes in individuals with prediabetes, or in preserving beta cell function in individuals with recent onset of the disease.

“The less complex the immune response is,” Dr. Bluestone says, “the easier it should be to induce tolerance, at least in theory. I believe that if you were to take on autoimmune disease earlier on, you would be looking at a less intense immune response. If you can arrest the disease while there is still islet function, then you wouldn’t need to transplant islets and wouldn’t have the alloimmune response to worry about. At the end of the day, prevention or early intervention is going to be an important target. “We have millions of people out there with type 1 diabetes,” says Dr. Bluestone. “So it’s hard to avoid thinking about how to use tolerance for cell replacement or beta cell regeneration therapy as well.”

PROGRESS ON SEVERAL FRONTS

An approach to tolerance that has long been of interest to researchers is called “co-stimulatory blockade.” The immune system requires two signals to the T cells to activate a response. If only one signal is present without the second, T cells become “anergic” or inactive, and unable to attack later even in the presence of both signals.

Currently, scientists know of several co-stimulatory pathways, and attempts to manipulate them began with what is known as the CD28 pathway (CD28 is a molecule on the surface of T cells involved in triggering the autoimmune attack). A drug developed to interfere with this pathway, called belatacept (LEA29Y), was developed by Bristol-Myers Squibb in collaboration with JDRF-funded researchers Thomas C. Pearson, M.D., and Christian P. Larsen, M.D., at Emory University. The drug has been found to be effective in studies of non-human primates.

A phase II clinical trial of belatacept versus cyclosporine in kidney transplant recipients demonstrated that it functioned as well the older drug, and avoided many of the side effects associated with cyclosporine. Belatacept is now moving into Phase III trials in kidney transplantation.

Camillo Ricordi, M.D., who directs the Diabetes Research Institute at the University of Miami, and has led several important studies on islet transplantation, characterizes the past, present, and future of diabetes cures in terms of eras: we are now in the era of immunosuppression, while research is moving into the era of tolerance, and ultimately aiming for the era of self-tolerance and beta cell regeneration.
“We will reach the twilight of islet transplantation when restoration of tolerance to autoantigens will be induced in patients with type 1 diabetes, and regeneration of insulin- producing tissue will be obtained from the patient’s own precursor/stem cells,” Dr. Ricordi says. “Islet transplant scientists will have accomplished their contributing role, having exploited the procedure to reach this ultimate step in the pathway of reparative medicine.”

NEW ANTIBODIES MAY PREVENT DIABETES

IMMUNE TOLERANCE MIGHT BE THE KEY TO STOPPING TYPE 1 DIABETES OR PREVENTING IT ALTOGETHER. Recent success with two different anti-CD3 monoclonal antibodies, in studies in the United States and in France, is providing renewed hope for the strategy. About 15 to 40 percent of the beta cells are still functioning when type 1 diabetes is diagnosed, so the goal is to preserve that remaining function and perhaps allow the cells to regenerate.

Anti-CD3 antibodies block the action of T cells by interfering with the receptors on the T cell surface, preventing the immune attack. Early studies with a mouse-derived anti-CD3 antibody produced serious side effects in human subjects, but two “humanized” versions have now been developed: ChAglyCD3 and hOKT3_1(Ala-Ala).

Lucienne Chatenoud, M.D., Ph.D., of the Necker Hospital in Paris, recently published the results of a JDRF-funded Phase II clinical trial of ChAglyCD3, as a means of stopping diabetes in newly diagnosed patients. Dr. Chatenoud’s study was a project of the JDRF Center for Beta Cell Therapy in Diabetes, directed by Daniel Pipeleers, M.D., Ph.D.
Patients in the multicenter study who received either the antibody or a placebo for six days were followed for 18 months. Residual beta cell function was better maintained in the antibody group than in the placebo group at six, 12, and 18 months. The insulin dose given to study participants increased in the placebo group, in fact, but did not increase in those who had received the antibody.

This study follows JDRF-funded research published in 2002 by Kevan Herold, M.D., of Columbia University College of Physicians and Surgeons, and Jeffrey Bluestone, Ph.D., di-rector of the JDRF Center for Islet Transplantation at the University of California at San Francisco-University of Minnesota. This trial, using hOKT3_1(Ala-Ala), demonstrated that the drug was safe and efficacious when administered as a single course at time of diagnosis. Subjects in the trial had lower insulin requirements over a two-year follow-up period.

Drs. Herold and Bluestone are currently engaged in two trials of hOKT3_1(Ala-Ala), one in which the antibody is given a second time one year after the first, and the other in which three doses are given over the first 18 months following diagnosis. The Immune Tolerance Network (ITN) and JDRF are among those providing funding for the further study of the antibody at multiple centers in the United States and Canada.

Another ITN study is examining the safety and efficacy of Thymoglobulin, a rabbit polyclonal anti-thymocyte globulin in newly-diagnosed patients. Studies of anti-lymphocyte serum treatment in rodent models have shown promise, as has a limited study in humans. The study is headed by Stephen A. Gitelman, M.D., director of pediatric diabetes at UCSF, and is being conducted at five clinical centers.

For more information on ITN studies & trials, visit www.newonsetdiabetes.org