Induction Of Autoimmune Encephalomyelitis Research Articles

Does physical exercise improve or deteriorate treatment of multiple sclerosis with mitoxantrone? Experimental autoimmune encephalomyelitis study in rats

BackgroundMitoxantrone has proved efficacy in treatment of multiple sclerosis (MS). The fact that physical exercise could slow down the progression of disease and improve performance is still a debatable issue, hence; we aimed at studying whether combining mitoxantrone with exercise is of value in the management of MS.MethodsThirty-six male rats were divided into sedentary and exercised groups. During a 14-day habituation period rats were subjected to exercise training on a rotarod (30 min/day) before Experimental Autoimmune Encephalomyelitis (EAE) induction and thereafter for 17 consecutive days. On day 13 after induction, EAE groups (exercised &sedentary) were divided into untreated and mitoxantrone treated ones. Disease development was evaluated by motor performance and EAE score. Cerebrospinal fluid (CSF) was used for biochemical analysis. Brain stem and cerebellum were examined histopathological and immunohistochemically.ResultsExercise training alone did not add a significant value to the studied parameters, except for reducing Foxp3 immunoreactivity in EAE group and caspase-3 in the mitoxantrone treated group. Unexpectedly, exercise worsened the mitoxantrone effect on EAE score, Bcl2 and Bax. Mitoxantrone alone decreased EAE/demyelination/inflammation scores, Foxp3 immunoreactivity, and interleukin-6, while increased the re-myelination marker BDNF without any change in tumor necrosis factor-α. It clearly interrupted the apoptotic pathway in brain stem, but worsened EAE mediated changes of the anti-apoptotic Bcl2 and pro-apoptotic marker Bax in the CSF.ConclusionsThe neuroprotective effect of mitoxantrone was related with remyelination, immunosuppressive and anti-inflammatory potentials. Exercise training did not show added value to mitoxantrone, in contrast, it disrupts the apoptotic pathway.

In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS.

Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset. Strikingly, the progression of disease is driven by the in situ activation and expansion of a minority of MOG35-55-specific T cells that also recognize neurofilament-medium (NF-M)15-35, an intermediate filament protein expressed in neurons. This mobilization of bispecific T cells is critical for disease progression as adoptive transfer of NF-M15-35/MOG35-55 bispecific T cell lines caused full-blown disease in wild-type but not NF-M-deficient recipients. Moreover, specific tolerance through injection of NF-M15-35 peptide at the peak of disease halted experimental autoimmune encephalomyelitis progression. Our findings highlight the importance of polyspecific autoreactive T cells in the aggravation and perpetuation of central nervous system autoimmunity.

Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.

Proteome analysis of spinal cord during the clinical course of monophasic experimental autoimmune encephalomyelitis

The induction of autoimmune encephalomyelitis (EAE) in Lewis rats results in a period of exacerbation followed by complete recovery. Therefore, this model is widely used for studying the evolution of multiple sclerosis. In the present investigation, differentially expressed proteins in the spinal cord of Lewis rats during the evolution of EAE were assessed using the combination of 2DE and MALDI-TOF MS. The majority of the differentially expressed proteins were identified during the acute phase of EAE, in relation to naïve control animals. On the other hand, recovered rats presented a similar protein expression pattern in comparison with the naïve ones. This observation can be explained, at least in part, by the intense catabolism existent in acute phase due to nervous tissue damage. In recovered rats, we have described the upregulation of proteins that are apparently involved in the recovery of damaged tissue, such as light and medium neurofilaments, glial fibrillary acidic protein, tubulins subunits, and quaking protein. These proteins are involved mainly in cell growth, myelination, and remyelination as well as in astrocyte and oligodendrocyte maturation. The present study has demonstrated that the inflammatory response, characterized by an increase of the proliferative response and infiltration of autoreactive T lymphocytes in the central nervous system, occurs simultaneously with neurodegeneration.

Induction of autoimmune encephalomyelitis and uveitis in B6 and (B6×SJL) mice by peptides derived from myelin/oligodendrocyte glycoprotein

Previous studies have shown that immunization of the Lewis rat with myelin basic protein (MBP), an encephalitogenic antigen derived from the myelin sheath of the CNS, induced both experimental autoimmune encephalomyelitis (EAE) and anterior uveitis (AU). In the current study, we show that a major peptide derived from another encephalitogenic myelin protein—the myelin/oligodendrocyte glycoprotein (MOG35–55)—induced both encephalomyelitis and uveitis in (B6×SJL) F1 and wt-B6 mice. Pathological studies documented that an anterior uveitis was induced by MOG35–55. A similar disease pattern was induced by either active immunization with peptideMOG35–55 (pMOG35–55) or adoptive transfer of MOG35–55-specific T cells. The induced uveitis persisted for >60 days without remission. Our studies demonstrate for the first time that MOG is uveitogenic in mice that express the H-2 b genetic background. This new experimental model should provide a useful tool for the study of the pathogenesis of chronic AU and determination of the pathogenic mechanisms by which a large portion of MS patients develops uveitis.

A role for leptin in autoimmunity?

Leptin was first described as a hormone-like cytokine involved in the control of food intake. It is proposed to act as a ‘fat-o-stat’, being made by fat cells to limit food intake and promote fat breakdown. The discovery of leptin led to the hope that it might be used to treat obesity in humans because genetically obese ob/ob mice, when treated with leptin, lose weight. In humans, however, a lack of responsiveness to leptin, rather than a deficiency of leptin, might be responsible for certain types of obesity. In addition to its effects on food intake and fat metabolism, leptin has also been shown to activate CD4+ T cells via the long isoform of the leptin receptor. Structurally, leptin belongs to the helical cytokine family and its receptors belong to the hematopoeitic cytokine receptor superfamily. It therefore came as no surprise that leptin would have effects on immunity. Decreased levels of leptin during starvation or malnutrition in humans leads to immunosuppression, and chronic leptin deficiency has been shown to decrease T-helper 1 (Th1) cell responses and increase Th2 cell function.A recent report by Matarese et al. 1xRequirement for Leptin in the induction and progression of autoimmune encephalomyelitis. Matarese, G. et al. J. Immunol. 2001; 166: 5909–5961PubMedSee all References1 now indicates that leptin could be important for autoimmunity. The role of leptin in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), has been studied. Naturally, leptin-deficient mice (C57BL/6J-ob/ob) were studied for their responses to an immunodominant peptide from an oligodendrocyte glycoprotein that induces EAE in wild-type mice. The leptin-deficient mice showed no neurological impairment, either after immunization with the peptide or following the adoptive transfer of pathogenic T cells. However, chronic leptin administration in these mice made them susceptible to both treatments. When wild-type mice were treated with leptin, their disease was severely exacerbated. These effects of leptin were attributed to a pronounced Th1-type response.Therefore, it appears that leptin is required for the induction and propagation of autoimmune-mediated demyelination. This effect on the expansion and maintenance of pathogenic Th1 cells indicates that inhibition of leptin might be well worth pursuing as an immunomodulatory therapy for MS.