Mesenchymal Stem Cells Attenuate the Adverse Effects of Immunosuppressive Drugs on Distinct T Cell Subopulations

Stem Cell Rev Rep. 2017 Feb;13(1):104-115. doi: 10.1007/s12015-016-9703-3.

Abstract

Immunosuppressive drugs are widely used to treat undesirable immune reaction, however their clinical use is often limited by harmful side effects. The combined application of immunosuppressive agents with mesenchymal stem cells (MSCs) offers a promising alternative approach that enables the reduction of immunosuppressive agent doses and simultaneously maintains or improves the outcome of therapy. The present study aimed to determinate the effects of immunosuppressants on individual T cell subpopulations and to investigate the efficacy of MSC-based treatment combined with immunosuppressive drugs. We tested the effect of five widely used immunosuppressants with different action mechanisms: cyclosporine A, mycophenolate mofetil, rapamycin, and two glucocorticoids - prednisone and dexamethasone in combination with MSCs on mouse CD4+ and CD8+ lymphocyte viability and activation, Th17 (RORγt+), Th1 (T-bet+), Th2 (GATA-3+) and Treg (Foxp3+) cell proportion and on the production of corresponding key cytokines (IL-17, IFNγ, IL-4 and IL-10). We showed that MSCs modulate the actions of immunosuppressants and in combination with immunosuppressive drugs display distinct effect on cell activation and balance among different T lymphocytes subpopulations and exert a suppressive effect on proinflammatory T cell subsets while promoting the functions of anti-inflammatory Treg lymphocytes. The results indicated that MSC-based therapy could be a powerful strategy to attenuate the negative effects of immunosuppressive drugs on the immune system.

Keywords: Immunomodulation; Immunosuppressive drugs; Mesenchymal stem cells; Stem cell therapy; T cells.

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cyclosporine / pharmacology
  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Female
  • Flow Cytometry
  • Glucocorticoids / pharmacology*
  • Immunosuppressive Agents / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / metabolism
  • Mice, Inbred BALB C
  • Mycophenolic Acid / pharmacology
  • Prednisone / pharmacology
  • Sirolimus / pharmacology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology

Substances

  • Cytokines
  • Glucocorticoids
  • Immunosuppressive Agents
  • Dexamethasone
  • Cyclosporine
  • Mycophenolic Acid
  • Prednisone
  • Sirolimus