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  • Researchers believe that the homing patterns of primed Th-1 cells are different from those of primed Th-2 cells. In addition, Th-2 cells seem to turn over very rapidly—there is circumstantial evidence of Th-2 cells homing away from the islet and dying in the adjacent lymphoid aggregate.

  • Cytotoxic T lymphocytes (CTLs) appear to be involved in the initial insult, but not enough to cause disease or killing. Experiments with NOD Class I knockouts showed that both CD8 and CD4 cells are required. Results suggest that IL-10 can attract CD8 cells and enhance CD8 CTL activity in-vitro. However, researchers found relatively few CD8 cells in the infiltrate compared to CD4s and B-cells. Breeding a Class I knockout onto an NOD mouse would apparently require nine backcrosses.

Noel Rose of Johns Hopkins University described a new model he and his coworkers have developed showing the role of IFN-gamma in inducing autoimmune thyroiditis. This involves transgenic mice that express IFN-gamma in response to thyroglobulin promoter. The results are dramatic: the mice develop severe thyroiditis, their thyroids are almost completely infiltrated and destroyed, and they become profoundly hypothyroid, with very low levels of circulating T4. All of this is caused by local expression of IFN-gamma in the thyroid. The mice in question were C57 blacks, a susceptible strain.

T-CELL SUBSET CHOICE ON THE OUTCOME OF AUTOIMMUNE DISEASE17

Transgenic T-cell models allow researchers to ask questions that cannot be asked in clinical disease, primarily because they limit the dramatic diversity of diabetes. In both humans and NOD mice, diabetes involves a plethora of antiens and T-cells and cytokines. Researchers try to constrain these variables in such a way as to gain some insight on the total disease.

When a naive T-cell first enters the islet or encounters antigen, it becomes a Th-0 or initially activated cell that can produce both IL-4 and IFN-gamma, as well as a host of other lymphokines. IFN-gamma will stimulate macrophages to make IL-12, which will drive the Th-0 cell towards the Th-1 phenotype. IL-4, on the other hand—either autocrine or paracrine (from a cell not yet defined, possibly a mast cell or CD 1-restricted CD4-positive T-cell) —will drive the Th-0 cell towards the Th-2 phenotype. These are the two very distinct arms of the immune system. IL-4 feeds back and down-regulates IL-12 responsiveness, and IL-12 down-regulates IL-4 responsiveness—a very nice polarizing system. Other researchers have shown that T-complement (Tc-1 and Tc-2) cells are very analogous to the Th-1 and Th-2 phenotypes, with the same signature lymphokines.

17  

Based on a presentation by Jonathan Katz, M.D.



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