pathways carry out their injurious actions. Cytokines and the toxic levels of nitric oxide (NO) that they produce can be manipulated in a variety of ways and could provide a target for therapeutic interventions in demyelinating disorders.
Antigen-specific tolerance, a method of antigen-specific immunomodulation, relies on administering an MS-related antigen in a manner that induces tolerance, thereby reducing the immune response to that antigen. Myelin basic protein (MBP) acts as a classical encephalitogenic autoantigen in certain EAE models, which has raised hopes for the development of T-cell-based therapies in which MS patients could be vaccinated with targeted portions of the MBP molecule to induce tolerance and prevent further T-cell-mediated attack. However, as reviewed in the “Immunopathology” section of Chapter 2, the human response to MBP is more complex than that in these EAE models. Indeed, MBP does not act as a classic autoantigen in humans, and even among EAE models, it is highly variable. Generally, it appears that the T-cell response against myelin proteins also differs greatly between individual patients, suggesting that immune therapies might have to be individually tailored for different patients.
Another concern of this approach is that the immune response to antigen administration follows an unusual dose-response curve. Although low-dose administration of most drugs is generally the safest course when beginning clinical trials, low-dose administration of antigen can, in fact, sometimes induce unsafe immune responses, whereas high doses can induce tolerance.
Vaccination, of course, would be an attractive therapeutic avenue. In fact, numerous variants of vaccination have been proposed. These include vaccination with whole myelin-specific T cells,8,33 with T-cell receptor peptides,13,107,116 DNA-encoding autoantigens, or T-cell receptor (TCR) sequences.64,111 Some of these therapies were quite impressive in EAE models when immunization was induced against a known target autoantigen (for example, MBP, MOG, or PLP), but at least in the case of TCR vaccination, the therapy failed in human MS. This is already an active area of corporate research, which has thus far has not fulfilled our hopes. Although potentially of significant therapeutic value, the induction of tolerance remains poorly understood, making it difficult to test clinically.
For the most part, T cells are considered to underlie the immune-mediated attack on myelin, but one class of T cells—suppressor cells—can suppress the activity of pathogenic T cells and might play a protective role in MS.57 Several