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  • Researchers repeated the oral experiments using pig brain GAD and eventually baculoviral-expressed GAD to remove questions about specificity of response. However, they also found that—while there isn’t an additive effect—the best results are obtained by giving both antigens.

  • Researchers are now looking at costimulation and using antibodies such as neutralizing IL-4 and neutralizing IL-10.

  • Transfer of protection depends on both CD4 and CD8 cells, but mainly CD4.

  • Researchers have not looked at the question of prior maternal sensitization, but they have found that age at time of immunization is important.

  • These experiments used human insulin, but insulin is a highly conserved molecule. Human and pig insulin differ by only one amino acid, human and mouse by only three amino acids. Human and pig brain GAD are somewhat less conserved, perhaps 70 percent homologous. The possibility of foreign protein response makes it difficult to factor in the results.

CYTOKINE MODIFICATION OF AUTOREACTIVITY16

There are two general theories with regard to autoimmune disease:

  1. The antigen is the primary effector of the immune response, but a pathogenic response leads to disease; and

  2. Disease is a problem of immune regulation.

It is well known that Th-1 and Th-2 cells counterregulate each other. Th-1 cells are thought to promote autoimmune disease, but their action can be counterre-gulated by Th-2 cytokines, particularly IL-10 and IL-4 and, to a lesser extent, tumor growth factor beta (TGF-beta).

Working with NOD mice, which are a good model for human diabetes, researchers first tried to determine whether IL-10—whose primary role is to down-regulate IFN-gamma (the prototypic Th-1 cytokine) —could regulate this autoimmune response. This was done by eliciting the cytokine locally, in the pancreatic islets of a transgenic (BALB/c) mouse, using the insulin promoter. This attracted inflammatory lymphocytes, but this response did not induce diabetes in a nonsusceptible mouse.

IL-10. The next step was to see whether IL-10, which down-regulates IFN-gamma, is capable of regulating the disease in the NOD mouse. Researchers introduced the genetic loci onto the BALB/c background by backcrossing to F1s, then backcrossed again to N2s, at which point they expected to

16  

Based on a presentation by Nora Sarvetnick, M.D.



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