Production of Neurotrophins by Activated T Cells: Implications for Neuroprotective Autoimmunity

Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Journal of Autoimmunity (Impact Factor: 8.41). 12/2000; 15(3):331-45. DOI: 10.1006/jaut.2000.0441
Source: PubMed


Neurotrophins (NTs) promote neuronal survival and maintenance during development and after injury. However, their role in the communication between the nervous system and the immune system is not yet clear. We observed recently that passively transferred activated T cells of various antigen specificities home to the injured central nervous system (CNS), yet only autoimmune T cells specific to a CNS antigen, myelin basic protein (MBP), protect neurons from secondary degeneration after crush injury of the rat optic nerve. Here we examined the involvement of NTs in T-cell-mediated neuroprotection, and the possible significance of the antigen specificity of the T cells in this activity. Analysis of cytokine and NT expression in various rat T cell lines showed that the T cells express mRNA for cytokines of Th1, Th2, and Th3 phenotypes. In addition, the T cells express mRNA and protein specific to nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5. Antigen activation significantly increased NT secretion. Thus, reactivation of CNS autoimmune T cells by locally presented antigens to which they are specific can lead to enhanced secretion of NTs and possibly also of other factors in injured optic nerves. mRNA for TrkA, TrkB and p75 receptors was expressed in the injured nerve, suggesting that these specific receptors can mediate the effects of the T-cell-derived NTs. The neuroprotective effect of the passively transferred autoimmune anti-MBP T cells in injured optic nerves was significantly decreased after local applicaiton of a tyrosine kinase inhibitor known to be associated with NT-receptor activity. These results suggest that the neuroprotective effect of autoimmune T cells involves the secretion of factors such as NTs by the T cells reactivated by their specific antigen in the injured CNS. T cell intervention in the injured CNS might prove to be a useful means of promoting post-injury CNS maintenance and recovery, possibly via supply of NTs and other factors.

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Available from: Philip Lazarovici, Sep 30, 2015
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    • "One mechanism proposed for autoimmune lymphocyte-mediated tissue repair is the production of neurotrophins (e.g., brain-derived neurotrophic factor (BDNF)) (Hammarberg et al., 2000; Moalem et al., 2000) and/or anti-inflammatory cytokines (e.g., IL-10, transforming growth factor (TGF)-β) (Tyor et al., 2002; Zhou et al., 2009a). However, the cell type(s) responsible for the production of neurotrophins and anti-inflammatory mediators within the injured CNS, i.e., whether they are effector cells or induced T regs (iTregs) that bind CNS proteins, or even non-antigen-specific bystander cells recruited to the injury site, has not been definitively established. "
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    ABSTRACT: Over the past 15 years an immense amount of data has accumulated regarding the infiltration and activation of lymphocytes in the traumatized spinal cord. Although the impact of the intraspinal accumulation of lymphocytes is still unclear, modulation of the adaptive immune response via active and passive vaccination is being evaluated for its preclinical efficacy in improving the outcome for spinal-injured individuals. The complexity of the interaction between the nervous and the immune systems is highlighted in the contradictions that appear in response to these modulations. Current evidence regarding augmentation and inhibition of the adaptive immune response to spinal cord injury is reviewed with an aim toward reconciling conflicting data and providing consensus issues that may be exploited in future therapies. Opportunities such an approach may provide are highlighted as well as the obstacles that must be overcome before such approaches can be translated into clinical trials.
    Experimental Neurology 08/2014; 258:78–90. DOI:10.1016/j.expneurol.2014.03.003 · 4.70 Impact Factor
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    • "Another mechanism by which A91 immunization could be reducing apoptosis is through the action of BDNF. Previous studies have shown that anti-MBP T cells release neurotrophic factors [38] [39]. Furthermore, anti-A91 T lymphocytes are capable of releasing significant amounts of BDNF [14]. "
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    ABSTRACT: Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF- α ). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF- α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy.
    10/2013; 2013(7):827517. DOI:10.1155/2013/827517
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    • "Unexpectedly, high BDNF and NGF were associated with lower MRI CCV and higher T1 and T2 volumes, whilst BDNF levels in the highest quartile were associated with lower MTR means. This can be interpreted as either reactive neuroplasticity with upregulation of neurotrophins following injury, or as markers of inflammation, as both have been shown to play a regulatory role in inflammation [20]. Similarly, patients with higher BDNF, but not NGF levels were found to have lower PASAT scores. "
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    ABSTRACT: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment. SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored. Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p = 0.043, Nfh 0-24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin. The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.
    PLoS ONE 08/2013; 8(8):e70019. DOI:10.1371/journal.pone.0070019 · 3.23 Impact Factor
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