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see a 10 percent incidence of diabetes. Instead, they found a 94 percent incidence of diabetes in MHC-susceptible animals and no diabetes in IL-10-negative, MHC-susceptible animals. Mice with BALB/c MHC did not develop diabetes.

In other words, the effect of IL-10 was completely the opposite of what they had expected—not only did it accelerate the disease process, it also seemed to overcome the requirement for a lot of susceptibility information. (There are numerous susceptibility alleles in the NOD mouse, and more are being mapped all the time.) It seemed that IL-10 was actually a very strong potentiator of disease, at least in this and other transgenic mouse models. To see whether or not IL-10 plays a role in the natural disease, researchers have conducted depletion experiments with neutralizing (anti-IL-10) antibodies. In one experiment, NOD mice that were treated with anti-IL-10 from a young age developed far less insulitis than controls. In another experiment, irradiated NOD mice were injected with sensitized lymphocytes from diabetic mice and then treated with anti-IL-10, but the neutralizing antibody had no effect in this transfer model, which involved older (9-week old) mice.

Researchers interpret these results to indicate that IL-10 is required early on in the natural disease, but that it is dispensable later on. NOD disease differs from other autoimmune diseases in its diversity—many new antigens are still being identified, and a corresponding variety of T cells mediate and regulate the disease. Hence, the progression of the disease seems to involve three stages:

  1. Presentation (seeing the antigen or antigens);

  2. Diversification (sensitizing lots of T cells to islet antigens); and

  3. Effector phase (leading to destruction).

Researchers hypothesize that IL-10 acts in the diversification process, specifically through its ability to activate B cells and (through them) to diversify the immune response. Researchers are conducting further experiments to test this hypothesis, using anti-IL-10-treated NOD mice, but focussing on responses to peptides of GAD. The two immunodominant determinants, GAD 34 and GAD 35, respond similarly in the presence or absence of anti-IL-10, but the neutralizing antibody inhibits the spreading of the cryptic determinants, GAD 23 and GAD 17. Since there are high ratios of B cells in the islet infiltrates, this response may be critical to the clinical manifestation in the natural NOD disease, and possibly in the human disease as well.

IL-4. Unlike, IL-10, IL-4 totally blocks the disease. This colony of NOD mice has an 85-percent incidence of diabetes, usually developing the disease between 16 and 24 weeks. Targeted IL-4 to the pancreatic islets reduced the incidence of diabetes to zero, for over a year. To determine whether this reflects a state of tolerance, researchers transplanted NOD islets into transgenic mice that express IL-4 and looked for signs of rejection. The graft was accepted, indicating tolerance of an unknown mechanism.



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