Multiple sclerosis (MS) is often characterized by an exacerbating/remitting course with chronic-progression of clinical disability. We have developed an animal model of experimental autoimmune encephalomyelitis (EAE) that shows a similar clinical profile. Immunization of (SWKxSJL)F1 mice with the immunodominant p139-151 determinant of myelin proteolipid protein (PLP) results in acute EAE, and recovery from the primary attack is followed by a relapsing- remitting pattern of disease with a subsequent chronic-progression of disability and demyelination reminiscent of MS. A number of studies have shown that acquired recognition of new self- determinants, a process commonly referred to as determinant spreading, accompanies chronic relapse and progression of EAE. We have recently shown that determinant spreading in EAE is an ordered physiologic process in which defined myelin self-determinants are recognized in a sequential predictable cascade. Moreover, we have found that tolerance induction after disease onset to spreading vs non-spreading determinants inhibits the subsequent chronic-progression of disease. Our results indicate that determinant spreading is not an epiphenomenon but is instead a pathogenic process mediating the progression of autoimmunity and providing a foundation for therapeutic intervention of on going disease. Our overall hypothesis is that autoimmune disease is a developmental evolving process in which predictable self recognition events accumulate in an orderly manner and cause chronic-progressive disease. In the current application, we will define the extent to which spreading is predictable by identifying features common to spreading cascades resulting from EAE induction by different means and with different determinants. In addition, we will define the therapeutic hierarchy of spreading determinants by tolerizing with peptides representing different stages of the spreading cascade. These experiments will identify determinants providing optimal protection from disease progression. Finally, we will determine the optimum conditions for interrupting the spreading cascade by immune deviation with determinant- specific Th2 T cells. The relevance of our work on the predictability of murine determinant spreading patterns lies in our complementary observations that the development of both EAE and MS share remarkably similar patterns of self-recognition plasticity. Our ultimate goal is to treat ongoing autoimmune demyelinating disease by predicting and therapeutically targeting the determinant spreading cascade. The studies outlined in this application will provide a rationale for the development of such therapeutic strategies.
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