Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) induced in laboratory animals by active immunization with myelin antigens or by the adoptive transfer of myelin-specific CD4+
T cells. It is widely used as an animal model of multiple sclerosis (MS) and as a prototype of organ-specific autoimmunity. Until recently, EAE and MS were considered Th1 diseases, mediated by IL-12p70–polarized, IFN-γ–producing effector cells. This impression was based, in large part, on the association between clinical disease activity and expression of IFN-γ and IL-12p40 (a subunit of IL-12p70) in CNS tissues, cerebrospinal fluid, and circulating leukocytes (1
). In addition, activated macrophages are the predominant leukocyte in CNS infiltrates of afflicted animals and patients, similar to the infiltrates that characterize Th1-dependent hypersensitivity and antimicrobial responses in the periphery (4
Recent findings, however, suggest that the cytokine pathways underlying encephalitogenic T cell development and function are more complex than previously appreciated. Deficiency of IL-17 or IL-23 (a heterodimeric monokine composed of IL-12p40 and p19 chains that expands and/or stabilizes Th17 cells) (6
) confers partial or complete resistance, respectively, against MOG35-55
–induced EAE in C57BL/6 mice, whereas deficiency of IFN-γ or IL-12p70 does not (8
). Furthermore, myelin-specific Th17 cell lines that have been expanded with IL-23 are efficient autoimmune effector cells (11
). Collectively, these observations invite an alternative interpretation of the mechanism of action of IL-12p40 in neuroinflammation; namely, that its role is in the production of IL-23 and reinforcement of the Th17 effector cell population, rather than (or in addition to) the production of IL-12p70 and promotion of Th1 differentiation.
Some investigators have assumed that the newly recognized importance of IL-23/Th17-dependent events in at least some forms of EAE negates the formerly favored model of pathogenesis that highlights IL-12p70/Th1-driven pathways. However, we and others have demonstrated that IL-12p70, as well as IL-23, directly promotes encephalitogenicity because ordinarily innocuous lineage-uncommitted or tolerized myelin-specific T cells acquire the ability to transfer disease after antigenic challenge in the presence of recombinant IL-12p70 (12
). This suggests that myelin-specific cells, cultured under conditions that favor the development of either Th1 or Th17 cells, are capable of mediating similar clinical syndromes, most likely via engagement of distinct proinflammatory pathways.
Indeed, here we show that IL-12– and IL-23–modulated T cell lines, derived from proteolipid protein (PLP)139–151/IFA-primed SJL donors, trigger a clinically indistinguishable myelopathy upon transfer into naive syngeneic hosts. Despite their similarities, the disease induced by each of these cell lines differs in CNS chemokine expression patterns as well as in the extent of optic nerve involvement and the composition and positioning of infiltrating leukocytes within the spinal cord at peak disability. Of greater therapeutic relevance, the two forms of EAE differ in responsiveness to specific immunomodulatory interventions.