The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform
Michal Schwartz - One of the best experts on this subject based on the ideXlab platform.
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Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: Boosting Autoimmunity to fight-off chronic neuroinflammation
Journal of autoimmunity, 2014Co-Authors: Michal Schwartz, Kuti BaruchAbstract:Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS). As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy. Yet, over the last decade, it became clear that Autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis. Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis. Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and Protective Autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging. Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self. Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost Protective Autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.
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Protective Autoimmunity: A Unifying Model for the Immune Network Involved in CNS Repair
The Neuroscientist : a review journal bringing neurobiology neurology and psychiatry, 2014Co-Authors: Michal Schwartz, Catarina RaposoAbstract:Immune activity in the CNS parenchyma under various acute and chronic neurodegenerative conditions has been often interpreted as a sign of pathological inflammation. The apparent resemblance of the local neuroinflammatory processes to autoimmune diseases, such as multiple sclerosis (MS), generated the view that, despite differences in etiology and pathology, neurodegenerative disorders with a local inflammatory component can benefit from systemic anti-inflammatory therapy. In addition, as CNS self-reactive T cells are associated with the etiology of MS, Autoimmunity was assumed to solely reflect pathology, and therefore, was universally linked to autoimmune disease. Yet, it is becoming increasingly clear that CNS-specific T cells, along with circulating and local innate immune cells, can enhance CNS healing processes following non-infectious injuries, or any deviation from homeostasis, including chronic pathological conditions. Here, we discuss the theory of “Protective Autoimmunity,” which describes the ...
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Protective Autoimmunity functions by intracranial immunosurveillance to support the mind: The missing link between health and disease.
Molecular psychiatry, 2010Co-Authors: Michal Schwartz, Ravid ShechterAbstract:Protective Autoimmunity functions by intracranial immunosurveillance to support the mind: The missing link between health and disease
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Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: The role of innate immunity
Neuroscience, 2008Co-Authors: Michal Schwartz, Anat London, Ravid ShechterAbstract:Our research group has been working for more than a decade on the cross-talk between the immune and the nervous systems. Due to the unique nature of the central nervous system (CNS) as an immune privileged site, it was commonly believed that the nervous system functions optimally without any immune intervention, and that any immune cell infiltration to the CNS is a sign of pathology. However, since the immune system constitutes the body's major defense and repair mechanism, it seemed unreasonable that the CNS would have completely lost the need for assistance from this system. This insight prompted us to revisit the entire question of whether immune cells are required for recovery from CNS injuries. We subsequently made numerous fundamental observations that led us to formulate a unified theory linking all neurodegenerative conditions; thus, we suggested that "T-cell immunity to self maintains the self," at least in the CNS. According to this view, immunity to self ("Protective Autoimmunity") provides a pivotal role in maintenance, protection, and repair of the healthy and diseased CNS. We further showed that the T cells mediate their effect, at least under pathological conditions, by controlling the recruitment of blood-borne monocytes, which play a crucial local role that cannot be replaced by the resident microglia. Boosting of such a T cell response specific for brain proteins, while carefully choosing the antigen, the carrier, timing, dosing, and regimen should be considered as a way of augmenting a physiological repair mechanism needed to ameliorate disease conditions while restoring equilibrium needed for protection, repair and renewal; such therapy is not intended to modify a single mediator of a single disease, but rather, would serve as an approach for adjusting the levels of the immune response needed to restore a lost balance.
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Autoimmunity and adult stem cells in CNS maintenance and repair: Implications for acute injuries, neurodegenerative diseases, and mental dysfunction
2006Co-Authors: Michal Schwartz, Hadas Schori, Hila Avidan, Oleg Butovsky, Yael Shani, Maya Koronyo, Sharon Bakalash, Michal Cardon, Gil M. Lewitus, Asia RollsAbstract:The immune system is known to be important for defense against external intruders. The possibility that immune cells also protect the body from destructive self-compounds (‘the enemy within’) was demonstrated by our group 7 years ago. We found that autoimmune T cells specific to central nervous system (CNS) autoantigens play a neuroProtective role following an injury to the CNS (Moalem et al., 1999). This phenomenon, which we termed ‘Protective Autoimmunity’, implies that there is a distinction between Autoimmunity and autoimmune disease; the former is a purposeful response needed to fight off adverse conditions (whatever their primary cause) that result from tissue damage, whereas the latter occurs when this purposeful response is out of control. According to this view, specificity to autoantigens does not imply an attack on tissues expressing these selfproteins; rather, such specificity ensures homing of T cells to sites of injury. We have established that CNS-specific T cells, provided that their activity is well controlled, interact with CNS-resident microglia to the benefit of the injured CNS (Schwartz et al., 2003). Thus, for example, immunization with myelin-associated antigens confers neuroprotection and functional recovery after contusive spinal cord injury (Hauben et
Jonathan Kipnis - One of the best experts on this subject based on the ideXlab platform.
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Bacterial DNA confers neuroprotection after optic nerve injury by suppressing CD4+CD25+ regulatory T-cell activity
Investigative ophthalmology & visual science, 2007Co-Authors: Thomas V. Johnson, Carl B. Camras, Jonathan KipnisAbstract:PURPOSE. Protective Autoimmunity attenuates secondary degeneration after central nervous system (CNS) injury. Such neuroprotection is achieved via activation of autoimmune CD4CD25 effector T cells (Teffs) or suppression of naturally occurring CD4CD25 regulatory T cells (Tregs). In this study the ability of bacterial DNA, characterized by unmethylated CpG islands, to downregulate Treg activity and therefore, to confer neuroprotection was investigated. METHODS. The effects of CpG on suppressive activity of mouse Tregs were studied by coculturing Tregs with Teffs and measuring proliferation by radiolabeled thymidine. The neuroProtective effects of CpG-mediated Treg suppression was examined in rats after optic nerve crush. RESULTS. Teff proliferation in response to T-cell receptor stimuli was significantly reduced when the Teffs were cocultured with Tregs, compared with Teff activation when cultured alone. Treating Tregs with CpG reduced their suppressive activity and restored Teff proliferation to baseline levels. CpG injection in rats with optic nerve crush conferred significant neuroprotection compared with that in untreated control rats (118 8 cells/mm 2 vs. 69 5 cells/mm 2 , respectively; mean SEM; P 0.05). CpG-mediated neuroprotection was accompanied by significantly increased T-cell infiltration at the injury site. Similar CpG treatment of athymic nude rats yielded no neuroprotection, further suggesting a T-cell-dependent mechanism of CpG action. CONCLUSIONS. These findings strongly support the notion that alleviation of Treg suppression after injury benefits neuronal survival. Bacterial DNA attenuation of Treg suppressive activity may represent an evolutionary adaptation that curbs the amplified infection risk after CNS trauma, due to blood‐brain barrier breakdown. This study may prompt development of new neuroProtective therapies aimed at the immune system, to benefit the injured CNS. (Invest Ophthalmol Vis Sci. 2007; 48:3441‐3449) DOI:10.1167/iovs.06-1351
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Protective Autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases.
Journal of the neurological sciences, 2005Co-Authors: Michal Schwartz, Jonathan KipnisAbstract:Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened Autoimmunity. We discovered that Autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of Protective Autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications. We also offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals.
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Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells.
European journal of immunology, 2004Co-Authors: Hila Avidan, Jonathan Kipnis, Oleg Butovsky, Rachel R. Caspi, Michal SchwartzAbstract:Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated beta-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4(+)CD25(+) regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with beta-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated beta-amyloid. These findings support the concept of "Protective Autoimmunity", show that a given T cell-based vaccination is Protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.
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Low-dose γ-irradiation promotes survival of injured neurons in the central nervous system via homeostasis-driven proliferation of T cells
The European journal of neuroscience, 2004Co-Authors: Jonathan Kipnis, Tal Mizrahi, Ehud Hauben, Hila Avidan, Yifat Markovich, Tatyana B. Prigozhina, Shimon Slavin, Michal SchwartzAbstract:Protective Autoimmunity was only recently recognized as a mechanism for attenuating the progression of neurodegeneration. Using a rat model of optic nerve crush or contusive spinal cord injury, and a mouse model of neurodegenerative conditions caused by injection of a toxic dose of intraocular glutamate, we show that a single low dose of whole-body or lymphoid-organ gamma-irradiation significantly improved the spontaneous recovery. Animals with severe immune deficiency or deprived of mature T cells were unable to benefit from this treatment, suggesting that the irradiation-induced neuroprotection is immune mediated. This suggestion received further support from the findings that irradiation was accompanied by an increased incidence of activated T cells in the lymphoid organs and peripheral blood and an increase in mRNA encoding for the pro-inflammatory cytokines interleukin-12 and interferon-gamma, and that after irradiation, passive transfer of a subpopulation of suppressive T cells (naturally occurring regulatory CD4(+)CD25(+) T cells) wiped out the irradiation-induced protection. These results suggest that homeostasis-driven proliferation of T cells, induced by a single low-dose irradiation, leads to boosting of T cell-mediated neuroprotection and can be utilized clinically to fight off neurodegeneration and the threat of other diseases in which defense against toxic self-compounds is needed.
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therapeutic vaccine for acute and chronic motor neuron diseases implications for amyotrophic lateral sclerosis
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Doychin N Angelov, Hadas Schori, Jonathan Kipnis, Eti Yoles, Stefan Waibel, Orlando Guntinaslichius, Mithra Lenzen, Wolfram F Neiss, Toma L Tomov, A ReuterAbstract:Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ± 7 days (n = 15) to 263 ± 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of Protective Autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.
Antonio Ibarra - One of the best experts on this subject based on the ideXlab platform.
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The Severity of Spinal Cord Injury Determines the Inflammatory Gene Expression Pattern after Immunization with Neural-Derived Peptides
Journal of Molecular Neuroscience, 2018Co-Authors: Elisa García, Adrian Flores-romero, Roxana Rodríguez-barrera, Raúl Silva-garcía, Liliana Blancas-espinoza, Antonio IbarraAbstract:Previous studies revealed that the intensity of spinal cord injury (SCI) plays a key role in the therapeutic effects induced by immunizing with neural-derived peptides (INDP), as severe injuries abolish the beneficial effects induced by INDP. In the present study, we analyzed the expression of some inflammation-related genes (IL6, IL12, IL-1β, IFNɣ, TNFα, IL-10, IL-4, and IGF-1) by quantitative PCR in rats subjected to SCI and INDP. We investigated the expression of these genes after a moderate or severe contusion. In addition, we evaluated the effect of INDP by utilizing two different peptides: A91 and Cop-1. After moderate injury, both A91 and Cop-1 elicited a pattern of genes characterized by a significant reduction of IL6, IL1β, and TNFα but an increase in IL10, IL4, and IGF-1 expression. There was no effect on IL-12 and INFɣ. In contrast, the opposite pattern was observed when rats were subjected to a severe spinal cord contusion. Immunization with either peptide caused a significant increase in the expression of IL-12, IL-1β, IFNɣ (pro-inflammatory genes), and IGF-1. There was no effect on IL-4 and IL-10 compared to controls. After a moderate SCI, INDP reduced pro-inflammatory gene expression and generated a microenvironment prone to neuroprotection. Nevertheless, severe injury elicits the expression of pro-inflammatory genes that could be aggravated by INDP. These findings correlate with our previous results demonstrating that severe injury inhibits the beneficial effects of Protective Autoimmunity.
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Protective Role of the Immune System in Spinal Cord Injury: Immunomodulation with Altered Peptide Ligands
Recovery of Motor Function Following Spinal Cord Injury, 2016Co-Authors: Paola Suarez-meade, Antonio IbarraAbstract:Spinal cord injury (SCI) is a phenomenon characterized by damage to the spinal cord and nerve roots, resulting in loss of physiological activity below the lesion. Injury to the spinal cord activates a cascade of cellular and molecular reactions in which the immune system plays an essential role, as there is an uncontrolled immune response that endows further damage to neural tissue. However, the activity of immune system at the site of injury can be modified in order to obtain a neuroProtective environment and promote SCI recovery. This strategy has been designed under the light of the innovative concept “Protective Autoimmunity” (PA) and can be stimulated with the use of altered peptide ligands (APL). Adequate immunomodulation with APL can be obtained with the peptide A91, which is a safe synthetic peptide derived from the myelin basic protein (MBP) that has proven to be effective in preclinical research. Immunization with A91 is carried out with the objective of preventing further damage and promoting neuropro‐ tection. This peptide has direct influence over SCI secondary mechanisms such as inflammation, lipid peroxidation, and apoptosis. Preclinical results suggest that immunization with A91 could be an effective treatment in the clinical field, providing a better quality of life to SCI patients.
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Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.
BMC neuroscience, 2016Co-Authors: Susana Martiñón, Elisa García-vences, Diana Toscano-tejeida, Adrian Flores-romero, Roxana Rodríguez-barrera, Manuel Ferrusquia, Rolando Hernández-muñoz, Antonio IbarraAbstract:Background After spinal cord (SC)-injury, a non-modulated immune response contributes to the damage of neural tissue. Protective Autoimmunity (PA) is a T cell mediated, neuroProtective response induced after SC-injury. Immunization with neural-derived peptides (INDP), such as A91, has shown to promote—in vitro—the production of neurotrophic factors. However, the production of these molecules has not been studied at the site of injury.
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Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats.
PloS one, 2015Co-Authors: Yolanda Cruz, Humberto Mestre, Jonathan Lorea, Jennifer Hyuna Kim-lee, Judith Herrera, Raúl Mellado, Vanesa Gálvez, Leopoldo Cuellar, Carolina Musri, Antonio IbarraAbstract:Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate Protective Autoimmunity (PA). The most renowned of these peptides is copolymer-1 (Cop-1) also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood-brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke. The aim of this work was to evaluate the effect of Cop-1 on neurogenesis and neurological recovery during the acute phase (7 days) and the chronic phase of stroke (60 days) in a rat model of transient middle cerebral artery occlusion (tMCAo). BDNF and NT-3 were quantified and infarct volumes were measured. We demonstrated that Cop-1 improves neurological deficit, enhances neurogenesis (at 7 and 60 days) in the SVZ, SGZ, and cerebral cortex through an increase in NT-3 production. It also decreased infarct volume even at the chronic phase of tMCAo. The present manuscript fortifies the support for the use of Cop-1 in acute ischemic stroke.
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Development of Protective Autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury
PloS one, 2012Co-Authors: Susana Martiñón, Elisa García, Gabriel Gutiérrez-ospina, Humberto Mestre, Antonio IbarraAbstract:Protective Autoimmunity (PA) is a physiological response to central nervous system trauma that has demonstrated to promote neuroprotection after spinal cord injury (SCI). To reach its beneficial effect, PA should be boosted by immunizing with neural constituents or neural-derived peptides such as A91. Immunizing with A91 has shown to promote neuroprotection after SCI and its use has proven to be feasible in a clinical setting. The broad applications of neural-derived peptides make it important to determine the main features of this anti-A91 response. For this purpose, adult Sprague-Dawley rats were subjected to a spinal cord contusion (SCC; moderate or severe) or a spinal cord transection (SCT; complete or incomplete). Immediately after injury, animals were immunized with PBS or A91. Motor recovery, T cell-specific response against A91 and the levels of IL-4, IFN-γ and brain-derived neurotrophic factor (BDNF) released by A91-specific T (TA91) cells were evaluated. Rats with moderate SCC, presented a better motor recovery after A91 immunization. Animals with moderate SCC or incomplete SCT showed significant T cell proliferation against A91 that was characterized chiefly by the predominant production of IL-4 and the release of BDNF. In contrast, immunization with A91 did not promote a better motor recovery in animals with severe SCC or complete SCT. In fact, T cell proliferation against A91 was diminished in these animals. The present results suggest that the effective development of PA and, consequently, the beneficial effects of immunizing with A91 significantly depend on the severity of SCI. This could mainly be attributed to the lack of TA91 cells which predominantly showed to have a Th2 phenotype capable of producing BDNF, further promoting neuroprotection.
Elisa García - One of the best experts on this subject based on the ideXlab platform.
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The Severity of Spinal Cord Injury Determines the Inflammatory Gene Expression Pattern after Immunization with Neural-Derived Peptides
Journal of Molecular Neuroscience, 2018Co-Authors: Elisa García, Adrian Flores-romero, Roxana Rodríguez-barrera, Raúl Silva-garcía, Liliana Blancas-espinoza, Antonio IbarraAbstract:Previous studies revealed that the intensity of spinal cord injury (SCI) plays a key role in the therapeutic effects induced by immunizing with neural-derived peptides (INDP), as severe injuries abolish the beneficial effects induced by INDP. In the present study, we analyzed the expression of some inflammation-related genes (IL6, IL12, IL-1β, IFNɣ, TNFα, IL-10, IL-4, and IGF-1) by quantitative PCR in rats subjected to SCI and INDP. We investigated the expression of these genes after a moderate or severe contusion. In addition, we evaluated the effect of INDP by utilizing two different peptides: A91 and Cop-1. After moderate injury, both A91 and Cop-1 elicited a pattern of genes characterized by a significant reduction of IL6, IL1β, and TNFα but an increase in IL10, IL4, and IGF-1 expression. There was no effect on IL-12 and INFɣ. In contrast, the opposite pattern was observed when rats were subjected to a severe spinal cord contusion. Immunization with either peptide caused a significant increase in the expression of IL-12, IL-1β, IFNɣ (pro-inflammatory genes), and IGF-1. There was no effect on IL-4 and IL-10 compared to controls. After a moderate SCI, INDP reduced pro-inflammatory gene expression and generated a microenvironment prone to neuroprotection. Nevertheless, severe injury elicits the expression of pro-inflammatory genes that could be aggravated by INDP. These findings correlate with our previous results demonstrating that severe injury inhibits the beneficial effects of Protective Autoimmunity.
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Development of Protective Autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury
PloS one, 2012Co-Authors: Susana Martiñón, Elisa García, Gabriel Gutiérrez-ospina, Humberto Mestre, Antonio IbarraAbstract:Protective Autoimmunity (PA) is a physiological response to central nervous system trauma that has demonstrated to promote neuroprotection after spinal cord injury (SCI). To reach its beneficial effect, PA should be boosted by immunizing with neural constituents or neural-derived peptides such as A91. Immunizing with A91 has shown to promote neuroprotection after SCI and its use has proven to be feasible in a clinical setting. The broad applications of neural-derived peptides make it important to determine the main features of this anti-A91 response. For this purpose, adult Sprague-Dawley rats were subjected to a spinal cord contusion (SCC; moderate or severe) or a spinal cord transection (SCT; complete or incomplete). Immediately after injury, animals were immunized with PBS or A91. Motor recovery, T cell-specific response against A91 and the levels of IL-4, IFN-γ and brain-derived neurotrophic factor (BDNF) released by A91-specific T (TA91) cells were evaluated. Rats with moderate SCC, presented a better motor recovery after A91 immunization. Animals with moderate SCC or incomplete SCT showed significant T cell proliferation against A91 that was characterized chiefly by the predominant production of IL-4 and the release of BDNF. In contrast, immunization with A91 did not promote a better motor recovery in animals with severe SCC or complete SCT. In fact, T cell proliferation against A91 was diminished in these animals. The present results suggest that the effective development of PA and, consequently, the beneficial effects of immunizing with A91 significantly depend on the severity of SCI. This could mainly be attributed to the lack of TA91 cells which predominantly showed to have a Th2 phenotype capable of producing BDNF, further promoting neuroprotection.
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Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury
Journal of neuroscience research, 2011Co-Authors: Elisa García, Susana Martiñón, Humberto Mestre, Nayeli Flores, Raúl Silva-garcía, Emma S. Calderón-aranda, Antonio IbarraAbstract:Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its Protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which Protective Autoimmunity promotes neuroprotection.
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Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury
Neuroscience letters, 2010Co-Authors: Antonio Ibarra, Susana Martiñón, Elisa García, Nayeli Flores, Rafael Reyes, María G. Campos, Marcial Maciel, Humberto MestreAbstract:Lipid peroxidation (LP) is one of the most harmful mechanisms developed after spinal cord (SC) injury. Several strategies have been explored in order to control this phenomenon. Protective Autoimmunity is a physiological process based on the modulation of inflammatory cells that can be boosted by immunizing with neural-derived peptides, such as A91. Since inflammatory cells are among the main contributors to lipid peroxidation, we hypothesized that Protective Autoimmunity could reduce LP after SC injury. In order to test this hypothesis, we designed two experiments in SC contused rats. First, animals were immunized with a neural-derived peptide seven days before injury. With the aim of inducing the functional elimination of CNS-specific T cells, for the second experiment, animals were tolerized against SC-protein extract and thereafter subjected to a SC injury. The lipid-soluble fluorescent products were used as an index of lipid peroxidation and were assessed after injury. Immunization with neural-derived peptides reduced lipid peroxidation after SC injury. Functional elimination of CNS-specific T cells avoided the beneficial effect induced by Protective Autoimmunity. The present study demonstrates the beneficial effect of immunizing with neural-derived peptides on lipid peroxidation inhibition; besides this, it also provides evidence on the neuroProtective mechanisms exerted by Protective Autoimmunity.
Humberto Mestre - One of the best experts on this subject based on the ideXlab platform.
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Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats.
PloS one, 2015Co-Authors: Yolanda Cruz, Humberto Mestre, Jonathan Lorea, Jennifer Hyuna Kim-lee, Judith Herrera, Raúl Mellado, Vanesa Gálvez, Leopoldo Cuellar, Carolina Musri, Antonio IbarraAbstract:Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate Protective Autoimmunity (PA). The most renowned of these peptides is copolymer-1 (Cop-1) also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood-brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke. The aim of this work was to evaluate the effect of Cop-1 on neurogenesis and neurological recovery during the acute phase (7 days) and the chronic phase of stroke (60 days) in a rat model of transient middle cerebral artery occlusion (tMCAo). BDNF and NT-3 were quantified and infarct volumes were measured. We demonstrated that Cop-1 improves neurological deficit, enhances neurogenesis (at 7 and 60 days) in the SVZ, SGZ, and cerebral cortex through an increase in NT-3 production. It also decreased infarct volume even at the chronic phase of tMCAo. The present manuscript fortifies the support for the use of Cop-1 in acute ischemic stroke.
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Development of Protective Autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury
PloS one, 2012Co-Authors: Susana Martiñón, Elisa García, Gabriel Gutiérrez-ospina, Humberto Mestre, Antonio IbarraAbstract:Protective Autoimmunity (PA) is a physiological response to central nervous system trauma that has demonstrated to promote neuroprotection after spinal cord injury (SCI). To reach its beneficial effect, PA should be boosted by immunizing with neural constituents or neural-derived peptides such as A91. Immunizing with A91 has shown to promote neuroprotection after SCI and its use has proven to be feasible in a clinical setting. The broad applications of neural-derived peptides make it important to determine the main features of this anti-A91 response. For this purpose, adult Sprague-Dawley rats were subjected to a spinal cord contusion (SCC; moderate or severe) or a spinal cord transection (SCT; complete or incomplete). Immediately after injury, animals were immunized with PBS or A91. Motor recovery, T cell-specific response against A91 and the levels of IL-4, IFN-γ and brain-derived neurotrophic factor (BDNF) released by A91-specific T (TA91) cells were evaluated. Rats with moderate SCC, presented a better motor recovery after A91 immunization. Animals with moderate SCC or incomplete SCT showed significant T cell proliferation against A91 that was characterized chiefly by the predominant production of IL-4 and the release of BDNF. In contrast, immunization with A91 did not promote a better motor recovery in animals with severe SCC or complete SCT. In fact, T cell proliferation against A91 was diminished in these animals. The present results suggest that the effective development of PA and, consequently, the beneficial effects of immunizing with A91 significantly depend on the severity of SCI. This could mainly be attributed to the lack of TA91 cells which predominantly showed to have a Th2 phenotype capable of producing BDNF, further promoting neuroprotection.
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Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury
Journal of neuroscience research, 2011Co-Authors: Elisa García, Susana Martiñón, Humberto Mestre, Nayeli Flores, Raúl Silva-garcía, Emma S. Calderón-aranda, Antonio IbarraAbstract:Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its Protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which Protective Autoimmunity promotes neuroprotection.
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Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury
Neuroscience letters, 2010Co-Authors: Antonio Ibarra, Susana Martiñón, Elisa García, Nayeli Flores, Rafael Reyes, María G. Campos, Marcial Maciel, Humberto MestreAbstract:Lipid peroxidation (LP) is one of the most harmful mechanisms developed after spinal cord (SC) injury. Several strategies have been explored in order to control this phenomenon. Protective Autoimmunity is a physiological process based on the modulation of inflammatory cells that can be boosted by immunizing with neural-derived peptides, such as A91. Since inflammatory cells are among the main contributors to lipid peroxidation, we hypothesized that Protective Autoimmunity could reduce LP after SC injury. In order to test this hypothesis, we designed two experiments in SC contused rats. First, animals were immunized with a neural-derived peptide seven days before injury. With the aim of inducing the functional elimination of CNS-specific T cells, for the second experiment, animals were tolerized against SC-protein extract and thereafter subjected to a SC injury. The lipid-soluble fluorescent products were used as an index of lipid peroxidation and were assessed after injury. Immunization with neural-derived peptides reduced lipid peroxidation after SC injury. Functional elimination of CNS-specific T cells avoided the beneficial effect induced by Protective Autoimmunity. The present study demonstrates the beneficial effect of immunizing with neural-derived peptides on lipid peroxidation inhibition; besides this, it also provides evidence on the neuroProtective mechanisms exerted by Protective Autoimmunity.
