JDF COUNTDOWN Magazine


Transplantation: Fighting Match

By Robert Dinsmoor

The body's battle over the beta cell may be a true case of the good guys versus the bad guys.

Could catching a certain type of cold or flu actually protect a child from getting diabetes? That is just one intriguing possibility raised by research results coming out of a JDF-funded Program of Excellence in Canada. For decades, researchers have known that diabetes is caused by an attack by the body's immune system on the insulin-producing beta cells of the pancreas. Tantalizing new evidence indicates that there is a part of the immune system whose specific purpose is to protect the beta cells from destruction. Now the Canadian researchers are trying to identify the immune system's "good guys" and "bad guys" in order to help the good guys win and thereby help islet transplants succeed.


RETHINKING AUTOIMMUNITY

The autoimmune process of diabetes seems to start when the immune system recognizes and attacks proteins on the surface of the beta cells, possibly mistaking them for proteins of an invading organism. From here, the process leading to diabetes is a complex and poorly understood chain of events. White blood cells, called cytotoxic or "killer" T cells, flood into the pancreatic islets and cause an inflammation known as insulitis. Over the course of years, the beta cells are gradually destroyed, and once about half or more of them are gone, the symptoms of diabetes begin to appear.

One promising experimental treatment has been to give diabetic patients transplants of healthy pancreatic islets. However, these transplanted islets face the same problems of rejection by the immune system that are seen in most types of transplants, in addition to the autoimmune attack that caused the diabetes in the first place.

Alexander Rabinovitch, M.D., and his colleagues at the University of Alberta in Edmonton want to find out exactly how these immune-system rejection processes work and how they might someday be blocked. To answer these questions, experts in such diverse fields as immunology, genetics, biochemistry, microbiology, and surgery will use the latest technology available to focus on key points in the disease process.

The traditional thinking among scientists has been that in genetically prone individuals, an environmental factor such as a virus somehow triggers an autoimmune response against the beta cells. Certain viruses such as rubella, Coxsackie, and cytomegalovirus have been implicated as possible triggers for diabetes. Accordingly, the best way to prevent diabetes would be to identify the culprit viruses and prevent them from initiating an autoimmune response. Yet in recent years this simplistic view has been challenged by a number of confounding observations.

In several studies, BB rats and NOD mice (strains specifically bred to develop diabetes) that were raised in an environment free of pathogens such as viruses had an increased incidence of diabetes, but those infected with viruses had a decreased incidence of the disease.

Another observation is that the incidence of Type I diabetes is lower in developing countries than in industrialized Western nations, where the overall level of sanitation is somewhat better, although this difference could be due to a number of factors.

Researchers also have shown that giving complete Freund's adjuvant (CFA), a solution containing dead tuberculosis bacteria, to young NOD mice and BB rats can keep them from developing diabetes. What makes this so paradoxical is that the adjuvant is thought to stimulate the immune system rather than suppress it.

No one knows exactly how infections might bestow protection from diabetes. One theory, according to team member John Elliott, M.D., Ph.D., could be described by the adage "The devil makes work for idle hands."

"The notion is that in autoimmune disease, if the immune system is busy fighting off microbial invaders, it doesn't have time to attack its own cells," he says.

According to another theory, a given virus might have several strains, some that cause diabetes and some that don't. Consequently, being exposed to a particular strain of the virus that does not trigger diabetes might confer immunity to the other strains of the virus—and thus protection against diabetes.

The view that is emerging from recent studies is that diabetes is a disorder of "immunoregulation." In other words, the destruction of the beta cells results from a shift in the balance of power between immune factors that promote destruction of the beta cells and those that protect against it. Through a broad range of experiments, Dr. Rabinovitch and his colleagues have begun to identify at least some of the "good" and "bad" components of the immune system. It now appears, for instance, that specific T cells called T-helper-1 (or Th1) cells and the messenger proteins (or cytokines) they produce are responsible for promoting beta-cell destruction. The "good" immune complex, which works against the Th1 cells, includes T-helper-2 (Th2) cells and the cytokines they produce.

STIMULATING THE IMMUNE SYSTEM

Following up on the observation that complete Freund's adjuvant can prevent diabetes in NOD mice and BB rats, Ray V. Rajotte, Ph.D., also of the Alberta team, has shown that injecting CFA into NOD mice can also prevent the recurrence of diabetes after islet transplantation. CFA cannot be used in a trial involving humans, so the team examined another, more clinically acceptable adjuvant called Bacillus Calmette-Guerin or BCG, which contains a strain of weakened bacteria and has been used in some countries as a tuberculosis vaccine. They found that BCG, too, decreased the incidence of diabetes in NOD mice after islet transplantation. In fact, some NOD mice treated with BCG were given a second islet transplantation to replace the first and still did not develop diabetes—showing that BCG bestows lasting protection against diabetes.

How do these adjuvants protect against diabetes? For years, the effect was viewed as completely mysterious, but these researchers are now unraveling some of the clues. Although the exact mechanism is still unknown, they have shown that adjuvants increase the levels of the protective cytokines, which appear to suppress destruction of the beta cells.

According to Dr. Elliott, BCG has joined the arsenal of experimental therapies for preventing diabetes. Recently, researchers in Canada, the United States, Germany, Greece, and Israel have begun testing BCG vaccination in children with newly diagnosed diabetes to see if they can preserve their remaining islets.

SIGHTS ON THE CYTOKINES

A major thrust of the program’s work has been to identify the "good" and "bad" cytokines in diabetes. They start by removing beta cells from NOD mice at different stages in the progression of diabetes—both initially and after islet transplantation. Then they subject the cells to highly sensitive tests made possible by molecular biology technology, which can measure infinitesimal amounts of these cytokines in the inflamed islets.

Already, the team has discovered that cytokines known as interleukin-2 (IL-2) and interferon gamma, produced by the Th1 cells, are more often seen when infiltration leads to beta-cell destruction. On the other hand, cytokines called interleukin-4 (IL-4) and interleukin-10 (IL-10), produced by Th2 cells, are more often seen when inflammation of the beta cells is reversed, as when mice and rats are treated with the adjuvants.

"Step A has been to identify which cytokines are there and how they relate to the disease," says Dr. Rabinovitch. "Step B is determining whether administering the 'good' cytokines, IL-4 and IL-10, can reproduce the effects of complete Freund's adjuvant, which is working in mysterious ways, and can then be a therapeutic approach. And the answer is yes, it can." The researchers have administered IL-4 and IL-10 to NOD mice getting syngeneic, or same-species, islet grafts and have been able to delay the recurrence of the disease. "Now we're considering the possibility of giving these cytokines to patients."

Using cytokines therapeutically is not some far-off dream, says Dr. Rabinovitch. Pharmaceutical firms are already manufacturing various cytokines in industrial amounts. They are already considering clinical trials of some of these cytokines in such serious and life-threatening diseases as inflammatory bowel disease and septic shock. If they are shown to be effective in these diseases, with an acceptable level of safety, then they could undergo clinical trials in diabetes.

GETTING THE GOODS ON GAD

Only recently, researchers have identified a protein on the surface of beta cells called glutamic acid decarboxylase, or GAD, as the first known target of the immune system in diabetes.

Furthermore, two recent landmark studies showed that immunizing young NOD mice with GAD can greatly reduce their risk of developing diabetes. Yet because so little is known about the possible side effects of GAD, clinical trials of GAD immunization are years away.

Bhagirath Singh, Ph.D., Dr. Elliott, and colleagues at Alberta are now in the process of studying those T cells that specifically react to GAD and have cloned a number of them. With these T-cell clones in hand, they have been trying to identify which ones are involved in destroying beta cells and which ones suppress this destruction. By identifying the suppressor T cells and discovering how they protect against diabetes, they may be able to find a way to exploit this protective effect. They now suspect that GAD immunization activates the "good" Th2 cells.

One key area of interest is to identify those specific peptides that T cells are responding to when NOD mice are immunized with GAD. "Then it may be possible to immunize with that purified peptide and get a similar effect," suggests Dr. Elliott. "But this is in the mouse model, and it's not exactly clear what the repercussions are going to be in humans."

From COUNTDOWN magazine, Summer 1996, Vol. XVII, No. 2


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