Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that immunization with myelin in incomplete Freund's adjuvant (IFA) is able to promote robust regeneration of corticospinal tract fibers in adult mice. In the present study the effectiveness of such immunization with myelin was compared to that of a combination of two axon growth inhibitors in myelin, Nogo-66 (the 66-amino-acid inhibitory region of Nogo-A) and myelin-associated glycoprotein (MAG). The effectiveness of two adjuvants, IFA and aluminum hydroxide (Alum), was also compared, the latter being one that can be used in humans. In addition, larger dorsal overhemisections were made at the lower thoracic level, which resulted in a larger scar. These studies were carried out in SJL/J mice, a mouse strain that is susceptible to autoimmune experimental allergic encephalomyelitis (EAE). None of the immunized mice developed EAE. Long-distance axon regeneration and sprouting of the corticospinal tract was seen in myelin and Nogo-66/MAG immunized mice. Alum was as effective or better than IFA as the adjuvant. Overall, the robustness of axon growth and sprouting was greater in mice immunized with myelin. The abundance of this growth was less than in our earlier work in which smaller lesions were made, pointing to the possible influence of inhibitors in the scar. This work shows, however, that axon growth inhibitors in myelin can be selectively blocked using this immunization approach to promote long-distance axon regeneration in the spinal cord.
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PMID:Immunization with myelin or recombinant Nogo-66/MAG in alum promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord. 1281 57

Inhibitors associated with CNS myelin are thought to be important in the failure of axons to regenerate after spinal cord injury and in other neurodegenerative disorders. Here we show that targeting the CNS-specific inhibitor of neurite outgrowth Nogo A by active immunization blunts clinical signs, demyelination and axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Mice vaccinated against Nogo A produce Nogo-specific antibodies that block the neurite outgrowth inhibitory activity associated with CNS myelin in vitro. Passive immunization with anti-Nogo IgGs also suppresses EAE. Our results identify Nogo A as an important determinant of the development of EAE and suggest that its blockade may help to maintain and/or to restore the neuronal integrity of the CNS after autoimmune insult in diseases such as MS. Our finding that Nogo A is involved in CNS autoimmune demyelination indicates that this molecule may have a far more complex role than has been previously anticipated.
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PMID:The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. 1518 1

Myelin-derived proteins, such as tenascin-R (TN-R), myelin associate glycoprotein (MAG), and Nogo-A, inhibit the CNS regeneration. By targeting specifically the inhibitory epitopes, we have investigated whether vaccination with a recombinant DNA molecule encoding multiple domains of myelin inhibitors may be useful in CNS repair. We show here that the recombinant DNA vaccine is able to activate the immune system but does not induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Importantly, it promotes axonal regeneration in a spinal cord injury model. Thus, the application of DNA vaccine, encoding multiple specific domains of major inhibitory proteins and/or their receptors, provides another promising approach to overcome the inhibitory barriers during CNS regeneration.
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PMID:Recombinant DNA vaccine encoding multiple domains related to inhibition of neurite outgrowth: a potential strategy for axonal regeneration. 1552 55

Nogo-66, the extracellular 66 aa loop of the Nogo-A protein found in CNS myelin, interacts with the Nogo receptor and has been proposed to mediate inhibition of axonal regrowth. It has been shown that immunization with Nogo-A promotes recovery in animal models of spinal cord injury through induction of Ab production. In this report, studies were performed to characterize the immune response to Nogo-66 and to determine the role of Nogo in experimental autoimmune encephalomyelitis (EAE). Immunization of EAE-susceptible mouse strains with peptides derived from Nogo-66 induced a CNS immune response with clinical and pathological similarities to EAE. The Nogo-66 peptides elicited strong T cell responses that were not cross-reactive to other encephalitogenic myelin Ags. Using a large scale spotted microarray containing proteins and peptides derived from a wide spectrum of myelin components, we demonstrated that Nogo-66 peptides also generated a specific Ab response that spreads to several other encephalitogenic myelin Ags following immunization. Nogo-66-specific T cell lines ameliorated established EAE, via Nogo-66-specific Th2 cells that entered the CNS. These results indicate that some T cell and B cell immune responses to Nogo-66 are associated with suppression of ongoing EAE, whereas other Nogo-66 epitopes can be encephalitogenic.
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PMID:Immunity to the extracellular domain of Nogo-A modulates experimental autoimmune encephalomyelitis. 1555 95

The Nogo gene products were described first as myelin-associated inhibitors that prevent neuronal regeneration upon injury. Recent findings have also implicated Nogo in several neuronal pathologies that are not induced by physical injury. Nogo-A may be an important determinant of autoimmune demyelinating diseases, as active immunization with Nogo-A fragments attenuates the symptoms of experimental autoimmune encephalomyelitis (EAE). Nogo-A levels are elevated markedly in hippocampal neurons of patients with temporal lobe epilepsy (TLE), in brain and muscle of patients with amyotrophic lateral sclerosis (ALS), and in schizophrenic patients. Concrete evidence for a direct role of Nogo-A in the latter neuropathies is not yet available, but such a role is logically in line with new findings associated with localization of Nogo-A and Nogo-Nogo-66 receptor (NgR)-mediated signaling. We speculate on possible linkages between the effect of aberrant elevation of Nogo levels and the signaling consequences that could lead to nervous system pathology.
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PMID:Nogo signaling and non-physical injury-induced nervous system pathology. 1561 32

In recent years, knowledge about the physiological functions of the Nogo-A protein has grown considerably, and this molecule has evolved from being one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin, to several other potentially important roles in different areas such as nervous system development, epilepsy, vascular physiology, muscle pathology and CNS tumors. Therapeutically, targeting the Nogo-A protein by means of the immune response has been tried in an attempt to block neurite growth inhibition and promote regeneration in spinal cord injury models; the immune response to Nogo-A, however, has not been extensively studied. We propose to review recent evidence that Nogo-A may also play an important role in autoimmune demyelinating diseases such as experimental autoimmune encephalomyelitis and multiple sclerosis, including that Nogo-66 derived epitopes are encephalitogenic antigens in susceptible mouse strains, and that the immune response to Nogo-66 antigens includes both strong T cell and B cell activation, with epitope spreading of the antibody response to other myelin molecules. In CNS immunotherapy, careful targeting of neural self-antigens is a prerequisite in order to avoid unexpected deleterious effects, and increasing knowledge about the immune response to Nogo-A may provide a safe basis for the development of relevant therapeutic alternatives for several neurological conditions.
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PMID:Nogo in multiple sclerosis: growing roles of a growth inhibitor. 1668 57

Antibodies against the neurite outgrowth inhibitor Nogo-A enhance axonal regeneration following spinal cord injury. However, antibodies directed against myelin components can also enhance CNS inflammation. The present study was designed to assess the efficacy of DNA vaccination for generating antibodies against Nogo-A and to study their pathogenic potential in a mouse model for multiple sclerosis. Mice were immunized by a single i.m. injection of a plasmid expression vector encoding either full length membrane-integral Nogo-A equipped with a signal peptide or two versions of its large N-terminal extramembrane region. The presence of serum antibodies to Nogo-A was measured 4 weeks after injection by ELISA, Western blotting and immunohistochemistry. DNA vaccination efficiently induced production of Nogo-A-specific antibodies that recognized recombinant, intracellular Nogo-A in cell culture but also stained native Nogo-A on the oligodendrocyte surface. Experimental autoimmune encephalomyelitis was induced in DNA-vaccinated mice by immunization with proteolipid peptide (a.a. 139-154). In contrast to vaccination with DNA encoding myelin oligodendrocyte glycoprotein that exacerbates this disease, Nogo-A DNA vaccination did not enhance clinical severity of disease. In summary, DNA vaccination is a simple and efficient method for generating an antibody response to Nogo-A. No pathogenicity was observed even during a full-blown inflammatory response of the central nervous system.
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PMID:DNA vaccination efficiently induces antibodies to Nogo-A and does not exacerbate experimental autoimmune encephalomyelitis. 1849 10

The etiology of multiple sclerosis (MS) has not been fully elucidated, however evidence supports an autoimmune disease model notable for the infiltration of pro-inflammatory immune cells into sites of active demyelination and axonal injury. Previous findings demonstrate that neutralization of Nogo, a protein originally identified as a myelin-associated inhibitor (MAI) of axon regeneration, ameliorates experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. More efficient axonal regeneration was suggested as a mechanism underlying the improved EAE outcome. However, neutralization of Nogo also led to an anti-inflammatory shift of T cell cytokines during EAE suggesting that another therapeutic mechanism may involve regulation of immune cell responses. Here we report that human immune cells from healthy individuals and MS patients express Nogo receptor1 (NgR1) indicating that they may be subject to regulation by MAIs. B cells, T cells and monocytes express NgR1 in a regulated fashion upon activation. While direct stimulation of human immune cells with an inhibitory fragment of Nogo does not impact their in vitro proliferation or cytokine production, the immune cells display reduced adhesion and enhanced motility in response to myelin, effects that are in part attenuated by antagonizing NgR1 signaling. We conclude that NgR1 alters the motility of immune cells exposed to myelin and may thus impact their behaviour within the CNS, particularly under conditions when immune cell activation is heightened.
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PMID:Myelin regulates immune cell adhesion and motility. 1932 85

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Despite progress in understanding immunogenetic aspects of this disease, the mechanisms involved in lesion formation are unknown. To gain new insights into the neuropathology of MS, we used an innovative integration of Fourier transform infrared (FT-IR) microspectroscopy, bioinformatics, and a synchrotron light source to analyze macromolecular changes in the CNS during the course and prevention of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. We report that subtle chemical and structural changes not observed by conventional histology were detected before the onset of clinical signs of EAE. Moreover, trained artificial neural networks (ANNs) could discriminate, with excellent sensitivity and specificity, pathology from surrounding tissues and the early stage of the disease progression. Notably, we show that this novel measurement platform can detect characteristic differences in biochemical composition of lesion pathology in animals partially protected against EAE by vaccination with Nogo-A, an inhibitor of neural outgrowth, demonstrating the potential for automated screening and evaluation of new therapeutic agents.
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PMID:Early detection of the chemical changes occurring during the induction and prevention of autoimmune-mediated demyelination detected by FT-IR imaging. 1979 90

Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4(+) Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure.
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PMID:Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis. 2209 81


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