Tacrolimus inhibits Th1 and Th17 responses in MuSK-antibody positive myasthenia gravis patients

Exp Neurol. 2019 Feb:312:43-50. doi: 10.1016/j.expneurol.2018.11.006. Epub 2018 Nov 22.

Abstract

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK- MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL-2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-γ, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-γ and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-γ. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG.

Keywords: Follicular T helper cell; MuSK-myasthenia gravis; Myasthenia gravis; Pathogenic Th17 cells; Regulatory T helper cell; Tacrolimus; Th1; Th17.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Male
  • Middle Aged
  • Myasthenia Gravis / drug therapy
  • Myasthenia Gravis / immunology
  • Myasthenia Gravis / metabolism*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / immunology
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cholinergic / immunology
  • Receptors, Cholinergic / metabolism*
  • Tacrolimus / pharmacology
  • Tacrolimus / therapeutic use*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*
  • Young Adult

Substances

  • Immunosuppressive Agents
  • Receptors, Cholinergic
  • MUSK protein, human
  • Receptor Protein-Tyrosine Kinases
  • Tacrolimus