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

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.

IL-27 Promotes Human Placenta–Derived Mesenchymal Stromal Cell Ability To Induce the Generation of CD4+IL-10+IFN-γ+ T Cells via the JAK/STAT Pathway in the Treatment of Experimental Graft-versus-Host Disease

“…MSCs, which are involved in the differentiation of different T cell subsets, can also regulate T cell functions, such as the secretion of type 1/type 2 cytokines. Recent works showed that MSCs inhibit TNF-a, IFN-g, IL-2, IL-6, and IL-17 expression in CD4 + and CD8 + T cells, whereas they upregulate IL-4, IL-10, and TGF-b expression in CD4 + T cells (18,51,52). IL-10 has been shown to be one of the primary mediators by which CD4 + CD25 + Tregs mitigate the severity of GVHD, and donor as well as host B cellderived IL-10 contributes to the suppression of GVHD (53,54).…”

Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in�vitro

“…in a rat model of liver transplantation, Xu et al (16) found that the proportion of Treg cells in peripheral blood mononuclear cells in the rapamycin treatment group was higher compared with the group treated with tacrolimus. Hajkova et al (17) reported that the inhibitory effects of BM-MScs on cd4 + rorγt + Th17 were significantly reduced after treatment with tacrolimus. The addition of rapamycin significantly reduced the expression of il-17, whereas rapamycin significantly increased the expression of Foxp3 in the co-culture of MScs and cd4 + T cells.…”

Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease

“…Studies have shown that MSCs achieved direct immune regulation after the contact with effector T cells by releasing NO or Fas/FasL pathway, which induced apoptosis [32]. MSCs could directly secrete anti-inflammatory cytokines such as transforming growth factor (TGF-β), interleukin 6 (IL-6), interleukin 10 (IL-10), indolamine 2,3-dioxygenase (IDO), vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM), prostaglandin E2 (PGE2) and expression inhibitory co-stimulatory molecules such as programmed death ligand-1 (PD-L1) to realize the function of immunoregulation [40][41][42]. Further, it has been reported that Th1 and Th17 cells completed the repolarization process attributed to the increased expression of PD-L1 on MSCs, expanding in proportion of Th2 and Treg cells [43,44].…”

“…However, different types or doses of immunosuppressants may lead to completely different responses. Hajkova et al indicated that the combination of MSCs and immunosuppressive agents not only promoted cell proliferation and Tregs function, but modulated the balance of distinct T-lymphocyte subsets [42]. Inoue et al demonstrated the immunosuppressive effects of MSCs showed in vitro.…”