The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis

Beers, David R.; Zhao, Weihua; Appel, Stanley H.

doi:10.1001/jamaneurol.2018.0043

Cited by 22 publications

(15 citation statements)

References 14 publications

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“…This is in line with the recognized dual role that histamine plays for instance in microglia, that is, detrimental under healthy conditions and beneficial within inflammatory environments . It might also be explained by histaminergic drugs acting on cell types that per se possess dual roles in ALS pathogenesis, for instance microglia and immune cells preventing disease progression at early stages while inducing pathogenic responses at later stages …”

Section: Discussionsupporting

confidence: 68%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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Background Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti‐inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine‐mediated therapeutic strategy in ALS mice. Methods We adopted an integrative multi‐omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)‐G93A mice that recapitulate key ALS features, with the brain‐permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1‐G93A motor neuron‐like cells. Results We identified 13 histamine‐related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine‐related genes overlapped with genomic regions disrupted by DNA copy number and with ALS‐linked pathogenic variants. Histidine treatment in SOD1‐G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro . Conclusions Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine‐related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi‐gene network responsible for ALS and, furthermore, in the drug development process.

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Section: Discussionsupporting

confidence: 68%

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Apolloni

Amadio

Fabbrizio

et al. 2019

J cachexia sarcopenia muscle

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“…Tregs maintain homeostasis by inhibiting effector T-cell proliferation and cytokine production, shutting down an overactive immune response. In accord with the pro-inflammatory state reported in peripheral blood from ALS patients, fewer Tregs have also been observed in patient and rodent models of ALS [ 13 , 14 , 93 , 136 ]. Treg levels were found to correlate with disease progression rates in mutant SOD1 mice, and passive transfer of Tregs suppressed neuroinflammation and prolonged survival in these animals [ 169 ].…”

Section: Introductionsupporting

confidence: 57%

Inflammation in ALS/FTD pathogenesis

McCauley¹,

2018

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. However, despite the prominent role of neuro- and systemic inflammation in ALS/FTD, and experimental evidence in rodents that altering microglial function can mitigate pathology, therapeutic approaches to decrease inflammation have thus far failed to alter disease course in humans. Here, we review the characteristics of inflammation in ALS/FTD in both the nervous and peripheral immune systems. We further discuss evidence for direct influence on immune cell function by mutations in ALS/FTD genes including C9orf72, TBK1 and OPTN, and how this could lead to the altered innate immune system “tone” observed in these patients.

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“…Our study did not investigate the mechanisms involved in clinical improvement. The suggested role of natural killer cells [ 44 ] and regulatory T cells [ 45 , 46 ] is in line with the mechanism of action of MSC described by other authors [ 47 – 50 ]. Some studies indicated that human neural stem cells transplanted into a spinal cord in patients with ALS differentiated into neurons which were still detected 2.5 years after administration; however, it is not known whether the same happens after administration of MSC [ 51 ].…”

Section: Discussionsupporting

confidence: 76%

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Barczewska

Maksymowicz

Zdolińska-Malinowska

et al. 2020

Stem Cell Rev and Rep

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Objective Amyotrophic lateral sclerosis (ALS) is still incurable. Although different therapies can affect the health and survival of patients. Our aim is to evaluate the effect of umbilical mesenchymal stem cells administrated intrathecally to patients with amyotrophic lateral sclerosis on disability development and survival. Methods This case-control study involved 67 patients treated with Wharton’s jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database which contains patient records from 23 ALS clinical studies (phase 2/3). Patients in the treatment and reference groups were fully matched in terms of race, sex, onset of symptoms (bulbar/spinal), FT9 disease stage at the beginning of therapy and concomitant amyotrophic lateral sclerosis medications. Progression rates prior to treatment varied within a range of ± 0.5 points. All patients received three intrathecal injections of Wharton’s jelly-derived mesenchymal stem cells every two months at a dose of 30 × 10 6 cells. Patients were assessed using the ALSFRS-R scale. Survival times were followed-up until March 2020. Results Median survival time increased two-fold in all groups. In terms of progression, three response types measured in ALSFRS-R were observed: decreased progression rate ( n = 21, 31.3%), no change in progression rate ( n = 33, 49.3%) and increased progression rate ( n = 13, 19.4%). Risk-benefit ratios were favorable in all groups. No serious adverse drug reactions were observed. Interpretation Wharton’s jelly-derived mesenchymal stem cells therapy is safe and effective in some ALS patients, regardless of the clinical features and demographic factors excluding sex. The female sex and a good therapeutic response to the first administration are significant predictors of efficacy following further administrations. Graphical Abstract Medical therapeutic experiment with retrospective case-control analyses Electronic supplementary material The online version of this article (10.1007/s12015-020-10016-7) contains supplementary material, which is available to authorized users.

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The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis

Abstract: 14. Liguori C, Mercuri NB, Izzi F, et al. Obstructive sleep apnea is associated with early but possibly modifiable Alzheimer's disease biomarkers changes. Sleep. 2017;40(5):zsx011.

Cited by 22 publications

References 14 publications

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Inflammation in ALS/FTD pathogenesis

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

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