Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to multiple sclerosis (MS). It has been suggested that relapses of EAE and MS may be associated with, and even driven by, T cells specific for novel epitopes that are primed during the course of tissue destruction in the target organ or in secondary lymphoid tissues. We show, however, that IFNγ and IL-17 responses against the immunizing epitope remain dominant through out the course of multiphasic EAE. Furthermore, induction of tolerance against a putative secondary epitope did not prevent clinical relapses. © 2007 Wiley-Liss, Inc.