T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS

Department of Pathology, Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2008; 105(46):17913-8. DOI: 10.1073/pnas.0804610105
Source: PubMed

ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)(G93A) transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1(G93A) spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRbeta deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1(G93A) (TCRbeta-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.

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    ABSTRACT: In a previous study, we reported that central injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A SOD1 mice. In the present study, we found that central MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of ALS mice (G93A SOD1). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (Treg ; CD4(+) /CD25(high) /FoxP3(+) ) and the mRNA expression of several cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, IL-13 and TGF-β). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 h or 72 h. Based on a FACS analysis, we found that co-culture with MSCs increased the Treg /total T lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-γ and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFN-γ mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-γ mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-β were markedly elevated, along with GATA mRNA, in both HC and ALS PBMCs co-cultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated to the increase in Treg induction. These findings of Treg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; DOI:10.1111/jnc.12814 · 4.24 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1(G93A) transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2(-/-) mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1(G93A) splenic microenvironment, focusing on CD4(+) T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2(-/-) and SOD1(G93A) mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1(G93A) unfractionated splenocytes into RAG2(-/-) mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1(G93A) CD4(+) T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1(G93A) mice were able to maintain FMN survival levels, WT CD4(+) T cells alone could not. Importantly, these results suggest that SOD1(G93A) CD4(+) T cells retain neuroprotective functionality when removed from a dysfunctional SOD1(G93A) peripheral splenic microenvironment. These results also indicate that the SOD1(G93A) central nervous system microenvironment is able to re-activate CD4(+) T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1(G93A) peripheral splenic microenvironment may compromise neuroprotective CD4(+) T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1(G93A) mice.
    Brain Behavior and Immunity 06/2014; DOI:10.1016/j.bbi.2014.05.019 · 6.13 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.
    Frontiers in Cellular Neuroscience 11/2013; 7:214. DOI:10.3389/fncel.2013.00214 · 4.18 Impact Factor


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