Article

Immunity to self and self-maintenance: what can tumor immunology teach us about ALS and Alzheimer's disease?

Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 07/2008; 29(6):287-93. DOI: 10.1016/j.tips.2008.03.006
Source: PubMed

ABSTRACT Mounting evidence from the last decade has shown that the immune system not only fights pathogens but also protects the body against cancer. More recently, immune surveillance has been shown to be important for maintaining the functional integrity of the central nervous system. The immune system, however, does not always prevail; tumors do grow and eventually kill their host, and devastating neurodegenerative conditions do develop. Neurodegenerative diseases, like tumors, lie dormant long before clinical symptoms appear. We propose that at this dormant stage, an ongoing competition between the local disease-causing factors and the immune system's attempts to contain them takes place. Onset of clinical symptoms occurs after disease-causing factors escape immune surveillance. Identifying the immune escape mechanisms and circumventing them soon after the emergence of clinical symptoms could lead to the development of novel therapeutic intervention for some of the most devastating neurodegenerative disorders.

0 Followers
 · 
75 Views
  • Source
    • "In addition to activation along an inflammatory pathway, microglia can also become activated along several other pathways as well (Michelucci et al., 2009; Derecki et al., 2011). Microglia can assume a form of activation through which they maintain the health of neurons (Butovsky et al., 2006; Schwartz and Ziv, 2008b; Ekdahl et al., 2009; Kosloski et al., 2010). When in the growth promoting mode, microglia release Insulin-like growth factor-1 (IGF-1; Butovsky et al., 2005; Ekdahl et al., 2009; Kosloski et al., 2010; Schwartz and Shechter, 2010a; Ron-Harel et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper reviews both the evidence that supports the characterization of depression as an inflammatory disorder and the different biochemical mechanisms that have been postulated for the connection between inflammation and depression. This association offers credible explanation for the short term efficacy of antidepressants, which have short term anti-inflammatory effects. Evidence for those anti-inflammatory effects is discussed. Evidence of the contrary long-term effects of antidepressants, which increase rather than decrease inflammation, is also reviewed. It is argued that this increase in inflammation would predict an increase in chronicity among depressed patients that have been treated with antidepressants drugs, which has been noted in the literature. A brief discussion of alternatives for decreasing inflammation, some of which have demonstrated efficacy in ameliorating depression, is presented.
    Frontiers in Psychology 08/2012; 3:297. DOI:10.3389/fpsyg.2012.00297 · 2.80 Impact Factor
  • Source
    • "Moreover, the spontaneous recovery from CNS insults and the ability to cope with mental stress was shown to be T celldependent (Cohen et al., 2006; Kipnis et al., 2004b; Lewitus and Schwartz, 2009; Moalem et al., 1999; Yoles et al., 2001). Since basal immune maintenance is not sufficient to counteract the forces that drive neurotoxicity, boosting the protective T-cell response can be accomplished either by active immunization with the relevant self CNS antigens or via modulation of the naturally occurring T regulatory cells (Tregs), which constitutively suppress potential anti-self helper (CD4 + ) T cells (Kipnis et al., 2002; Schwartz and Ziv, 2008). One way to achieve this aim is by administration of poly-YE, a high-molecular-weight copolymer (22–45 kDa) of glutamate and tyrosine with immunomodulatory properties (Cady et al., 2000; Vidovic and Matzinger, 1988), which is able to down-regulate the suppressive properties of Tregs (Ziv et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.
    Brain Behavior and Immunity 09/2011; 26(1):159-69. DOI:10.1016/j.bbi.2011.09.002 · 6.13 Impact Factor
  • Source
    • "The peroxisome proliferatoractivated receptor gamma (PPARγ) agonist, pioglitazone, a thiazolidinedione anti-diabetic agent, with reported anti-inflammatory properties, improved muscle strength, body weight and survival as well as demonstrated delayed disease onset when compared to nontreated SOD1- G93A mice (Schutz, et al., 2005). Copaxone, an immune modulatory drug has also been shown to affect survival; however, later results have not been confirmed (Gordon, et al., 2006, Haenggeli, et al., 2007, Schwartz and Ziv, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis (ALS) are progressive and devastating disorders of the nervous system without cure. Although a number of distinct, but not mutually exclusive, mechanisms can affect disease pathogenesis, neuroinflammation stands in common. Neuroinflammatory responses occur as a consequence of oxidative and excitotoxic neuronal damage, mitochondrial dysfunction, and protein aggregation. Thus, it is believed drugs that modulate inflammation may combat disease progression. Such strategies include those commented on in the report by Arie Neymotin et al. demonstrating lenalidomide's anti-inflammatory and neuroprotective responses in the G93A mutant superoxide dismutase-1 mouse model of ALS (Neymotin et al., 2009). While anti-inflammatory interventions may be required, they may not be sufficient to positively affect clinical outcomes. The targeting of combinations of pathogenic events including clearance of disaggregated proteins together with neuroprotective and immune modulatory strategies may all be required to facilitate positive therapeutic outcomes. This may include the targeting of both innate and adaptive neurotoxic immune responses. This commentary is designed to summarize the promises and perils in achieving immunoregulation for brain homeostatic responses and inevitable therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are discussed with a particular focus on ALS.
    Experimental Neurology 03/2010; 222(1):1-5. DOI:10.1016/j.expneurol.2009.12.018 · 4.62 Impact Factor
Show more