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Stem Cell Reviews and Reports

, Volume 13, Issue 1, pp 104–115 | Cite as

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

  • Michaela Hajkova
  • Barbora Hermankova
  • Eliska Javorkova
  • Pavla Bohacova
  • Alena Zajicova
  • Vladimir Holan
  • Magdalena KrulovaEmail author
Article

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

Mesenchymal stem cells Immunosuppressive drugs Stem cell therapy T cells Immunomodulation 

Notes

Acknowledgements

This study was supported by grant 80815 from the Grant Agency of Charles University, the grant 14-12580S, and by the projects SVV 260310, UNCE 204013, NPU-I:LO1508 and NPU-I: LO1309 and P41-20504151.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Dobbels, F., Moons, P., Abraham, I., et al. (2008). Measuring symptom experience of side-effects of immunosuppressive drugs: the modified tranplant symptom occurrence and distress scale. Transplant International, 21, 764–773.CrossRefPubMedGoogle Scholar
  2. 2.
    Hoogduijn, M. J., Crop, M. J., Peeters, A. M. A., et al. (2007). Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells and Development, 16, 597–604.CrossRefPubMedGoogle Scholar
  3. 3.
    Kern, S., Eichler, H., Stoeve, J., Klueter, H., & Bieback, K. (2006). Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells, 24, 1294–1301.CrossRefPubMedGoogle Scholar
  4. 4.
    Kong, Q.-F., Sun, B., Bai, S., et al. (2009). Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-beta. Journal of Neuroimmunology, 207, 83–91.CrossRefPubMedGoogle Scholar
  5. 5.
    Svobodova, E., Krulova, M., Zajicova, A., et al. (2012). The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells and Development, 21, 901–910.CrossRefPubMedGoogle Scholar
  6. 6.
    Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105, 1815–1822.CrossRefPubMedGoogle Scholar
  7. 7.
    Haynesworth, S. E., Baber, M. A., & Caplan, A. I. (1996). Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. Journal of Cellular Physiology, 166, 585–592.CrossRefPubMedGoogle Scholar
  8. 8.
    Horwitz, E. M., Gordon, P. L., Koo, W. K. K., et al. (2002). Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proceedings of the National Academy of Sciences of the United States of America, 99, 8932–8937.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Javorkova, E., Trosan, P., Zajicova, A., Krulova, M., Hajkova, M., & Holan, V. (2014). Modulation of the early inflammatory microenvironment in the alkali-burned eye by systemically administered interferon-gamma-treated mesenchymal stromal cells. Stem Cells and Development, 23, 2490–2500.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Gu, Y., Xue, Q., Chen, Y.-J., et al. (2013). Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells. Human Immunology, 74, 267–276.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim, S.-Y., Lee, J.-H., Kim, H. J., et al. (2012). Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. American Journal of Physiology—Lung Cellular and Molecular Physiology, 302, L891–L908.CrossRefPubMedGoogle Scholar
  12. 12.
    Ciccocioppo, R., Bernardo, M. E., Sgarella, A., et al. (2011). Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut, 60, 788–798.CrossRefPubMedGoogle Scholar
  13. 13.
    Casiraghi, F., Azzollini, N., Cassis, P., et al. (2008). Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. Journal of Immunology, 181, 3933–3946.CrossRefGoogle Scholar
  14. 14.
    Cejkova, J., Trosan, P., Cejka, C., et al. (2013). Suppression of alkali-induced oxidative injury in the cornea by mesenchymal stem cells growing on nanofiber scaffolds and transferred onto the damaged corneal surface. Experimental Eye Research, 116, 312–323.CrossRefPubMedGoogle Scholar
  15. 15.
    Buron, F., Perrin, H., Malcus, C., et al. (2009). Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: an in vitro study using human cells. Transplantation Proceedings, 41, 3347–3352.CrossRefPubMedGoogle Scholar
  16. 16.
    Hoogduijn, M. J., Crop, M. J., Korevaar, S. S., et al. (2008). Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation, 86, 1283–1291.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen, T. L., Wang, J. A., Shi, H., et al. (2008). Cyclosporin A pre-incubation attenuates hypoxia/reoxygenation-induced apoptosis in mesenchymal stem cells. Scandinavian Journal of Clinical & Laboratory Investigation, 68, 585–593.CrossRefGoogle Scholar
  18. 18.
    Popp, F. C., Eggenhofer, E., Renner, P., et al. (2008). Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transplant Immunology, 20, 55–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Eggenhofer, E., Renner, P., Soeder, Y., et al. (2011). Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transplant Immunology, 25, 141–147.CrossRefPubMedGoogle Scholar
  20. 20.
    Ge, W., Jiang, J., Baroja, M. L., et al. (2009). Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. American Journal of Transplantation, 9, 1760–1772.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang, H., Qi, F., Dai, X., et al. (2014). Requirement of B7-H1 in mesenchymal stem cells for immune tolerance to cardiac allografts in combination therapy with rapamycin. Transplant Immunology, 31, 65–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Hajkova, M., Javorkova, J., Zajicova, A., et al. (2015). A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in a macrophage phenotype. Journal of Tissue Engineering and Regenerative Medicine. doi: 10.1002/term.2044.PubMedGoogle Scholar
  23. 23.
    Li, J.-F., Zhang, D.-J., Geng, T., et al. (2014). The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis. Cell Transplantation, 23, S113–S122.CrossRefPubMedGoogle Scholar
  24. 24.
    Peng, Y., Ke, M., Xu, L., et al. (2013). Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation, 95, 161–168.CrossRefPubMedGoogle Scholar
  25. 25.
    Perico, N., Casiraghi, F., Introna, M., et al. (2011). Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clinical Journal of the American Society of Nephrology, 6, 412–422.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fanigliulo, D., Lazzerini, P. E., Capecchi, P. L., Ulivieri, C., Baldari, C. T., & Laghi-Pasini, F. (2015). Clinically-relevant cyclosporin and rapamycin concentrations enhance regulatory T cell function to a similar extent but with different mechanisms: an in-vitro study in healthy humans. International Immunopharmacology, 24, 276–284.CrossRefPubMedGoogle Scholar
  27. 27.
    Kawabe, Y., & Ochi, A. (1991). Programmed cell death and extrathymic reduction of Vβ8+CD4+ T-cells in mice tolerant to Staphylococcus aureus enterotoxin. Nature, 349, 245–248.CrossRefPubMedGoogle Scholar
  28. 28.
    Crowe, S. M., Carlin, J. B., Stewart, K. I., Lucas, C. R., & Hoy, J. F. (1991). Predictive value of lymphocyte-CD4 numbers for the devlopment of oportunistic infections and malignancies in HIV-infected persons. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 4, 770–776.Google Scholar
  29. 29.
    Xu, G., Zhang, Y., Zhang, L., Ren, G., & Shi, Y. (2007). The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. Biochemical and Biophysical Research Communications, 361, 745–750.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Benvenuto, F., Ferrari, S., Gerdoni, E., et al. (2007). Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells, 25, 1753–1760.CrossRefPubMedGoogle Scholar
  31. 31.
    Normanton, M., Alvarenga, H., Hamerschlak, N., et al. (2014). Interleukin 7 plays a role in T lymphocyte apoptosis inhibition driven by mesenchymal stem cell without favoring proliferation and cytokines secretion. PloS One, 9, e106673.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Le Blanc, K., Rasmusson, I., Gotherstrom, C., et al. (2004). Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scandinavian Journal of Immunology, 60, 307–315.CrossRefPubMedGoogle Scholar
  33. 33.
    Talaat, R. M., Mohamed, S. F., Bassyouni, I. H., & Raouf, A. A. (2015). Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: correlation with disease activity. Cytokine, 72, 146–153.CrossRefPubMedGoogle Scholar
  34. 34.
    Ma, L., Zhang, H. M., Hu, K. B., et al. (2015). The imbalance between Tregs, Th17 cells and inflammatory cytokines among renal transplant recipients. BMC Immunology, 16. doi: 10.1186/s12865-015-0118-8.
  35. 35.
    Mohammadzadeh, A., Pourfathollah, A. A., Shahrokhi, S., Hashemi, S. M., Moradi, S. L. A., & Soleimani, M. (2014). Immunomodulatory effects of adipose-derived mesenchymal stem cells on the gene expression of major transcription factors of T cell subsets. International Immunopharmacology, 20, 316–321.CrossRefPubMedGoogle Scholar
  36. 36.
    Prado, C., de Paz, B., Gomez, J., Lopez, P., Rodriguez-Carrio, J., & Suarez, A. (2011). Glucocorticoids enhance Th17/Th1 imbalance and signal transducer and activator of transcription 3 expression in systemic lupus erythematosus patients. Rheumatology, 50, 1794–1801.CrossRefPubMedGoogle Scholar
  37. 37.
    Abadja, F., Atemkeng, S., Alamartine, E., Berthoux, F., & Mariat, C. (2011). Impact of mycophenolic acid and tacrolimus on Th17-related immune response. Transplantation, 92, 396–403.CrossRefPubMedGoogle Scholar
  38. 38.
    Weigel, G., Griesmacher, A., Karimi, A., Zuckermann, A. O., Grimm, M., & Mueller, M. M. (2002). Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients. Journal of Heart and Lung Transplantation, 21, 1074–1079.CrossRefPubMedGoogle Scholar
  39. 39.
    Chang, J. W., Hung, S. P., Wu, H. H., et al. (2011). Therapeutic effects of umbilical cord blood-derived mesenchymal stem cell transplantation in experimental lupus nephritis. Cell Transplantation, 20, 245–257.CrossRefPubMedGoogle Scholar
  40. 40.
    Goodwin, M., Sueblinvong, V., Eisenhauer, P., et al. (2011). Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells, 29, 1137–1148.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Miroux, C., Morales, O., Ouaguia, L., et al. (2012). Corticosteroids do not reverse the inhibitory effect of cyclosporine on regulatory T-cell activity in contrast to mycophenolate mofetil. Transplantation Proceedings, 44, 2834–2839.CrossRefPubMedGoogle Scholar
  42. 42.
    Rovira, J., Renner, P., Sabet-Baktach, M., et al. (2016). Cyclosporine A inhibits the T-bet-dependent antitumor response of CD8+ T cells. American Journal of Transplantation, 16, 1139–1147.CrossRefPubMedGoogle Scholar
  43. 43.
    Lemaitre, P. H., Vokaer, B., Charbonnier, L. M., et al. (2013). Cyclosporine A drives a Th17-and Th2-mediated posttransplant obliterative airway disease. American Journal of Transplantation, 13, 611–620.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Michaela Hajkova
    • 1
    • 2
  • Barbora Hermankova
    • 1
    • 2
  • Eliska Javorkova
    • 1
    • 2
  • Pavla Bohacova
    • 1
    • 2
  • Alena Zajicova
    • 2
  • Vladimir Holan
    • 1
    • 2
  • Magdalena Krulova
    • 1
    • 2
    Email author
  1. 1.Department of Cell Biology, Faculty of ScienceCharles UniversityPrague 2Czech Republic
  2. 2.Department of Transplantation Immunology, Institute of Experimental MedicineCzech Academy of SciencesPrague 4Czech Republic

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