Josephe Archie Honorat

The lactic acid bacterium Pediococcus acidilactici suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells.

Background Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is Multiple sclerosis (MS) which affects the central nervous system. We investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Methodology/Principal Findings P. acidilactici R037 was orally administered to EAE mice to investigate the effects of R037. R037 treatment suppressed clinical EAE severity as prophylaxis and therapy. The antigen-specific production of inflammatory cytokines was inhibited in R037-treated mice. A significant increase in the number of CD4+ Interleukin (IL)-10-producing cells was observed in the mesenteric lymph nodes (MLNs) and spleens isolated from R037-treated naive mice, while no increase was observed in the number of these cells in the lamina propria. Because only a slight increase in the CD4+Foxp3+ cells was observed in MLNs, R037 may primarily induce Foxp3− IL10-producing T regulatory type 1 (Tr1) cells in MLNs, which contribute to the beneficial effect of R037 on EAE. Conclusions/Significance An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing IL10-producing Tr1 cells. Our findings indicate the therapeutic potential of the oral administration of R037 for treating multiple sclerosis.

Xanthine Oxidase Mediates Axonal and Myelin Loss in a Murine Model of Multiple Sclerosis

Objectives Oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS). Though reactive oxygen species (ROS) are produced by various mechanisms, xanthine oxidase (XO) is a major enzyme generating ROS in the context of inflammation. The objectives of this study were to investigate the involvement of XO in the pathogenesis of MS and to develop a potent new therapy for MS based on the inhibition of ROS. Methods XO were assessed in a model of MS: experimental autoimmune encephalomyelitis (EAE). The contribution of XO-generated ROS to the pathogenesis of EAE was assessed by treating EAE mice with a novel XO inhibitor, febuxostat. The efficacy of febuxostat was also examined in in vitro studies. Results We showed for the first time that the expression and the activity of XO were increased dramatically within the central nervous system of EAE mice as compared to naïve mice. Furthermore, prophylactic administration of febuxostat, a XO inhibitor, markedly reduced the clinical signs of EAE. Both in vivo and in vitro studies showed infiltrating macrophages and microglia as the major sources of excess XO production, and febuxostat significantly suppressed ROS generation from these cells. Inflammatory cellular infiltration and glial activation in the spinal cord of EAE mice were inhibited by the treatment with febuxostat. Importantly, therapeutic efficacy was observed not only in mice with relapsing-remitting EAE but also in mice with secondary progressive EAE by preventing axonal loss and demyelination. Conclusion These results highlight the implication of XO in EAE pathogenesis and suggest XO as a target for MS treatment and febuxostat as a promising therapeutic option for MS neuropathology.

Dietary Yeasts Reduce Inflammation in Central Nerve System via Microflora

The intestinal microflora affects the pathogenesis of several autoimmune diseases by influencing immune system function. Some bacteria, such as lactic acid bacteria, have been reported to have beneficial effects on immune function. However, little is known about the effects of yeasts. Here, we aimed to investigate the effects of various dietary yeasts contained in fermented foods on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and to elucidate the mechanisms underlying these effects.

Sema4A inhibits the therapeutic effect of IFN-β in EAE.

Approximately one-third of patients with multiple sclerosis (MS) respond poorly to interferon-beta (IFN-β) therapy. Serum Sema4A is increased in MS patients, and those who have high Sema4A do not respond to IFN-β therapy. In this study, we investigated whether recombinant Sema4A abrogates the efficacy of IFN-β in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-β diminished the efficacy of IFN-β in EAE. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-β.

Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis

BackgroundAccumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1G93A mice).FindingsOrally administered R723 had sufficient access to spinal cord tissue of mSOD1G93A mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN- γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1 β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1G93A mice.ConclusionsJAK2 inhibitor was not effective against ALS symptoms in mSOD1G93A mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result.

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.

Neuromyelitis Optica: Diagnosis and Treatment

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system (CNS) characterized by optic neuritis and transverse myelitis. NMO is also known as Devic’s disease, after a case report by French neurologist Eugene Devic and his colleagues in the late nineteenth century. NMO has been considered a variant of multiple sclerosis (MS) and called opticospinal MS in Japan, where its prevalence is much higher than in Western countries. In 2004 however, an autoantibody, NMO-IgG (anti-aquaporin 4 antibody), was detected in the serum of patients with NMO, but not in patients with MS, indicating that NMO is independent of MS.

Reply to comment on: Dietary yeasts reduce inflammation in central nervous system via microflora

Reply to comment on: Dietary yeasts reduce inflammation in central nervous system via microflora Kazushiro Takata, Takayuki Tomita, Tatsusada Okuno, Makoto Kinoshita, Toru Koda, Josephe A. Honorat, Masaya Takei, Kouichiro Hagihara, Tomoyuki Sugimoto, Hideki Mochizuki, Saburo Sakoda & Yuji Nakatsuji* Department of Neurology, Osaka University Graduate School of Medicine D4, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan Discovery Research Laboratories, Kyorin Pharmaceutical Co., ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan Osaka General Medical Center, 3-1-56, Mandaihigashi, Sumiyoshi, Osaka, Osaka, 558-0056, Japan Research Division, Hirosaki University Graduate School of Science and Technology, 3-Bunkyocho, Hirosaki, Aomori 036-8560, Japan Department of Neurology, National Hospital Organization Toneyama, 5-5-1 Toneyama, Toyonaka, Osaka 560-8552, Japan

Neuroprotective effects of a xanthine oxidase inhibitor in progressive EAE by ameliorating mitochondrial dysfunction

devastating consequences, and others with little or no overt pathology. Adoptive immunotherapy is an approach that involves administration of anti-viral T cells and has shown promise in clinical studies for the treatment of cytomegalovirus, Epstein–Barr virus, and adenovirus infections. We model adoptive immunotherapy by transferring antiviral memory T cells into mice persistently infected from birth with lymphocytic choriomeningitis virus. Here, we demonstrate thatmemory T cells can completely purge the brain of persistently infected mice without causing blood brain barrier breakdown or tissue damage. This is accomplished by a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatorymonocytes. Interestingly, T cells enlist the support of nearly all brain resident myeloid cells (microglia) by converting them into CD11c-expressing antigen-presenting cells (APCs)— a cell population also found in the brain of a patient infected with human immunodeficiency virus. Two-photon imaging studies revealed that anti-viral CD8 T cells are more likely to decelerate and form stable interactions with brain-resident APCs than CD4 T cells. Importantly, CD11c microglia are resistant to apoptosis and do not undergo cell death following T cell engagement.We propose that non-cytopathic CNS viral clearance can be achieved by therapeutic memory T cells reliant on tailored chemoattractant production and interactions with resident myeloid cells.

Involvement of Sema4A in multiple sclerosis and neuromyelitis optica

The spinal route is considered as a treatment option for nononcologic neuropathic pain patients who have not achieved adequate Abstracts 43