Immunoregulatory Properties of Human Bone Marrow Mesenchymal Stem Cells on T Lymphocyte Proliferation

Document Type : Original Article (s)

Authors

1 MSc Student, Student Research Committee, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Professor, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Assistant Professor, Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

4 Lecturer, Department of Epidemiology and Biostatistics, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Bone marrow mesenchymal stem cells (BM-MSCs) have been shown to be highly immunosuppressive. In some studies, MSCs were found to suppress T cell proliferation and cytokine production.  Most researchers reported this effect to be mediated by soluble factors including IL-10, TGF-β1, nitric oxide, indoleamine 2,3-dioxygenase (IDO), and prostaglandin (PG) E2. Others however claim that cell-to-cell contact is necessary. Since the exact mechanism is still uncertain, this study tried to determine the mechanism underlying the immunoregulatory properties of human BM-MSCs and their ability to inhibit T-cell proliferation. In addition, role of cell-cell contact and dose-dependent immunomodulatory activities of these cell were explored.Methods: In this study, both mitogen- and alloantigen-activated T cells were cultured in the presence of different numbers of BM-MSCs. In some co-cultures, activated T cells were in direct contact to BM-MSC and in other co-cultures, they were separated from BM-MSCs by a permeable membrane. The proliferation of T lymphocytes was assayed with a cell proliferation enzyme-linked immunosorbent assay (ELISA) (Brdu).Findings: Although proliferation index of unstimulated T cells did not significantly differ in the presence or absence of BM-MSCs, the index was inversely related with BM-MSC presence in stimulated cells. Generally, the presence of BM-MSC resulted in a statistically significant decrease in PHA/alloantigen-induced proliferation of T lymphocytes. In addition, proliferation was significantly lower in transwell cultures than in stimulated lymphocytes without BM-MSCs (P < 0.05). Conclusion: The present study showed that BM-MSC suppressed T cells proliferation triggered by allogeneic PBMCs and mitogen (PHA). This effect is dose dependent and BM-MSCs do not necessarily require the cell-to-cell contact (direct contact) of MSC and lymphocytes. However, the suppression is reduced to some extent by the physical separation of MSCs and immune cells (indirect contact).

Keywords

References

  1. Cohnheim J. Uber entzundung und eiterung. J Arch Path Anta Physiol Klin Med. 1867; 40: 1-79.
  2. Li C, Zhang W, Jiang X, Mao N. Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells. Cell Tissue Res 2007; 330(3): 437-46.
  3. Le BK, Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 2007; 262(5): 509-25.
  4. DelaRosa O, Lombardo E, Beraza A, Mancheno-Corvo P, Ramirez C, Menta R, et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A 2009; 15(10): 2795-806.
  5. Kassem M, Kristiansen M, Abdallah BM. Mesenchymal stem cells: cell biology and potential use in therapy. Basic Clin Pharmacol Toxicol 2004; 95(5): 209-14.
  6. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006; 24(2): 386-98.
  7. Ramasamy R, Tong CK, Seow HF, Vidyadaran S, Dazzi F. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function. Cell Immunol 2008; 251(2): 131-6.
  8. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101(9): 3722-9.
  9. Maccario R, Podesta M, Moretta A, Cometa A, Comoli P, Montagna D, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90(4): 516-25.
  10. Dugast AS, Vanhove B. Immune regulation by non-lymphoid cells in transplantation. Clin Exp Immunol 2009; 156(1): 25-34.
  11. Nasef A, Mazurier CH, Bouchet S, François S, Chapel A, Thierry D, et al. Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cellular Immunology 2008; 253(1-2): 16-22.
  12. Brooke G, Rossetti T, Pelekanos R, Ilic N, Murray P, Hancock S, et al. Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials. Br J Haematol 2009; 144(4): 571-9.
  13. Kong QF, Sun B, Bai SS, Zhai DX, Wang GY, Liu YM, et al. 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. J Neuroimmunol 2009; 207(1-2): 83-91.
  14. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2(2): 141-50.
  15. Crop M, Baan C, Weimar W, Hoogduijn M. Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation. Transpl Int 2009; 22(4): 365-76.
  16. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25(11): 2739-49.
  17. Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Arch Immunol Ther Exp (Warsz) 2008; 56(1): 1-8.
  18. Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM, et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 2007; 179(3): 1595-604.
  19. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005; 105(5): 2214-9.
  20. Chang CJ, Yen ML, Chen YC, Chien CC, Huang HI, Bai CH, et al. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma. Stem Cells 2006; 24(11): 2466-77.
  21. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129(1): 118-29.
  22. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75(3): 389-97.
  23. Mahmud N, Pang W, Cobbs C, Alur P, Borneman J, Dodds R, et al. Studies of the route of administration and role of conditioning with radiation on unrelated allogeneic mismatched mesenchymal stem cell engraftment in a nonhuman primate model. Exp Hematol 2004; 32(5): 494-501.
  24. Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am 2003; 85-A(10): 1927-35.
  25. Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, et al. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 2004; 127(5): 1293-300.
  26. De Kok IJ, Peter SJ, Archambault M, van den Bos C, Kadiyala S, Aukhil I, et al. Investigation of allogeneic mesenchymal stem cell-based alveolar bone formation: preliminary findings. Clin Oral Implants Res 2003; 14(4): 481-9.
  27. Liu J, Lu XF, Wan L, Li YP, Li SF, Zeng LY, et al. Suppression of human peripheral blood lymphocyte proliferation by immortalized mesenchymal stem cells derived from bone marrow of Banna Minipig inbred-line. Transplant Proc 2004; 36(10): 3272-5.
  28. Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006; 24(11): 2582-91.
  29. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 2005; 35(5): 1482-90.
Journal of Isfahan Medical School
Volume 29, Issue 169 - Serial Number 169
November and December 2012
Pages 2552-2561

Files

History

  • Receive Date: 30 October 2011
  • Revise Date: 02 November 2024
  • Accept Date: 06 April 2022

Share

How to cite

Statistics