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Other Disease Models. Researchers have found interesting dichotomies involving these same pathways and lymphokine profiles; in nematode infections, for example, giving IL-4, results in lower fecundity of eggs in the gut and more rapid shedding of the eggs, with a curative effect. In leprosy, the tuberculoid form of the disease produces more IFN-gamma; and IL-2, while the lepromatous form produces higher antigen levels and more CD8 cells, IL-4, and IL-10. In listeriosis, the pathogen induces macrophages to release IL-12 that drives the response down the Th-1 pathway.

Experiments have show that genetic influences may establish “default pathways” in certain individuals or strains—predispositions that researchers will need to consider when developing vaccine strategies. In response to the leishmaniasis pathogen, for example, B10.D2 mice produce an initial burst of IL-4, followed by rising levels of IL-12 and ultimately a Th-1 response with rising levels of IFN-gamma; while BALB/c mice produce a sustained level of IL-4 with rising levels of IL-12 and ultimately a Th-2 response with low levels of IFN-gamma. In this case, it appears that the polarizing variable is not the IL-12 per se but the IFN-unresponsiveness of the BALB/c mouse compared with the B10.D2 mouse. Further experiments confirmed that the difference between the two responses lay in a constitutive part of the IL-12 beta chain; a surface component (which is inducible by IL-12) allows the IL-12 molecule to bind to the Th-1 cell surface, actually competing with the signalling pathway that tells the Th-1 cell to produce IFN-gamma.

Diabetes. Type 1 diabetes accounts for about 7 percent of all diabetics in the United States, some 1.4 million individuals. Since this is a T-cell-dependent disease, the relevant questions are (1) what kind of T-cells transfer the disease and (2) how these T-cells develop. Sequencing the T-cell receptor of a Class II-restricted, CD4-positive clone revealed nothing that would mark it as a diabetogenic T-cell. Researchers developed a transgenic mouse model in which to observe T-cell development in the thymus and periphery, and in which to learn how to control that development. The transgenic was crossed onto the C-alpha knockout background, because they lacked a neutralizing antibody for the endogenous alpha chain.

The result is a line of “hypertransgenic” mice with CD4-positive T-cells that differ from the original phenotype only in the expression of the V-beta-4 T-cell receptor. These mice, as well as the regular transgenic mice, develop destructive insulitis at about 120 days, with infiltration of the beta granules and loss of insulin production. The next question is what type of cells are important in transferring disease.

In an earlier experiment, islet-specific T-cells were generated and then forced their development towards either Th-1 or Th-2. When transferred into the mice, diabetes developed only in the Th-1 recipients. This experiment had no control for antigen specificity or receptor affinity and avidity, which play a role in determining Th-1 vs. Th-2 responses. However, researchers could use the

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