Aug. 3, 1999 CHAPEL HILL - Scientists at the University of North Carolina at Chapel Hill have used injections of protein fragments to prevent the development of type-I diabetes in a strain of mice that develop the disease. The peptide injections prevented progression to diabetes in animals that were on the verge of clinical disease.
The findings published August 1 in the Journal of Immunology suggest for the first time that peptide-based immunotherapy may prove of clinical value for people at risk of type-I diabetes. This form of diabetes is an autoimmune disease in which the body's own immune T cells target and destroy insulin-producing beta cells in the pancreas.
"We're taking fragments or peptides of GAD65, a protein produced by beta cells, and using them to divert the immune system, says Dr. Roland Tisch, assistant professor of microbiology and immunology at UNC-CH School of Medicine. Tisch has conducted pioneering diabetes immunotherapy research.
"Our work takes advantage of the highly specific recognition by the immune system of beta cells," the UNC researcher explains. He notes type-I diabetes is thought to involve an imbalance between two types of T cells -- Th1 and Th2.
"Under normal physiological conditions, it's thought there's a functional balance between Th1's and Th2's and that they regulate one another's function and development," Tisch says. "But in type-I diabetes, there appears to be a skewing towards Th1 development. And that's thought to be a contributing factor toward induction and progression of disease."
The new study was aimed at re-establishing that functional balance between Th1 and Th2 in a strain of mice that spontaneously develop diabetes. In a series of experiments, these non-obese diabetic (NOD) mice, 12 weeks old, were given injections of GAD65 peptides. The researchers hoped that some of these might prompt the immune system to produce Th2 cells.
"We were trying to immunize NOD mice under certain conditions to induce GAD65-specific Th2 cells, which in turn would suppress the activity of Th1 cells," Tisch says.
The animals at the age studied were not overtly diabetic, "but were poised at becoming diabetic. The pancreas was heavily inflamed, the autoimmune process was basically in full gear, the animals were just about to become overtly diabetic," Tisch says.
"So we were able to show that by immunizing NOD mice at this particular stage with a certain panel of GAD65 peptides, we could effectively induce Th2 cells and prevent further progression of disease. The animals do not develop overt diabetes."
Why use peptides and not the whole protein? According to the UNC researcher, several reasons apply.
"It's a relatively large protein and there's always the possibility that you may induce a cross-reactive response with another cell protein, another protein expressed somewhere in the body, and elicit an unwanted immune response," Tisch explains.
He adds: "However, if you use peptides, and the peptides essentially consist of only 16 to 20 amino acids, you minimize that possibility of cross-reaction with other cell proteins. In addition, peptides are far easier to work with, they're less costly to generate, and can be stored quite easily relative to intact native proteins."
The researcher emphasizes that not any GAD65 peptide could induce the protective effect. "Out of a panel of five different peptides tested, only two were shown to mediate that effect."
That the NOD mice studied already showed signs of significant autoimmunity has implications for clinical trials. In their journal report, Tisch and his co-authors conclude:
"These findings may be of importance in designing prophylactic therapies for humans included in diabetes prevention trials, since such individuals are currently selected on the basis of having developed significant levels of beta cell autoimmunity."
Co-authors of the report are UNC postdoctoral researcher Dr. Bo Wang, and Dr. David V. Serreze of the Jackson laboratory, Bar Harbor, Maine.
This study was funded by grants from the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Foundation.
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