Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor.

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.

Oral glatiramer acetate in experimental autoimmune encephalomyelitis: clinical and immunological studies.

Glatiramer acetate (GA, Copaxone, copolymer 1) for injection is an approved drug for relapsing-remitting multiple sclerosis. The clinical and immunological effects of GA were extensively studied in experimental autoimmune encephalomyelitis (EAE), the experimental animal model for MS. The effect of oral administration of GA was tested in both rodents and primates in acute as well as in chronic relapsing (CR) models of EAE. Oral GA was found to suppress acute EAE induced in rats, mice, and rhesus monkeys. The effect of GA was also tested in several models of CR-EAE: proteolipid protein and myelin oligodendrocyte glycoprotein induced CR-EAE in mice, CR-EAE in Biozzi mice, and CR-EAE in cynomolgus monkeys. In all the murine models, oral treatment with GA initiated at the peak of first relapse reduced the severity of disease and suppressed further relapses. Suppression of EAE with oral GA was associated with marked inhibition of spleen cell proliferation and Th1 cytokine (IL-2 and IFN-gamma) response to the respective autoantigens. GA-specific T cell lines of the Th2/3 type that inhibit EAE induction in vivo, similarly to those induced by injection of GA, could be isolated from spleens of GA-fed mice and rats. Furthermore, as demonstrated previously for GA-specific cells induced by the parenteral route, the orally induced GA-specific cells accumulate in the CNS and secrete in situ Th2 cytokines in response to both GA and MBP as well as brain-derived neurotrophic factor (BDNF). Although a clinical trial in MS with two doses of oral GA in enteric-coated tablets did not show a significant effect either at the clinical or immunological level, the results presented here suggest that oral GA may still be developed into a therapeutic modality in MS.

Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis.

We investigated the effect of laquinimod on inflammatory demyelination, axonal damage, cytokine profiles and migratory capacities of lymphocytes in C57BL/6 mice with active EAE induced with MOG(35-55) peptide. The mice were treated at disease induction and after disease onset. Spinal cords were assessed histologically. Cytokines and adhesive properties were analyzed in splenocytes. Preventive and therapeutic laquinimod treatment reduced clinical signs, inflammation, and demyelination. VLA-4-mediated adhesiveness and pro-inflammatory cytokines such as IL-17 were down-regulated in treated animals. Within lesions, treated mice showed similar axonal densities, but less acute axonal damage than controls. Laquinimod might thus protect myelin and axons by decreasing pro-inflammatory cytokines and impairing the migratory capacity of lymphocytes.