THE FUNCTIONAL-SIGNIFICANCE OF EPITOPE SPREADING AND ITS REGULATION BY COSTIMULATORY MOLECULES

Epitope spreading is a process whereby epitopes distinct from and non- cross-reactive with an inducing epitope become major targets of an ong oing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infect ion and secondary to chronic tissue destruction that occurs during pro gressive autoimmune disease. We have investigated the functional signi ficance of this process in the chronic stages of both autoimmune and v irus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experime ntal autoimmune encephalomyelitis (R-EAE) induced with defined encepha litogenic myelin peptides, CD4(+) T cells specific for endogenous epit opes on both the initiating myelin protein (intramolecular epitope spr eading) and distinct myelin proteins (intermolecular epitope spreading ) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a maj or functional role in the chronic-progressive course of Theiler's muri ne encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4(+) T-cell-mediated immunopathology. In TMEV-IDD, my elin destruction is initiated by virus-specific CD4(+) T cells which t arget virus epitopes persisting in CNS-derived antigen-presenting cell s. However, the chronic stage of this progressive disease is associate d with the activation of CD4(+) T cells specific for multiple myelin e pitopes. In both models, the temporal course of T-cell activation occu rs in a hierarchical order of epitope dominance, spreading first to th e most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predom inantly by CD28/B7-1 costimulatory interactions, as antagonism of B7-1 -mediated co-stimulation using anti-B7-1 F(ab) fragments is an effecti ve ameliorative therapy for ongoing disease. The process of epitope sp reading has obvious important implications for the design of antigen-s pecific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes as sociated with chronic tissue destruction.