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Human Multiple Sclerosis (human + multiple_sclerosis)
Selected AbstractsDistinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuliGLIA, Issue 3 2007Pamela A. Carpentier Abstract Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis. © 2006 Wiley-Liss, Inc. [source] Interleukin-4 and interleukin-10 modulate nuclear factor ,B activity and nitric oxide synthase-2 expression in Theiler's virus-infected brain astrocytesJOURNAL OF NEUROCHEMISTRY, Issue 6 2002Eduardo Molina-Holgado Abstract In brain astrocytes, nuclear factor ,B (NF-,B) is activated by stimuli that produce cellular stress causing the expression of genes involved in defence, including the inducible nitric oxide synthase (NOS-2). Theiler's murine encephalomyelitis virus (TMEV) induces a persistent CNS infection and chronic immune-mediated demyelination, similar to human multiple sclerosis. The cytokines interleukin (IL)-4 and IL-10 inhibit the expression of proinflammatory cytokines, counteracting the inflammatory process. Our study reports that infection of cultured astrocytes with TMEV resulted in a time-dependent phosphorylation of I,B,, degradation of I,B, and I,B,, activation of NF-,B and expression of NOS-2. The proteasome inhibitor MG-132 blocked TMEV-induced nitrite accumulation, NOS-2 mRNA expression and phospho-I,B, degradation, suggesting NF-,B-dependent NOS-2 expression. Pretreatment of astrocytes with IL-4 or IL-10 decreased p65 nuclear translocation, NF-,B binding activity and NOS-2 transcription. IL-4 and IL-10 caused an accumulation of I,B, in TMEV-infected astrocytes without affecting I,B, levels. The I,B kinase activity and the degradation rate of both I,Bs were not modified by either cytokine, suggesting de novo synthesis of I,B,. Indeed, IL-4 or IL-10 up-regulated I,B, mRNA levels after TMEV infection. Therefore, the accumulation of I,B, might impair the translocation of the NF-,B to the nucleus, mediating the inhibition of NF-,B activity. Overall, these data suggest a novel mechanism of action of IL-4 and IL-10, which abrogates NOS-2 expression in viral-infected glial cells. [source] Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates,ANNALS OF NEUROLOGY, Issue 3 2009Stefano Pluchino MD Objective Transplanted neural stem/precursor cells (NPCs) display peculiar therapeutic plasticity in vivo. Although the replacement of cells was first expected as the prime therapeutic mechanism of stem cells in regenerative medicine, it is now clear that transplanted NPCs simultaneously instruct several therapeutic mechanisms, among which replacement of cells might not necessarily prevail. A comprehensive understanding of the mechanism(s) by which NPCs exert their therapeutic plasticity is lacking. This study was designed as a preclinical approach to test the feasibility of human NPC transplantation in an outbreed nonhuman primate experimental autoimmune encephalomyelitis (EAE) model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the standard laboratory rodent. Methods We examined the safety and efficacy of the intravenous (IV) and intrathecal (IT) administration of human NPCs in common marmosets affected by human myelin oligodendrocyte glycoprotein 1-125,induced EAE. Treatment commenced upon the occurrence of detectable brain lesions on a 4.7T spectrometer. Results EAE marmosets injected IV or IT with NPCs accumulated lower disability and displayed increased survival, as compared with sham-treated controls. Transplanted NPCs persisted within the host central nervous system (CNS), but were also found in draining lymph nodes, for up to 3 months after transplantation and exhibited remarkable immune regulatory capacity in vitro. Interpretation Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in nonhuman primates without overt side effects. Immune regulation (rather than neural differentiation) is suggested as the major putative mechanism by which NPCs ameliorate EAE in vivo. Our findings represent a critical step toward the clinical use of human NPCs in MS. Ann Neurol 2009;66:343,354 [source] Delineating the impact of neuroantigen vs genetic diversity on MP4-induced EAE of C57BL/6 and B6.129 miceAPMIS, Issue 12 2009STEFANIE KUERTEN MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS) that encompasses both a time-dependent attack on central nervous system (CNS) regions and a B cell component, mirroring important features of human multiple sclerosis. Comparing C57BL/6 with B6.129 mice immunized with MP4, we point out similarities regarding these hallmarks and thus propose that they are largely dependent on the nature of the MP4 antigen itself, while differences between the two strains suggest that additional fine-tuning is brought about by the genetic repertoire of the animal. Overall, our data imply that (i) the interplay between both the antigenic trigger and genetic variables can define the outcome of MP4-induced autoimmune encephalomyelitis in C57BL/6 and B6.129 mice and (ii) that MP4 is not only a strong neuroantigen when it comes to reproducing the dynamics in effector mechanisms as is typical of the disease but also a promising agent for studying interindividual heterogeneity derived from genetic diversity in EAE/MS. [source] | |||||||||||||