Biomedical subjects

Michal Schwartz

Publications and source records attributed to Michal Schwartz.

62 records · Page 4Linked to original sources

PubMed2002

Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders.

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other. One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases. We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a 'universal antigen' by weakly activating a wide spectrum of self-reactive T cells.

Animals↗

PubMed2002

Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicity.

Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell-mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate-induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell-dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA-receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell-dependent endogenous protection, NMDA receptor antagonist reduced the glutamate-induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with alpha2-adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl-2, or DAP-kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate-induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA-antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low.

Animals↗

PubMed2002

Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity?

Immune cells have been shown to contribute to spontaneous recovery from central nervous system (CNS) injury. Here we show that adult female rats and mice recover significantly better than their male littermates from incomplete spinal cord injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult mice deprived of mature T cells. After spinal cord contusion in adult rats, functional recovery (measured by locomotor scores in an open field) was significantly worse in females treated with dihydrotestosterone prior to the injury than in placebo-treated controls, and significantly better in castrated males than in their noncastrated male littermates. Post-traumatic administration of the testosterone receptor antagonist flutamide promoted the functional recovery in adult male rats. These results, in line with the known inhibitory effect of testosterone on cell-mediated immunity, suggest that androgen-mediated immunosuppression plays a role in ISCI-related immune dysfunction and can therefore partly explain the worse outcome of ISCI in males than in female. We suggest that females, which are more prone to develop autoimmune response than males, benefit from this response in cases of CNS insults.

Androgen Antagonists↗

PubMed2002

Autoimmunity as the body's defense mechanism against the enemy within: Development of therapeutic vaccines for neurodegenerative disorders.

Insults to the central nervous system (CNS), whether of microbial or microbe-free origin, result in tissue damage. Until recently, it was generally believed that only microbe-related damage elicits an adaptive immune response, the purpose of which is to eliminate the offending microorganisms. Recent studies in the author's laboratory suggest, however, that the body exhibits an adaptive immune response to microbe-free injuries as well. The immune response in this case is directed against dominant self-antigens residing in the damaged site, where such an adaptive anti-self immune response reinforces the protective activity of local resident cells by providing them with factors that can augment and regulate their capacity for buffering troublemakers such as destructive self-compounds emerging from the injured neural tissue. Because the specificity of this autoimmune response apparently depends not on the type but on the site of lesion, the response can be boosted by therapeutic vaccination for acute and chronic neurodegenerative conditions irrespective of their primary etiology. The results have far-reaching implications, both for microbial infections and for neurodegenerative diseases of the CNS.

Autoimmunity↗

PubMed2002

Neuroprotective effect of memantine in different retinal injury models in rats.

PURPOSE: To evaluate the neuroprotective effect of memantine, an NMDA receptor channel blocker, in two retinal ganglion cell (RGC) injury models in rats. METHODS: Neuroprotective effect of memantine was tested in partial optic nerve injury and chronic ocular hypertensive models. In the optic nerve injury model, memantine (0.1 - 30 mg/kg) was injected intraperitoneally immediately after injury. Two weeks later, optic nerve function was determined by measuring compound action potential and surviving RGC was determined by retrograde labeling with dextran tetramethyl rhodamine. Chronic ocular hypertension was attained by laser photocoagulation of episcleral and limbal veins. Memantine (5 or 10 mg/kg) was administered continuously each day with an osmotic pump, either immediately after or 10 days after first laser photocoagulation, for 3 weeks, after which RGC survival was determined. RESULTS: Two weeks after partial optic nerve injury, there was approximately 80% reduction in RGC number. Memantine (5 mg/kg) caused a twofold increase in compound action potential amplitude and a 1.7-fold increase in survival of RGCs, respectively. In the chronic ocular hypertension model there was 37% decrease in RGCs after 3 weeks of elevated intraocular pressure. Memantine (10 mg/kg daily) reduced ganglion cell loss to 12% when applied immediately after first laser photocoagulation, and prevented any further loss when applied 10 days after first laser photocoagulation. CONCLUSION: The protective effect of memantine suggests that excessive stimulation of NMDA receptors by glutamate is involved in causing cell damage in these RGC injury models.

Action Potentials↗

PubMed2002

Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: a paradigm shift.

Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.

Animals↗

PubMed2002

Resistance of retinal ganglion cells to an increase in intraocular pressure is immune-dependent.

PURPOSE: Glaucoma is widely accepted as a neurodegenerative disease in which retinal ganglion cell (RGC) loss is initiated by a primary insult to the optic nerve head, caused, for example, by increased intraocular pressure (IOP). In some cases, the surviving RGCs, despite adequate IOP control, may continue to degenerate as a result of their heightened susceptibility to self-destructive processes evoked by the initial damage. In animal models of mechanical or biochemical injury to the optic nerve or retina, a T-cell-mediated immune response evoked by the insult helps to reduce this ongoing loss. The current study was conducted to find out whether the ability to resist the IOP-induced loss of RGCs in a rat model is affected by the immune system. METHODS: The ocular veins and limbal plexus of rats of two strains differing in their resistance to experimental autoimmune encephalomyelitis (EAE) and in their ability to manifest a beneficial autoimmune response were laser irradiated twice to induce an increase in IOP. The pressure was measured weekly, and RGC losses were assessed 3 and 6 weeks after the first irradiation. To verify the existence of a relationship between the immune system and RGC survival, we assessed neuronal survival in Sprague-Dawley (SPD) rats devoid of mature T cells as well as after transferring splenocytes from Fisher rats, an EAE-resistant rat strain capable of manifesting T-cell-mediated neuroprotection, to rats of a major histocompatibility complex (MHC)-matched EAE-susceptible strain (Lewis), in which the ability to manifest such protective immunity is limited. RESULTS: Both 3 and 6 weeks after the increase in IOP was initiated, the number of surviving RGCs in SPD rats, a strain in which a beneficial autoimmune response can be evoked spontaneously, was significantly higher than in Lewis rats. Moreover, in SPD rats that were thymectomized at birth, the number of surviving RGCs after an increase in IOP as adults was significantly diminished. Passive transfer of splenocytes from Fisher rats to Lewis rats significantly reduced the IOP-induced loss of RGCs in the latter. CONCLUSIONS: In rats of different strains, a similar increase in IOP results in differing amounts of RGC loss. This disparity was found to correlate with immune potency. These findings may explain why patients with glaucoma experience different degrees of visual loss after pressure reduction, even when the severity of the disease at the time of diagnosis is similar. The results have far-reaching prognostic and therapeutic implications.

Animals↗

PubMedDate not supplied

Immune-based therapy for spinal cord repair: autologous macrophages and beyond.

Spinal cord injury is a devastating condition of the central nervous system (CNS), often resulting in severe loss of tissue, functional impairment, and only limited repair. Studies over the last few years have shown that response to the insult and spontaneous attempts at repair are multiphasic processes, with varying and sometimes conflicting requirements. This knowledge has led to novel strategies of therapeutic intervention. Our view is that a pivotal role in repair, maintenance, healing, and cell renewal in the CNS, as in other tissues, is played by the immune system. The mode and timing of intervention must be carefully selected, however, as the capacity of the CNS to tolerate local repair mechanisms is limited. Studies have shown that the spontaneously evoked early innate response to CNS injury is characterized by invasion of neutrophils and is unfavorable for cell survival. This is followed by a response of the resident innate immune cells (microglia), which however cannot supply all the needs of the damaged tissue; moreover, once evoked, and for as long as the damage persists, the microglial response remains beyond the capacity of the CNS to tolerate it. Immune-based clinical intervention is most effective in improving functional and morphological recovery when delayed for a certain period. Effective intervention might be in the form of (1) local injection of "alternatively activated" macrophages, (2) systemic injection of dendritic cells specific to CNS antigens, or (3) T-cell-based vaccination. The treatment of choice depends on the severity of the insult, the site of injury, the therapeutic window, and safety considerations.

Animals↗