Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE)

A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.In most patients, multiple sclerosis (MS) initially presents as a relapsing-remitting disease course that is marked by periodic, self-limiting attacks interspersed among prolonged periods of apparent clinical latency [1-5]. Although the etiology of MS is not understood, a prevalent theory is that molecular mimicry drives the encephalitogenic attack [6-8]. Molecular mimicry may be mediated by chronic infectious agents such as viruses that exhibit prolonged latency but periodically reactivate and consequently re-stimulate cross-reactive immunity. With each reactivation, these chronic infectious agents may elicit a new wave of effector and memory T cells with cross-reactive specificity for viral epitopes and self epitopes of CNS myelin. Focal infiltration of cross-reactive T cells into the CNS is coupled with T cell-reactivation upon recognition of the cross-reactive self-myelin antigens [9,10]. This process in turn drives inflammatory demyelination and neurologic dysfunction. These inflammatory processes are then postulated to elicit negative feedback pathways and compensatory regulatory responses that enable spontaneous remission and recovery. In many patients, this relapsing-remitting form of MS evolves into a chronic progressive disease in which periodic attacks are subsumed by an insidious and conti