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Vaccines for the 21st Century: A Tool for Decisionmaking
fic immunological way. Based on this experience in NOD mice, the researchers have organized a Diabetes Prevention Trial Type 1, which is ongoing. They have also conducted further experiments in antigen-specific immunotherapy in the NOD mouse.
The strategy in general is to tolerize against the harmful Th-1 immune cells, and if possible transform the response from a harmful Th-1 to an ostensibly harmless Th-2. This can be accomplished by immunizing with various antigens and adjuvants, either orally or intravenously. Three possible autoantigens have the greatest relevance for human diabetes:
Glutamic acid decarboxylase (GAD), usually GAD-65 rather than a higher molecular weight isoform;
Transmembrane tyrosine phosphatases, one called IA2 and the other IA2-beta; and
Insulin and insulin receptors.
Experiments with IA-2 and IA-2-beta are ongoing; results are available for experiments with GAD and insulin.
Oral Antigen Therapy Experiment. In one experiment, NOD mice were fed doses of 1.0 milligram (mg) of insulin or 0.5 mg of GAD (from pig brain) per day. Over time, most of the controls developed diabetes, while insulin and GAD both provided significant but not absolute protection. Feeding the two antigens together seems to have some additive effect, particularly in maintaining protection. At about 12 weeks of age, when diabetes begins to occur in the NOD mouse colony, the insulitis score (based on level of inflammation observed by microscope) is much lower in mice fed GAD, insulin, or both.
This anergy or suppression of T-cell response is antigen-specific: feeding insulin suppresses insulin responses; feeding GAD suppresses GAD responses; and feeding together suppresses both, but there is no bystander suppression. Most of the antibodies in the NOD mouse are of the IgG-B2 variety, and oral feeding doesn’t suppress the animal’s ability to make antibodies, or switch the subtype of antibodies made.
Two cytokines of interest are induced: tumor necrosis factor beta (TNF-beta) and interferon gamma (IFN-gamma). Feeding regimes did not change TNF-beta levels, but controls had much higher levels of IFN-gamma in islet infiltrates, most of it from Th-1 CD4 cells. This is evidence of down-regulation of Th-1 response in animals fed insulin and/or GAD. In the Peyer’s patch, too, researchers found an inhibition of elaboration of messenger RNA for IFN-gamma, as well as increases in interleukin four (IL-4) and possibly IL-10, evidence of down-regulation of Th-1 response and possibly of up-regulation of Th-2.
Intravenous Antigen Therapy Experiments. Large amounts of IV insulin will kill the mice, so researchers used biologically inactive forms, including