Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson’s Disease

Reynolds, Ashley D.; Stone, Daniel B.; Hutter, Jessica A.L.; Benner, Eric J.; Mosley, R. Lee; Gendelman, Howard E.

doi:10.4049/jimmunol.0901852

Cited by 356 publications

(380 citation statements)

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“…Such counterregulation between local Treg cells will oppose local TH17 cells, as has been observed in models of Parkinson's disease. 70 Huntington's disease is triggered by mutant Huntingtin protein that is present throughout the body in addition to the CNS: pathogenic inflammatory immunity occurs and escalating levels of circulating IL-6 precede onset of clinical Huntington's disease symptoms. 71,72 Accordingly, peripheral IL-6 is being considered as an early predictor of disease progression in asymptomatic carriers.…”

Section: Implications Of the Lif/il-6 Axismentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.

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Section: Implications Of the Lif/il-6 Axismentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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“…While active immunization stimulates the immune system to produce antibodies against target proteins, passive immunization consists in directly administering antibodies that confer temporary protection against the disease. A third type of immunotherapy involving the activation of regulatory T-cells has also been explored for the potential treatment of AD and PD [59,60]. The advantage of humoral immunotherapy over other approaches is that it allows for the generation of antibodies targeting specific conformations of Aβ, tau, or α-syn (monomers, oligomers, and/or fibrils) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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“…Indeed, neuronal loss is accompanied by robust microgliosis, astrocytosis, and release of proinflammatory neurotoxic mediators [8][9][10][11]. Recent works from our own laboratories have served to highlight the role of effector T cells (Teffs) and regulatory T cells (Tregs) in attenuating such neuroinflammatory response cascades [12,13]. The balance between effector T cells and Treg activities leads to respective degenerative or protective effects in the brain, depending on defined T-cell polarity and cell phenotype [2,12,[14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Recent works from our own laboratories have served to highlight the role of effector T cells (Teffs) and regulatory T cells (Tregs) in attenuating such neuroinflammatory response cascades [12,13]. The balance between effector T cells and Treg activities leads to respective degenerative or protective effects in the brain, depending on defined T-cell polarity and cell phenotype [2,12,[14][15][16][17]. Immune profiles performed in patients with PD support a functional balance between the cells as circulating immunocyte profiles demonstrate increased proinflammatory profiles and decreased Treg function [18].…”

Section: Introductionmentioning

confidence: 99%

“…Mobilizing specific regulatory T-cell adaptive immune responses affects microglial reactivity and protect against nigrostriatal degeneration [12,13,19]. The use of immunomodulatory compounds, such as granulocyte macrophage colony-stimulating factor (GM-CSF) and vasoactive intestinal peptide (VIP), shifts immune phenotypes and functions from neurotoxic to neuroprotective regulatory responses [13,[19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

et al. 2016

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Neuroprotective immunity is defined by transformation of T-cell polarity for therapeutic gain. For neurodegenerative disorders and specifically for Parkinson's disease (PD), granulocyte-macrophage colony stimulating factor or vasoactive intestinal peptide receptor 2 (VIPR2) agonists elicit robust anti-inflammatory microglial responses leading to neuronal sparing in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. While neurotherapeutic potential was demonstrated for PD, there remain inherent limitations in translating these inventions from the laboratory to patients. One obstacle in translating such novel neurotherapeutics centers on the availability of suitable noninvasive methods to track disease progression and therapeutic efficacy. To this end, we developed manganese-enhanced magnetic resonance imaging (MEMRI) assays as a way to track a linkage between glial activation and VIPR2 agonist (LBT-3627)-induced neuroprotective immunity for MPTP-induced nigrostriatal degeneration. Notably, LBT-3627-treated, MPTP-intoxicated mice show reduced MEMRI brain signal intensities. These changes paralleled reduced astrogliosis and resulted in sparing of nigral tyrosine hydroxylase neurons. Most importantly, the data suggest that MEMRI can be developed as a biomarker tool to monitor neurotherapeutic responses that are relevant to common neurodegenerative disorders used to improve disease outcomes.

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Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson’s Disease

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/01/29/jimmunol.090185

Cited by 356 publications

References 37 publications

LIF in the regulation of T-cell fate and as a potential therapeutic

LIF in the regulation of T-cell fate and as a potential therapeutic

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

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