Study Indicates Special Vaccines Could Prevent Insulin-Dependent Diabetes

Plasmid DNA is circular genetic material obtained from bacteria. A chronic inflammatory disease, insulin-dependent diabetes, also called type I or juvenile onset diabetes, results from cells of the body's own immune system going awry and eventually killing other cells needed to produce insulin. In their experiments, UNC-CH researchers succeeded in preventing diabetes from starting in special laboratory mice that develop diabetes as they age. More importantly, the scientists say, they also halted progression of the illness in animals already affected.

" This work is very encouraging because it has the potential to be useful in clinical settings," said Dr. Roland Tisch, assistant professor of microbiology and immunology at the UNC-CH School of Medicine. "In the past, our group and others could manipulate the damaging auto-immune response in various animal models for type I diabetes but not in ways that would be readily feasible clinically."

A report on the research appears in the Feb. 1 issue of the Journal of Immunology. Besides Tisch, authors are Dr. Bo Wang, postdoctoral fellow; Dr. Donald J. Weaver, now a UNC-CH medical student; visiting scholar Dr. Bo Liu, Thi Bui, research assistant; Dr. James Arthos of the National Institutes of Health; and Dr. David V. Serreze, a researcher at Jackson Laboratory in Bar Harbor, Me.

"Recently, a Canadian group in Edmonton showed for the first time that islet beta cells -- the cells in the pancreas that produce insulin -- could be transplanted successfully in people with diabetes," Tisch said. "For more than a year, their patients have been free of insulin injections. A key issue, however, is that those individuals have had to take a cocktail of drugs that suppresses their immune systems, and they might have to continue taking it for the rest of their lives."

Such drugs are needed to prevent patients' immune systems from destroying the transplanted beta cells, the scientist said. But the compounds also could make recipients more susceptible to infectious diseases and cancers and produce other unknown but serious consequences when given over many years.

Tisch's group used genetic vaccines they created to re-establish the natural balance between two kinds of immune cells -- Th1 cells and Th2 cells. When misbehaving, the former attacks the critical insulin-producing islet beta cells, while the latter normally keep the former from doing that. When Th2 cells fail to do their job, Th1 cells eventually lead to type I diabetes.

"Our approach was relatively simple," Tisch said. "The vaccines allowed us to selectively suppress the body's auto-immune response while leaving the remainder of the immune response intact."

He and colleagues engineered their vaccines to express two different proteins -- one that activated T cells that recognize islet beta cells and another that boosted those T cells to develop into Th2 cells needed to hold Th1 cells in check. They then inserted the genes encoding those proteins, respectively named GAD65-IgGFc and IL-4, onto the injectable circular plasmids, which do not themselves produce an immune response.

"One of the appealing features of plasmid DNA vaccines, which in other forms already are being tested clinically against certain infectious diseases such as HIV-1and cancer, is that the DNA persists for long periods," Tisch said. "We gave our mice three injections in three weeks, and the majority of the animals have remained diabetes-free for more than a year. Ideally, human patients might require injection of plasmid DNA vaccines only every year or two."

The continuing research is part of a National Institutes of Health program project grant, co-sponsored by the Juvenile Diabetes Research Foundation, to UNC-CH and headed by Drs. Jenny Ting and Jeffrey A. Frelinger, professor and chair, respectively, of microbiology and immunology.