LLU&MC Scope Autumn 2000

Researcher receives grant to further develop diabetes vaccine

The quest to find a cure for type I diabetes-a disease which affects 300 out of every 100,000 people-has just received a major boost.

William H. R. Langridge, PhD

William H. R. Langridge, PhD, a researcher at Loma Linda University's Center for Molecular Biology and Gene Therapy, and professor of biochemistry, School of Medicine, announced that the Juvenile Diabetes Foundation (JDF) will fund his research efforts to find an effective treatment. "This grant of $200,000 will provide funding for two years," says Dr. Langridge, "during which time we will work on increasing the effectiveness of our approach."

Type I diabetes typically results when one's immune system mistakenly recognizes glutamic acid decarboxylase (GAD), insulin, and other related proteins as foreign and attacks the beta cells in the pancreas where these particular proteins are produced.

The destruction of the beta cells leads to high levels of "free sugars" in the bloodstream, normally metabolized by cells with the help of insulin.

The onset of type I diabetes most often happens at a young age-hence, the name juvenile diabetes mellitus-and those affected will likely spend the rest of their lives taking insulin shots, radically altering their diets, and suffering from a variety of diabetes-related diseases.

Based on the concept of tolerization-similar to the treatment of allergies-Dr. Langridge has successfully reduced the onset of type I diabetes in about half of the laboratory animals used in his studies.

"The JDF grant will allow us to work on increasing our percentages," he explains. "We're hoping to raise our percentages of protection significantly, ultimately reaching 100 percent protection."

Dr. Langridge and his colleagues have managed to fuse a nontoxic portion of the cholera toxin to the pancreatic self-antigens, insulin and GAD. The fusion genes encoding insulin or GAD are transferred into the potatoes, causing them to produce small amounts of insulin or GAD.

When ingested by laboratory animals, these genetically altered "spuds" protect as many as half of the animals.

Here is a simplified view of the process. "T-helper cells" (Th cells) are part of the body's immune response system. Th1 cells are responsible for "turning on" the immune response, while Th2 cells suppress the immune response.

One protein associated with the Coxsakie virus closely resembles the insulin protein. When a child is exposed to this virus, the body typically mounts an immune response involving Th1 cells. Once the virus is subdued, the body creates receptor cells to "remember" the Coxsakie virus, reducing the immune response time for future encounters.

The resemblance between a particular Coxsakie virus protein and insulin is so striking that the body is fooled into mounting an immune response against insulin. Once the body begins to recognize and attack particular proteins that are not foreign, these proteins become classified as autoantigens and the body's reaction as an autoimmune response.

With the onset of type I diabetes, the Th1 cells swarm to the pancreas where they detect the GAD and insulin auto antigens. These cells release cytokines (messenger proteins) into the islets of the pancreas containing GAD and insulin-producing beta cells, setting off a cascade of events that leads to inflammation and ultimate death of the besieged beta cells.

As more of the beta cells are destroyed, an individual will increasingly experience the symptoms of diabetes.

Dr. Langridge is seeking to reduce or even halt this immune response, thus saving the body's ability to create insulin.

When the genetically altered potatoes are ingested, small amounts of the insulin protein are delivered through the gut and, through a cascade of events, stimulate Th2 cells to release suppressor cytokines.

"Our new research will seek to double the amount of autoantigen expression in plants," Dr. Langridge explains. "By utilizing another autoantigen, GAD, we hope to double the opportunity for defeating the disease."

Typically, the protein GAD is the initial protein to become an autoantigen in type I diabetes. Insulin is the second.

"By introducing both GAD and insulin into the body in small amounts through the gut," Dr. Langridge points out, "we hope to significantly increase the body's tolerization response and perhaps double the protection against type I diabetes."

Using this technique, other proteins which eventually become autoantigens can be targeted in future experiments.

"Obviously we don't want to create high enough amounts of any particular protein to trigger a Th1 response," Dr. Langridge clarifies. "That 's why we're excited about the prospects of targeting a widening variety of autoantigens."

Using edible plants to produce low levels of certain autoantigens, Dr. Langridge feels, has the potential of providing a safe and economical way to protect against type I diabetes and other similar autoimmune diseases.

"Each step of our research," Dr. Langridge comments, "is taking us closer to finding an effective therapy to prevent a tragic and debilitating disease which has no present cure."

He adds, "If we can save even one young person from the ravages of type I diabetes, our efforts will be well worth it."

[Scope, Autumn 2000]