Abstract
Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) has been widely employed to evaluate new strategies to control MS, including procedures to induce immunological tolerance. Considering that skin exposure to protein antigens can induce tolerance and that vitamin D analogs conserve immunomodulatory potential and are less toxic, we investigated the efficacy of epicutaneous application of a myelin oligodendrocyte glycoprotein peptide (MOG35–55) associated with paricalcitol (PARI) on EAE development. Three and 11 days after EAE induction, C57BL/6 mice were treated with an occlusive patch containing MOG plus PARI. Clinical parameters were daily assessed, whereas immunological and histological evaluations were performed during the acute EAE phase. MOG and MOG + PARI significantly controlled disease development reducing weight loss and clinical score. Moreover, MOG and MOG + PARI reduced the inflammatory process and preserved the myelin sheath in the CNS. High percentages of Foxp3+ regulatory T cells (Tregs) and lower MHCII fluorescence intensity in dendritic cells in draining lymph nodes were concomitantly observed. MOG + PARI association was, however, more efficient being able to reduce disease incidence and clinical scores more significantly than MOG or PARI alone. This experimental group also displayed a higher ratio between mRNA expression for Foxp3 and RORc and a higher percentage of Foxp3+ cells in the CNS. Modulation of activation markers observed in microglial cells eluted from EAE treated mice were confirmed by in vitro studies with the BV-2 microglial cell line. The results show that MOG + PARI association applied by an epicutaneous route controlled EAE development. Protective involved mechanisms include mainly a higher proportion of Tregs and also a direct immunomodulatory effect of PARI on microglial cells.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune pathology of the central nervous system (CNS) characterized by local inflammatory infiltration, demyelination, and axonal damage, which affects mostly young adults [1]
EAE mice were treated every other day during 15 days with Vitamin D3 (VitD) or PARI, and MOG was co-administered on days 3 and 11
We demonstrated that the association of MOG with active VitD, delivered by i.p. route, controlled EAE development in C57BL/6 mice [37]
Summary
Multiple sclerosis (MS) is a chronic autoimmune pathology of the central nervous system (CNS) characterized by local inflammatory infiltration, demyelination, and axonal damage, which affects mostly young adults [1]. The etiology of MS remains elusive, but it is accepted that self-reactive Th1 and Th17 cells with specificity for myelin sheath antigens play a central role in initiation and perpetuation of CNS inflammation [2, 3]. Experimental autoimmune encephalomyelitis (EAE) is an artificially induced disease of the CNS that resembles MS in its clinical, histopathological, and immunological features. In this model, myelin-specific CD4+ T cells activated in peripheral lymphoid organs pass through the blood–brain barrier (BBB) and invade the CNS. Recognition of myelin peptides on the surface of local antigen-presenting cells (APCs) leads to reactivation of these CD4+ T cells, resulting in pro-inflammatory cytokine production, oligodendrocyte damage, and axonal demyelination [4,5,6]. In addition to myelin and axonal injury directly performed by TCD4+ and TCD8+ lymphocytes, this disease is mediated by persistent activation of microglial cells and macrophages, antibody, complement components and by a plethora of mediators as cytokines, nitric oxide (NO), and metaloproteinases [7,8,9]
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