Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis

Abstract

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 MEASURESIn 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 SOD1 G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice. RESULTSThe 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 SOD1 G93A 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 SOD1 G93A 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...

Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury

“…However, TNFR2 activation can stimulate the expansion of the population of T‐regulatory cells, which can alleviate pain in experimental autoimmune encephalomyelitis . T‐regulatory cells are also neuroprotective and can favor myelination in the CNS . Our study yielded one counterintuitive result when we observed an increased number of cells dying as a result of TNFR2 activation in the cord.…”

Regulatory T cells for amyotrophic lateral sclerosis/motor neuron disease: A clinical and preclinical systematic review

“…Studies in the patients with ALS also show a similar pattern compared with studies in the mouse models, and it has been observed that Tregs are significantly decreased with progression of the disease (Table ) and gradually lose their regulatory functions (Bargh et al, ; Henkel et al, ; Menon et al, ; Sheean et al, ). Recently, in a cohort study performed on 33 patients and 38 healthy controls, it was shown that the progression rate of ALS in patients was inversely correlated with total Treg count, although naive Tregs (CD45RA + ) were not correlated with the rate of disease progression (Sheean et al, ). They also used transgenic SOD1 G93A mice models to confirm their study results in humans.…”

“…Treatment with IL‐2c significantly increased the percentage of Tregs ( p < .001) and the mRNA expression level of Foxp3 ( p = .003) in SOD1 G93A mice compared with placebo‐treated SOD1 G93A mice. In addition, treatment with IL‐2c prolonged survival by 15.7 days in SOD1 G93A mice compared with placebo‐treated SOD1 G93A mice ( p = .003; Sheean et al, ).…”

“…Sheean et al's. () study was conducted on mSOD1 G93A mice (C57BL/6 strain) and used age‐matched wild‐type mice as controls. Mice were divided into three groups (IL‐2/IL‐2c [IL‐2 monoclonal antibody complex] + rapamycin, rapamycin alone, and placebo [normal saline] alone).…”

“…After statistical analysis in preclinical studies (Beers et al, ; Sheean et al, ; Vallarola et al, ), a significant increase was observed in the mean difference of the mRNA expression levels of FOXP3 and survival of mice (about 3.95 days) due to the treatment. Some of these studies also showed an increase in anti‐inflammatory cytokines and a reduction in inflammatory cytokines after treatment, which indicates the usefulness of Tregs in treating mice model of ALS.…”