Abstract
Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.
Highlights
Teriflunomide is a novel oral immunomodulatory drug recently approved in several locations as a disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS) [1]
Immune cell activation and proliferation, which are critical for the progression of autoimmune diseases such as MS, are dependent on de novo pyrimidine synthesis [2], and extensive in vitro studies have shown that teriflunomide is a selective and reversible inhibitor of mitochondrial dihydro-orotate dehydrogenase (DHO-DH) [3], the key enzyme involved in this process [4, 5]
Immunohistochemical analysis of the spinal cord indicated that EAE induction was associated with significant infiltration of CD3+ T cells and Iba1+ macrophages/microglia at all four disease stages (Figures 2 and 3A,B; Table 1), and with spinal cord infiltration of myeloperoxidase-positive neutrophils at acute attack and relapse (Figure 3C; Table 1)
Summary
Teriflunomide is a novel oral immunomodulatory drug recently approved in several locations as a disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS) [1]. Immune cell activation and proliferation, which are critical for the progression of autoimmune diseases such as MS, are dependent on de novo pyrimidine synthesis [2], and extensive in vitro studies have shown that teriflunomide is a selective and reversible inhibitor of mitochondrial dihydro-orotate dehydrogenase (DHO-DH) [3], the key enzyme involved in this process [4, 5]. Experimental autoimmune encephalomyelitis (EAE) is a wellstudied animal model of human MS [8, 9]. The Dark Agouti (DA) rat model of EAE mimics certain aspects of the clinical course of disease in people with RRMS [9], typified by progressive, sustained demyelination, and associated axonal loss [13,14,15]. Most animals recover from paralysis and experience remission, but may undergo one or more relapses [10]
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