FUNCTIONAL EVIDENCE FOR EPITOPE SPREADING IN THE RELAPSING PATHOLOGY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the n europathologic T cell repertoire, we show that the majority of the imm unopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) mole cule is directed at the PLP139-151 epitope and that responses to secon dary encephalitogenic PLP epitopes may contribute to the later relapsi ng phases of disease. Intermolecular epitope spreading was demonstrate d by showing the development of T cell responses to PLP139-151 after a cute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intr amolecular epitope spreading was demonstrated by showing that endogeno us host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acut e central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP17 8-191-specific responses are activated as a result of and correlate wi th the degree of acute tissue damage, since they do not develop in mic e tolerized to the initiating epitope before expression of acute disea se. Most importantly, we show that the PLP178-191-specific responses a re capable of mediating R-EAE upon adoptive secondary transfer to naiv e recipient mice. Furthermore, induction of tolerance to intact PLP (w hich inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficie nt to prevent relapsing disease. These results strongly support a cont ributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical ep isodes and have important implications for the design of antigen-speci fic immunotherapies for the treatment of chronic autoimmune disorders in humans.