The progression of
experimental allergic encephalomyelitis (EAE) in certain mouse strains has been reported to involve a broadening of the response to myelin
antigens, apparently resulting from priming to endogenous determinants of the myelin sheath. The phenomenon has been termed determinant spread. Interest in this effect has centered on the mechanism it offers to explain the progressive, relapsing and remitting course of EAE and indeed of
multiple sclerosis. We have conducted a systematic, longitudinal study in SJL mice to look for determinant spread during relapsing and remitting EAE, correlating
epitope recognition and
cytokine production with disease severity. Disease was induced using three of the four encephalitogenic proteolipid
protein or
myelin basic protein epitopes, and responses to each of four
epitopes recognized by SJL T cells were tracked through
acute disease, remission and relapse. The responses of lymph node cells, splenocytes and central nervous system (CNS)-infiltrating T cells were analyzed. While marginal, transient responses to secondary
epitopes were detectable in splenocytes, CNS-infiltrating cells showed a dominant response to the original disease-inducing
epitope without evidence of a shift to other determinants during relapse. Disease relapse was correlated with an increase in CNS-infiltrating cells and a high proliferative and
interferon (IFN)-gamma response to the disease-inducing
peptide. During remission, there was a decrease in numbers of cells infiltrating the CNS. These cells were down-regulated, showing low if any response to the myelin
peptides tested as measured by proliferation, production of IFN-gamma or production of
IL-4. Our findings argue strongly against a causal role for determinant spread in disease relapse as observed in these models of EAE.