IL-17A in Autoimmune Inflammation of the Central Nervous System: A Promising Therapeutic Target in Multiple Sclerosis?

ABSTRACT

Discovery of the IL-23/Th17 axis brought to an end the era of the Th1/Th2 paradigm and radically advanced our understanding of autoimmunity. Experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS), was highly instrumental in discovery of the IL-23/Th17 axis and the ensuing rapid progress in the field. Despite an early start and subsequent intense focus on the role of this axis in EAE and MS, some basic questions remained controversial, such as the role of IL-17A, a signature cytokine of Th17 lineage. Copious production of IL-17A combined with its pro-inflammatory effects offered a plausible explanation for the pronounced encephalitogenicity of Th17 cells. A body of experimental data from a number of laboratories demonstrated its important, if not essential, role in EAE, thus pointing to this cytokine as a promising therapeutic target in MS. Findings that MS lesions contain high percentages of Th17 and Tc17 cells and large quantities of IL-17A, similar to EAE, further supported this view. Unexpectedly, two recent findings raised doubts that IL-17A should still be considered an attractive target in MS: contradictory to previous findings, both overexpression and genetic deficiency or neutralization of IL-17A had no significant effect in EAE; in a clinical trial, treatment with anti-IL-12/23p40 antibody did not have a beneficial effect in MS, which came as a surprise since analogous approaches efficaciously suppressed EAE. Here we review findings about the role of IL-17A in EAE, with an emphasis on its potential as a therapeutic target in MS.

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