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Original Investigation
June 2018

Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model

Author Affiliations
  • 1Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
  • 2Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia
  • 3Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  • 4Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  • 5Department of Physiology, Anatomy, and Microbiology, La Trobe University, Bundoora, Victoria, Australia
  • 6Westmead Hospital, Westmead, New South Wales, Australia
  • 7Western Clinical School, University of Sydney, New South Wales, Australia
  • 8Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia
  • 9Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, Australia
JAMA Neurol. 2018;75(6):681-689. doi:10.1001/jamaneurol.2018.0035
Key Points

Question  Are regulatory T-cells associated with a slower rate of disease progression in amyotrophic lateral sclerosis?

Findings  In this study, the expansion of endogenous regulatory T-cells in a mouse model of amyotrophic lateral sclerosis significantly prolonged survival time and was associated with preserved motor neuron soma size, marked suppression of glial cell immunoreactivity, and increased neuroprotective gene-expression profiles. Regulatory T-cells were also shown to correlate with a slower rate of disease progression in patients with amyotrophic lateral sclerosis.

Meaning  Therapies aimed at modulating regulatory T-cells in patients with amyotrophic lateral sclerosis may prove therapeutically beneficial.


Importance  Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo.

Objective  To assess the role of Tregs in regulating the pathophysiology of ALS in humans and the therapeutic outcome of increasing Treg activity in a mouse model of the disease.

Design, Setting, and Participants  This prospective multicenter human and animal study was performed in hospitals, outpatient clinics, and research institutes. Clinical and function assessment, as well as immunological studies, were undertaken in 33 patients with sporadic ALS, and results were compared with 38 healthy control participants who were consecutively recruited from the multidisciplinary ALS clinic at Westmead Hospital between February 1, 2013, and December 31, 2014. All data analysis on patients with ALS was undertaken between January 2015 and December 2016. Subsequently, we implemented a novel approach to amplify the endogenous Treg population using peripheral injections of interleukin 2/interleukin 2 monoclonal antibody complexes (IL-2c) in transgenic mice that expressed mutant superoxide dismutase 1 (SOD1), a gene associated with motor neuron degeneration.

Main Outcomes and Measures  In patients with ALS, Treg levels were determined and then correlated with disease progression. Circulating T-cell populations, motor neuron size, glial cell activation, and T-cell and microglial gene expression in spinal cords were determined in SOD1G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice.

Results  The cohort of patients with ALS included 24 male patients and 9 female patients (mean [SD] age at assessment, 58.9 [10.9] years). There was an inverse correlation between total Treg levels (including the effector CD45RO+ subset) and rate of disease progression (R = −0.40, P = .002). Expansion of the effector Treg population in the SOD1G93A mice was associated with a significant slowing of disease progression, which was accompanied by an increase in survival time (IL-2c–treated mice: mean [SD], 160.6 [10.8] days; control mice: mean [SD], 144.9 [10.6] days; P = .003). Importantly, Treg expansion was associated with preserved motor neuron soma size and marked suppression of astrocytic and microglial immunoreactivity in the spinal cords of SOD1G93A mice, as well as elevated neurotrophic factor gene expression in spinal cord and peripheral nerves.

Conclusions and Relevance  These findings establish a neuroprotective effect of Tregs, possibly mediated by suppression of toxic neuroinflammation in the central nervous system. Strategies aimed at enhancing the Treg population and neuroprotective activity from the periphery may prove therapeutically useful for patients with ALS.