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related to IL-1-beta-converting enzyme (ICE) into an active tetramer that can cleave a number of molecules.

Genetic evidence for this pathway can be seen in mice that are homozygously deficient for the IL-2 receptor; such animals have a severe disregulation of peripheral T-cell homeostasis and are unable to eliminate mature T-cells as they are supposed to do. The SEB experiment described above demonstrated that animals lacking the IL-2 receptor are unable to delete V-beta-8 cells from their mature repertoire. Other experiments have shown that deficiencies in the TNF receptor will also prevent mature T-cell death. And the immunology community has known for some time that mice as well as children with mutations in the Fas molecule will develop lymphoproliferative autoimmune disease very early in life.

Controlled Use of Programmed T-Cell Death in Autoimmune Therapy. To determine whether the active programmed cell death pathway could be used in a controlled way, to eliminate T-cells that were causing T-cell disease, researchers used an animal model—experimental allergic encephalomyelitis (EAE) —in laboratory mice. EAE was first observed in patients who were vaccinated against rabies but developed a disease that looked a lot like multiple sclerosis (MS). It is a murine autoimmune disease in which CD4 cells react against various protein components of the myelin sheath, causing demyelinization and inflammation that leads to various neurological deficits, including paralysis and sensory defects. Certain forms of EAE are relapsing conditions very similar to human MS.

The protocol follows the paradigm of the SEB experiment described above to see if readministration of large doses of antigen at defined times would program a fraction of the activated T-cells for death and thereby prevent the autoimmune sequelae. The clinical results demonstrated that repeated doses of 400 micrograms of antigen, coadministered with 30,000 units of IL-2, can dramatically suppress the severity of the disease compared with untreated mice. In fact, two of the five animals in the experimental group showed no signs of disease and were indistinguishable from their litter mates.

Since pretreatment is unlikely in a clinical setting, researchers also delayed the administration of therapy for 9 days (until the first symptoms of disease) and then 17 days (until the first signs of chronic disease, namely the first wave of paralysis). Administering MBP alone at day 9 dramatically reduced the severity of disease, and even at day 17, when the disease was fully established, the treatment produced statistically significant improvement. Even after 40 days, following the second wave of paralysis, treatment produced statistically significant improvement in clinical scores, although it did not reverse the damage to the spinal cords. After several months, the treatment has proved to be very long-lasting, and most of the animals do not suffer relapses.

This does not seem to be a classic suppressive-type mechanism, however, since readministering encephalogenic T-cells causes re-exacerbation of the di-



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