EPITOPE SPREADING OCCURS IN ACTIVE BUT NOT PASSIVE EAE INDUCED BY MYELIN BASIC-PROTEIN

Using experimental allergic encephalomyelitis, EAE, as a model for the study of autoimmune demyelinating disease in the CNS, previous studie s have indicated that spread may occur with respect to the specificity of T cell responses during disease. This phenomenon, known as epitope spreading, is central to therapeutic strategies in multiple sclerosis (MS). However, in EAE, the clinical course, neuropathology and immuno pathogenesis vary depending upon host factors and the method of diseas e induction. Since passive EAE in SJL/J mice resembles MS clinically a nd neuropathologically, this model was chosen to study the immune phen omenon of epitope spreading. T cells specific for whole 18.5 kDa MBP w ere used to initiate disease since MBP or one of its naturally occurri ng cleavage fragments may initiate a more physiological immune respons e than one generated to an artificially designed synthetic peptide. Wh ile a progressive increase in T cell responsiveness specific for the i mmunodominant MBP 87-106 region was observed during disease, there was no evidence of either intermolecular epitope spreading to the immunod ominant region of proteolipid protein (PLP) 139-151 or of intramolecul ar epitope spreading to the exon 2 encoded region of MBP, which is spl iced out of 18.5 kDa MBP. In addition there was no shift in immunodomi nance toward the subdominant MBP 16-35 region during disease. In contr ast, during active EAE induced by MBP, epitope spreading to the immuno dominant epitope of PLP, 139-151, was observed. These data demonstrate that immune responses generated during passive versus active EAE may differ, and suggest that significant epitope spreading does nor occur in chronic relapsing demyelinating disease initiated with T cells spec ific for whole MBP in the absence of exogenous antigen, complete Freun d's adjuvant and pertussis. Implications of these findings with regard to epitope spreading in MS are discussed.