Search PubMed⌕ Search

Biomedical subjects

Michal Schwartz

Publications and source records attributed to Michal Schwartz.

At least 37 records · Page 2Linked to original sources
PubMed2005

Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective.

'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.

Amyloid beta-Peptides↗
PubMed2005

Lessons for glaucoma from other neurodegenerative diseases: can one treatment suit them all?

The past decade has seen growing acceptance that glaucoma should be viewed as a slowly progressive neurodegenerative disease. According to this view, in glaucoma (as in other such diseases), whatever the primary risk factors, at any given time some neurons are still healthy but are threatened with destruction owing to the toxicity emanating from the degenerating neurons. It follows that any intervention that protects surviving neurons and rescues the marginally damaged ones should slow down progression of the disease. This novel view of glaucoma prompted scientists to compare glaucoma with other neurodegenerative diseases with respect to mediators of disease progression and ways in which the spread of damage, or 'secondary degeneration', can be attenuated. Studies of partial crush injury of the rat optic nerve, a model of secondary degeneration established in our laboratory, led us to conceptualize the 'enemy within' as a flood of neurotoxic self-compounds issuing from the degenerating nerve. With this model, pharmacological and molecular approaches were employed to identify and test potentially therapeutic neuroprotective compounds and methodologies, leading us ultimately to the serendipitous discovery of protective autoimmunity as the body's defense against destructive self-compounds. Mediators of self-perpetuating acute and chronic degeneration identified in the injured optic nerve were also detected in other sites of central nervous system (CNS) damage. This finding led scientists to screen drugs that had proven to be beneficial in other disease models for their use in glaucoma therapy. It also opened the way to studies of the direct effects of these toxic mediators on retinal ganglion cell survival and ways to prevent the degenerative outcome. Although no single model can fully simulate human glaucoma or any other neurodegenerative disease, the availability of different models of optic nerve damage and the similarity of findings in the optic nerve and in other parts of the CNS have led to significant progress toward development of a cure for glaucoma.

Animals↗
PubMed2005

Therapeutic T cell-based vaccination for neurodegenerative disorders: the role of CD4+CD25+ regulatory T cells.

A well-controlled local immune response is needed for recovery from CNS injury, and autoimmune T cells play a key role in mediating this response. Autoimmunity, at least in the context of the CNS, is the body's fighting force against self-derived destructive compounds, and "tolerance to self" (traditionally though mistakenly equated with nonresponsiveness) should be viewed as the ability to tolerate autoimmune responses without developing an autoimmune disease. This physiological repair mechanism is controlled by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg cells), with an on/off switch regulated by brain-derived compounds. We suggest that ongoing neurodegeneration after acute injuries results from insufficiency of the endogenous fighting force, and chronic neurodegenerative diseases reflect age-related deterioration of the body's two principal regulators: the central nervous system (CNS) and the immune system. If so, then the restoration or boosting of immune function might bridge the gap between such manifestations of CNS-related risk factors and the defensive capacity of the immune system. Boosting of peripheral immunity by the use of weak agonists of CNS self-antigens, might offer a promising potential therapy for different neurodegenerative conditions. This could be accomplished either by vaccination with a universal weak T cell-reactive antigen or with altered peptide ligands of self-antigens, or by weakening the suppressive effect of autoimmunity (e.g., by eliminating Treg cells). T cells that home to the damaged CNS might then help restore local homeostasis by controlling the local microglial response. Because neurodegenerative diseases possess common features (deriving from the local chaos), the same vaccine might protect against several different disorders associated with impaired motor, sensory, cognitive, or mental functions of the brain.

Animals↗
PubMed2005

Controlled autoimmunity in CNS maintenance and repair: naturally occurring CD4+CD25+ regulatory T-Cells at the crossroads of health and disease.

T-cells directed to self-antigens ("autoimmune" T-cells) have traditionally been perceived as tending to attack the body's own tissues, and likely to exert their destructive effects unless they undergo deletion in the thymus during ontogeny. Naturally occurring CD4+CD25+ regulatory T-cells were viewed as thymus-derived cells that constitutively suppress any autoimmune T-cells that escaped thymic deletion. Studies in recent years suggest, however, that some autoimmune T-cells are necessary, at least in the central nervous system for neural maintenance and repair, possibly in part by rendering the resident microglia capable of fighting off adverse conditions, as well as for neural maintenance and repair. In line with this notion, the regulatory T-cells are thought to allow autoimmunity to exist in healthy individuals without causing an autoimmune disease. This proposed immune scenario and its implications for therapy are discussed.

Animals↗
PubMed2005

Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results.

OBJECT: A Phase I, open-label nonrandomized study was conducted to assess the safety and tolerability of incubated autologous macrophages administered to patients with acute complete spinal cord injury (SCI). METHODS: This therapy was first tested in rat models of spinal cord transection and contusion, in which it was shown to promote motor recovery. The procedure developed for clinical use consists of isolating monocytes from patient blood and incubating them ex vivo with autologous dermis. The resulting incubated autologous macrophages were injected into the patient's spinal cord immediately caudal to the lesion within 14 days of injury. Patients underwent preoperative and follow-up neurological assessment (American Spinal Injury Association [ASIA] standards), electrophysiological monitoring (motor evoked and/or somatosensory evoked potentials), magnetic resonance imaging, and safety monitoring. Before macrophage administration, complete neurological functional loss (ASIA Grade A) was confirmed in all patients. Of the eight patients in the study, three recovered clinically significant neurological motor and sensory function (ASIA Grade C status). During the study period, some adverse events were encountered, the most serious of which involved two cases of pulmonary embolism and one case of osteomyelitis that were treated and resolved without further complication. These and other adverse events appear to be similar to those encountered in other spinal cord-injured patients and are not considered a consequence of the experimental therapy. CONCLUSIONS: It is concluded that incubated autologous macrophage cell therapy is well tolerated in patients with acute SCI. Further clinical evaluation is warranted.

Acute Disease↗
PubMed2004

Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia.

Autoimmune CD4(+) T cells can mediate the ability to withstand neurodegenerative conditions. Here we show that the ability to spontaneously manifest a T cell-dependent protective response is restricted by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg); depletion of Treg was beneficial in two mouse strains (C57BL/6J and BALB/c/OLA) differing in their spontaneous T cell-dependent ability to withstand the consequences of optic nerve injury. Passive transfer of exogenous Treg was destructive in BALB/c/OLA mice (which can spontaneously manifest a T cell-dependent protective anti-self response to injury) but beneficial in C57BL/6J mice (which have only limited ability to manifest such a response). This dichotomy was resolved by the finding that, in severe combined immunodeficient mice, a beneficial effect is obtained by passive transfer of either Treg-free CD4(+) T cells (Teff) or Treg alone, indicating that neuroprotection can be achieved by either Treg or Teff in the absence of the other. We attribute these disparate effects of Treg to their differential interaction (in part via IL-10 and transforming growth factor beta) with local innate immune cells (microglia) in the presence and in the absence of effector T cells. Activation of microglia by pro- and antiinflammatory cytokines in suitably controlled amounts might trigger different signal transduction pathways, each of which induces a neuroprotective microglial phenotype. These results suggest that, under neurodegenerative conditions, the effects of Treg, and possibly also of other regulatory T cells, might not be uniform, and that their expression in different individuals might be genetically determined. Therefore, therapeutic intervention based on induction of regulatory T cells might have limitations.

Animals↗
PubMed2004

Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration.

Fighting off neuronal degeneration requires a well controlled T-cell response against self-antigens residing in sites of the CNS damage. The ability to evoke this response is normally suppressed by naturally occurring CD4+CD25+ regulatory T-cells (Treg). No physiological compound that controls Treg activity has yet been identified. Here, we show that dopamine, acting via type 1 dopamine receptors (found here to be preferentially expressed by Treg), reduces the suppressive activity and the adhesive and migratory abilities of Treg. Treg activity was correlated with activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway. Systemic injection of dopamine or an agonist of its type 1 receptors significantly enhanced, via a T-cell-dependent mechanism, protection against neuronal death after CNS mechanical and biochemical injury. These findings shed light on the physiological mechanisms controlling Treg and might open the way to novel therapeutic strategies for downregulating Treg activity (e.g., in neuronal degeneration) or for strengthening it (in autoimmune diseases).

Animals↗
PubMed2004

T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.

Amphetamine↗
PubMed2004

Autoimmunity as an immune defense against degenerative processes: a primary mathematical model illustrating the bright side of autoimmunity.

Self-tolerance, or the ability of the immune system to refrain from destroying the organism's own tissues, is a prerequisite for proper immune system operation. How such self-tolerance is achieved is still a subject of debate. The belief that autoimmunity poses a continuous threat to the organism was challenged by data demonstrating that autoimmunity has a protective function after traumatic injury to the central nervous system. This finding led us to suggest the 'comprehensive immunity' approach by which autoimmunity is viewed as a special case of immunity, namely as a defense mechanism that operates by fighting against the threat of potential destructive activity originated or mediated within the organism, similarly to the immune defense that operates against the threat from exogenous pathogens. We present a primary mathematical spatio-temporal model that supports this concept. The numerical solutions of this model illustrate the beneficial operation of a well-controlled immune response specific to self-antigens residing in the site of lesion. The model also explains how the response to self might be tolerated on a day-to-day basis. In addition, we demonstrate that the same autoimmune response, operating at different levels of regulation, can lead to either an autoimmune disease or a degenerative disorder. This preliminary qualitative model supports our contention that the way autoimmunity is perceived should be revised.

Animals↗
PubMed2004

Vaccination for glaucoma: dream or reality?

Glaucoma is a neurodegenerative disease of the optic nerve, which continues to progress even if the primary cause of degeneration is identified and alleviated. At any given time the affected optic nerve contains fibers that are amenable to neuroprotection, and will escape degeneration provided that the proper pharmacological or other intervention is applied. Autoimmunity has long been viewed as a deleterious phenomenon that should be terminated or at least minimized in order to preserve health. We recently demonstrated, however, that T cells specific to self-proteins residing in the site of CNS insult can be protective. With the aim of boosting autoimmunity for neuroprotection without risking the induction of an autoimmune disease, we developed the use of Cop-1 (an FDA-approved drug for the treatment of multiple sclerosis) as an active vaccination for neuroprotection. Cop-1 is a synthetic polymer that weakly cross-reacts with a wide range of self-reacting T cells. Vaccination with Cop-1 resulted in significant neuroprotection in rat models of optic nerve crush and chronic glaucoma. Thus, boosting of a T cell-based mechanism, which we have termed 'protective autoimmunity', promotes recovery of the damaged optic nerve. Current studies in our laboratory are aimed at translating this treatment into a clinical therapy.

Animals↗
PubMed2004

Optic nerve crush: protection and regeneration.

In neurodegenerative disorders, as well as in acute central nervous system (CNS) injuries, the initial impairment triggers a cascade of destructive events, collectively termed secondary degeneration, which eventually cause much more extensive damage. To investigate the process of secondary degeneration and ways to prevent it, we designed a well-calibrated model of optic nerve crush injury. Until recently, the main purpose of the immune system was thought to be protection of the body against alien pathogens. Since mechanical or biochemical insults do not involve exogenous pathogens, recruitment of the adaptive immune system was not considered relevant in such cases. We recently demonstrated, however, that a T-cell-mediated immune response directed against self-antigens residing in the site of damage can be beneficial for the injured optic nerve or spinal cord. This protective autoimmune response was found to be spontaneously evoked in some individuals, but not strongly enough to significantly affect recovery. Our aim was to boost this protective response in those individuals capable of spontaneously manifesting it, and to induce it in those incapable of manifesting it spontaneously. Optimal functional recovery requires the application of a proper combination of neuroprotection and neuroregeneration.

Animals↗
PubMed2004

Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells.

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.

Amyloid beta-Peptides↗
PubMed2004

Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system.

After an injury to the central nervous system (CNS), activated microglia have been shown to contribute to the ongoing destructive processes leading to secondary neuronal degeneration. They can, however, also express neuroprotective activity. Studies from our laboratory point to the existence of a physiological T cell-mediated neuroprotective mechanism (adaptive immunity) that is amenable to boosting. We postulate that the beneficial or destructive outcome of the local microglial (innate) response is determined by a well-controlled dialog between the innate and the adaptive immune players. Here, we show that spontaneous or exogenously boosted T cell-mediated neuroprotection is correlated with early activation of microglia as antigen-presenting cells. We suggest that such microglial activity, if well controlled, is a crucial step in determining the fate of the neurons in a hostile environment.

Animals↗
PubMed2004

A common vaccine for fighting neurodegenerative disorders: recharging immunity for homeostasis.

Neurodegenerative conditions share common primary risk factors and mediators of disease progression. Because many degenerative disorders are age related, deteriorating immunity in aging patients might impose additional risk. Adaptive (T-cell-mediated) immunity is a defense mechanism that instructs microglia to fight off and clear away self-derived enemies. Such adaptive immunity can be boosted, without risking the development of autoimmune disease, by injecting weak agonists of self-antigens or by weakening the suppressive CD4+CD25+ regulatory T cells. If widely cross-reactive, the agonist might effectively counteract a variety of neurodegenerative disorders. Boosting of relevant T cells by vaccination could thus "recharge" a deteriorating immune system that has to contend with an increasing number of risk factors.

Animals↗
PubMed2004

The therapeutic window after spinal cord injury can accommodate T cell-based vaccination and methylprednisolone in rats.

Immune system activity has traditionally been considered harmful for recovery after spinal cord injury (SCI). Recent evidence suggests, however, that immune activity--and specifically autoimmune activity--is evoked by the insult, is beneficial if properly regulated and is amenable to boosting. Thus, for example, vaccination with an altered peptide ligand derived from myelin basic protein reduces the progressive degeneration of neurons that escaped the initial insult, thereby promoting recovery after SCI. As the steroid drug methylprednisolone (MP) is currently the only treatment available for patients with SCI, our purpose in the present study was to examine the mutual compatibility of the two treatments within the post-traumatic therapeutic window. We show, using rats of two different strains, that if MP is injected concomitantly with the therapeutic vaccination, the beneficial effect of the vaccination is diminished. However, if MP is given immediately after the insult and the vaccination 48 h later, MP does not detract from the beneficial effect of the vaccination. These results demonstrate that the therapeutic window after SCI can accommodate immediate administration of MP plus a delayed therapeutic vaccination.

Analysis of Variance↗
PubMed2004

Low-dose gamma-irradiation promotes survival of injured neurons in the central nervous system via homeostasis-driven proliferation of T cells.

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.

Animals↗
PubMed2004

A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice.

Chondroitin sulphate proteoglycan (CSPG) inhibits axonal regeneration in the central nervous system (CNS) and its local degradation promotes repair. We postulated that the enzymatic degradation of CSPG generates reparative products. Here we show that an enzymatic degradation product of CSPG, a specific disaccharide (CSPG-DS), promoted CNS recovery by modulating both neuronal and microglial behaviour. In neurons, acting via a mechanism that involves the PKCalpha and PYK2 intracellular signalling pathways, CSPG-DS induced neurite outgrowth and protected against neuronal toxicity and axonal collapse in vitro. In microglia, via a mechanism that involves ERK1/2 and PYK2, CSPG-DS evoked a response that allowed these cells to manifest a neuroprotective phenotype ex vivo. In vivo, systemically or locally injected CSPG-DS protected neurons in mice subjected to glutamate or aggregated beta-amyloid intoxication. Our results suggest that treatment with CSPG-DS might provide a way to promote post-traumatic recovery, via multiple cellular targets.

Animals↗