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: 11.54). 07/2008; 29(6):287-93. DOI: 10.1016/
Source: PubMed


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.

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    • "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). "
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    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
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    • "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). "
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    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 · 5.89 Impact Factor
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    • "The local inflammation in ALS, together with the compromised protective immune response [10], [13], encouraged us to search for novel immunoregulatory targets in this disease. The reported reduction of NKT cells in inflammatory autoimmune diseases [23], [25], [26], on one hand, and the need for autoimmune protective T cells in non-inflammatory neurodegenerative diseases such as ALS [27], on the other hand, prompted us to analyze the fate of these cells in ALS. We first examined whether there is any homing of NKT cells to the affected spinal cord of C57Bl/SJL mSOD1 mice, and found that their proportion increased significantly at the clinical end-stage of the disease (Fig. 1A). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4(+) T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.
    PLoS ONE 08/2011; 6(8):e22374. DOI:10.1371/journal.pone.0022374 · 3.23 Impact Factor
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