sease. The data supports the idea that the treatment effect comes from eliminating the offending T-cells. Histology revealed that untreated animals show severe disruption of myelin architecture and inflammatory cell infiltrate in the subarachnoid space, while treated animals show little or no disruption of the normal architecture.
Researchers also wondered whether there is a fundamental immunoregulatory problem that might prohibit apoptosis and thus lead to autoimmune disease. The current state of knowledge may not be sufficient to rule this out. However, researchers have repeated the MBP experiment with T-cells from a number of human MS patients and found that they could indeed induce dramatic apoptosis in vitro. They are now initiating studies to look at other antigens.
Conclusions. Researchers now believe that there is a sound scientific basis for a new class of vaccines that will target T-cells for programmed cell death using specific antigen. They are encouraged by preclinical studies that show that this is effective and safe. They are moving on to study this question in nonhuman primates, establishing a marmoset model of EAE. They urge IOM to consider this type of vaccine in their priorities.
In response to questions from the audience, Dr. Leonardo added the following:
Activated T-cells may represent a reservoir of antigen; when they undergo apoptosis, they release the antigen, recruiting inflammatory cells and leading to relapses.
Evidence suggests that T-cells are in fact killed, not just switched off or pushed away from their target tissues (e.g., the brain).
Costimulatory molecules and interactions (e.g., B7-CD28, CTL-A4-IgE) seem to have little effect on the killing phase, or indeed any time after the immune response is initiated. Once the cell is primed, it appears that antigen itself is sufficient to kill it; in fact, a strong TCR ligand alone is enough to kill the cell.
It appears that different molecular parts of the TCR are important for activation and death. For example, the epsilon chain is capable of stimulating IL-2 production, but the zeta chain is particularly important for programming the cell to die through Fas or TNF. However, researchers do not yet know how to manipulate these differences.
This appears to be a high-affinity phenomenon, in which the most avid cells would be most quickly deleted, but while low-level stimulation does not eliminate, researchers have not looked into the exact affinity requirements. [Dr. Berzofsky volunteered that high doses of antigen with high epitope densities will selectively produce apoptosis in high-affinity CTLs, but will actually stimulate low-affinity CTLs; he and his coworkers have not looked at CD4 CTLs in this regard.]