Regulatory T‐lymphocytes mediate amyotrophic lateral sclerosis progression and survival

Abstract

In amyotrophic lateral sclerosis (ALS) mice, regulatory T-lymphocytes (Tregs) are neuroprotective, slowing disease progression. To address whether Tregs and FoxP3, a transcription factor required for Treg function, similarly influence progression rates of ALS patients, T-lymphocytes from patients were assessed by flow cytometry. Both numbers of Tregs and their FoxP3 protein expressions were reduced in rapidly progressing ALS patients and inversely correlated with progression rates. The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates. Both FoxP3 and Gata3 were accurate indicators of progression rates. No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients. A 3.5-year prospective study with a second larger cohort revealed that early reduced FoxP3 levels were indicative of progression rates at collection and predictive of future rapid progression and attenuated survival. Collectively, these data suggest that Tregs and Th2 lymphocytes influence disease progression rates. Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Of interest, adoptive transfer of activated regulatory T‐cells or effector T‐cells from wild type mice into mSOD1 recipients leads to delayed motor symptoms and extended survival 59. Moreover, regulatory T‐cells are associated with slow progressing phases in mSOD1 mice and are negatively correlated with rapid progression in ALS patients 58, 60. Nonetheless, it appears that mSOD1 T‐cells are not functionally impaired 57, 58, 61.…”

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

“…The latter effect is very relevant to ALS as Tregs play an endogenous neuroprotective function by augmenting, among other mechanisms, the protective potential of microglia in ALS mice [29], and as the number of Tregs is inversely correlated with disease progression both in ALS mice and in patients [12,28]. Besides its activity on lymphocytes, fingolimod downregulates the production of proinflammatory cytokines and upregulates that of BDNF and glial cell-derived neurotrophic factor in microglial cultures, suggesting that in the CNS the drug might directly promote the neuroprotective effects of microglia [22].…”

“…Substantial numbers of infiltrating T cells and macrophages are found in the spinal cord of patients with ALS [8][9][10]; the majority of these migrating cells are described as T helper (Th) and T suppressor/cytotoxic cells [11], whereas a decreased number of regulatory T cells (Tregs) was observed in mice and patients with ALS during the rapidly progressing phase of the disease [12].…”

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Urate, which is lower in people with ALS than in controls, could serve a predictive or prognostic role [32][33][34][35][36]. Regulatory T cells, which are reduced in patients with rapidly progressive ALS, may be a predictive marker [37,38]. miR-155 (i.e., micro-RNA), a promising marker of inflammation, is found to be upregulated in patients with ALS and may be predictive or prognostic [39][40][41].…”