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Vaccines for the 21st Century: A Tool for Decisionmaking
B7.2 antibodies following the acute phase had no effect on relapses, either regulatory or enhancing, and that intact anti-B7.1 antibody actually exacerbated the disease. However, the Fab fragment of anti-B7.1 did protect animals from relapse, apparently by blockading the B7.1 molecule. Other studies have shown that the B7.1 molecule is dramatically up-regulated in the target organ during the preclinical stages of EAE, suggesting that it has a role in breaking down central nervous system (CNS) mononuclear cells into either F480 macrophages, B220 B-cells, or CD3 T-cells.
Potential for Peptide Immunotherapy in Progressive Autoimmune Disease. Researchers believe that tissue damage in TMEV is at least initiated because the virus is trophic for the CNS, where it lives in APC-like cells and can persist for long periods of time. Tolerizing animals with MSCH, as described above for MBP-induced EAE, has no effect at all on the development of TMEV-induced demyelinating disease. However, inducing tolerance against viral epiopes prior to infection does a very good job of shutting off the initiation of this disease. In fact, there are no neuroantigen-specific responses against MBP or PLP epitopes in the first 30 to 40 days after immunization, when the disease is already evident. By day 87, however, there is evidence of a response directed against the dominant 139–151 epitope of PLP, a response that first appears somewhere between days 42 and 52. And by day 164, there are responses not only against 139–151 but also against the secondary 178–191 epitope, the MOG epitope, and a third 56–70 epitope of PLP.
These findings strongly suggest that the tissue damage in the chronic, progressive TMEV model is initiated by virus-specific T-cells that target virus in the CNS and induce the initial inflammatory response. As tissue damage progresses, however, more and more self-epitopes seem to get recruited into this response. It is not yet clear whether these self-responses are playing a role in the chronic pathogenesis, or whether its course can be changed with peptide therapy; researchers are currently conducting reactivation, serial transfer, and tolerizing experiments—similar to those for EAE described above—to answer these questions.
For example, researchers are particularly interested in whether the initial self-response arises because of mimicry between 139–151 and some epitope in the virus, or because of the elaboration of myelin epitopes caused by the chronic inflammatory response. They identified three immunodominant epitopes of TMEV (lying on the VP1, VP2, and VP3 of the capsid) and developed T-cell clones and hybridomas specific for each. However, none of these hybridomas crossreacted with any of the neuroantigens or myelin epitopes that get recruited in the disease, nor do naive animals primed with neural epitopes develop any crossreactivity with the viral epitopes. This argues against molecular mimicry as an explanation of the disease, as does the fact that the response against self-antigens doesn’t arise until after tissue damage has occurred, whereas the