Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis

David R. Beers, Jenny S. Henkel, Weihua Zhao, Jinghong Wang, Ailing Huang, Shixiang Wen, Bing Liao, Stanley H. Appel

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25 +/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.

Original languageEnglish (US)
Pages (from-to)1293-1314
Number of pages22
JournalBrain
Volume134
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Regulatory T-Lymphocytes
Disease Progression
Microglia
Interleukin-4
T-Lymphocytes
Superoxide Dismutase
Survival
Poisons
Life Expectancy
Neurodegenerative Diseases

Keywords

  • FoxP3
  • IL-4
  • inflammation
  • microglia
  • regulatory T lymphocytes

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. / Beers, David R.; Henkel, Jenny S.; Zhao, Weihua; Wang, Jinghong; Huang, Ailing; Wen, Shixiang; Liao, Bing; Appel, Stanley H.

In: Brain, Vol. 134, No. 5, 01.05.2011, p. 1293-1314.

Research output: Contribution to journalArticle

Beers, David R. ; Henkel, Jenny S. ; Zhao, Weihua ; Wang, Jinghong ; Huang, Ailing ; Wen, Shixiang ; Liao, Bing ; Appel, Stanley H. / Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. In: Brain. 2011 ; Vol. 134, No. 5. pp. 1293-1314.
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