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  • Knockouts and backcrossing with various mouse strains can be problematic, because many of the traits of interest are in the same cluster of genes.

  • It is now assumed that the effector cell in diabetes is the CD-4-positive ultra-T-cell.

  • Th-2 transfers also result in massive eosinophil infiltration. The Th-2 cells themselves persist for 5 to 7 weeks at the longest, and dye experiments to trace their fate show that, like a lot of transferred cells, they end up in the liver and get stuck there. It is unclear why; researchers are currently conduting more detailed histology.

ANTIGEN-INDUCED PROGRAMMED T-CELL DEATH AS A NEW APPROACH TO IMMUNE THERAPY18

Another new class of vaccines has an intended effect the opposite of all currently available vaccines—that is, to extinguish rather than activate an immune response—by means of eliminating the catalytic cell of immune responses—the T-cell—by using antigen to specifically program those T-cells to die. Such vaccines could play an important role in the treatment of disease in which T-cells play an important role in pathogenesis, including autoimmune diseases, graft rejection, allergies, and some others. Such vaccines would use the inherent specificity of the immune system itself to treat immunological diseases.

Researchers were prompted to propose this class of vaccines in response to the surprising observation that T-cells could be specifically programmed to die by antigen. More surprisingly, the agent that primed them for receptor-driven death was IL-2 T-cell growth factor: when cells that are cycling IL-2 are exposed to a peptide antigen on the antigen-presenting cells, a large fraction of them undergo programmed death. Almost any TCR ligand will have this effect; the original observation involve 2C11, an antibody against the CD3-epsilon chain of the TCR. That this was apoptosis was indicated by the fact that IL-2 or 2C11 alone did not disrupt genomic DNA, whereas IL-2 followed by 2C11 resulted in DNA fragmentation suggesting cleavage between nucleosomes, one of the hallmarks of programmed cell death.

The usual in vitro protocol for producing this effect involves (1) exposing the T-cells to conA, a nonspecific TCR ligand that up-regulates the high-affinity IL-2 receptor; (2) bathing the cells in various doses of IL-2; (3) restimulating the cells with various doses of antigen; and (4) recovering viable cells from the culture. The results are from a strain of mouse that is transgenic for a T-cell receptor that recognizes a peptide of myelin basic protein (MBP), by virtue of which these mice are susceptible to a disease called experimental allergic encephalomyelitis (EAE, see below). As expected, T-cells proliferate in

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Based on a presentation by Michael J.Leonardo, M.D.



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