Tunç AKKOÇ, Nevsun İNANÇ, Deniz GENÇ, Noushin ZIBANDEH, Haner DİRESKENELİ

IFN-γ stimulated dental follicle mesenchymal stem cells regulate activated lymphocyte response in rheumatoid arthritis patients in vitro

Background/aim: Multipotent mesenchymal stem cells (MSCs) have been investigated in autoimmune diseases such as rheumatoidarthritis (RA) due to their immunomodulatory and regenerative properties. In this study, their immunosuppressive effects on peripheralblood mononuclear cells (PBMC) of RA patients were studied.Materials and methods: Dental follicle stem cells (DFSCs) were isolated from follicle tissue in the orofacial region. Characterizationand multipotency analyses were performed. Lymphocytes were isolated from peripheral venous blood of RA patients (n = 5) andhealthy individuals (n = 5). DFSCs were preincubated with IFN-γ for 48 h. PBMCs of RA patients and healthy individuals wereseparately cultured with or without DFSCs for 72 h. After culture period, lymphocyte proliferation and viability, the frequency of CD4+CD25+FoxP3+ T regulatory cells, IL-10 and TNF-α levels in the culture supernatants were measured via flow cytometry.Results: Our results demonstrated that DFSCs suppressed proliferation of T lymphocytes by increasing the number of FoxP3 expressingCD4+CD25+ T regulatory cells and suppressed lymphocyte apoptosis in RA patients. Also, DFSCs reduced TNF-α cytokine secretionand upregulated IL-10 secreting cells.Conclusions: Such cells could potentially be a source for future immunomodulatory treatments of RA patients.

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1. Burmester GR, Kivitz AJ, Kupper H, Arulmani U, Florentinus S, Goss SL, Rathmann SS, Fleischmann RM. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis 2015; 74: 1037-1044.
2. Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford) 2014; 53: 1560-1569.
3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J 2011; 365: 2205-2219.
4. Diarra D, Stolina M, Polzer K, , Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C et al. Dickkopf-1 is a master regulator of joint remodeling. . Nat Med 2007; 13: 156-163.
5. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 2010; 69: 1580-1588.
6. Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, Combe B, Cutolo M, de Wit M, Dougados M. Treating rheumatoid arthritis to target: recommendations recommendations of an international task force. Ann Rheum Dis 2010; 69: 631-637.
7. Mewar D, Wilson AG. Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors. Br J Pharmacol 2011; 162: 785-791.
8. Al-Nbaheen M, Vishnubalaji R, Ali D, Bouslimi A, Al-Jassir F, Megges M, Prigione A, Adjaye J, Kassem M, Aldahmash A. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev 2013; 9: 32-43.
9. Kim RH, Mehrazarin S, Kang MK. Therapeutic potential of mesenchymal stem cells for oral and systemic diseases. Dent Clin North Am 2012; 56: 651-675.
10. Bluestone JA. Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 2005; 5: 343-349.
11. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF therapy. J Exp Med 2004; 200: 277-285.
12. Esensten J, Wofsy D, Bluestone A. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 560-565.
13. Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, McCormick TS, Cooper KD. Dysfunctional blood and target tissue CD4CD25 high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005; 174: 164-173.
14. Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Cell Stem Cell 2008; 2: 141-150.
15. Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev 2014; 10(3): 351-175.
16. Lopez-Santalla M, Mancheño-Corvo P, Menta R, LopezBelmonte J, DelaRosa O, Bueren JA, Dalemans W, Lombardo E, Garin MI. Human adipose-derived mesenchymal stem cells modulate experimental autoimmune arthritis by modifying early adaptive T cell responses. Stem Cells 2015; 33: 3493-3503.
17. Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 2007; 56: 1175-1186.
18. Rackwitz L, Djouad F, Janjanin S, Nöth U, Tuan RS. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum 2005; 52: 2521-2529.
19. Benvenuto F, , Ferrari S, , Gerdoni E, , Gualandi F, , Frassoni F, Pistoia V, Mancardi G, Uccelli A. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 2007; 25: 1753-1760.
20. Arakaki R, Yamada A, Kudo Y, Hayashi Y, Ishimaru N. Mechanism of activation-induced cell death of T cells and regulation of FasL expression. Crit Rev Immunol 2014; 34: 301-314.
21. Yildirim S, Zibandeh N, Genc D, Ozcan EM, Goker K Akkoc T. The comparison of the immunologic properties of stem cells isolated from human exfoliated deciduous teeth, dental pulp, and dental follicles. Stem Cells Int 2016; 4682875. doi: 10.1155/2016/4682875
22. Gonzalez-Rey E, Gonzalez MA, Varela N, O’Valle F, Hernandez-Cortes P, Rico L, Büscher D, Delgado M. Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 241-248.
23. Ansboro S, Roelofs AJ, De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol 2017; 29: 201-207.
24. Ackermann C, Kavanaugh A. Tumor necrosis factor as a therapeutic target of rheumatologic disease. Expert Opin Ther Targets 2007; 11: 1369-1384.
25. Kay AG, Long G, Tyler G, Stefan A, Broadfoot SJ, Piccinini AM, Middleton J, Kehoe O. Mesenchymal stem cell conditioned medium reduces disease severity and immune responses in inflammatory arthritis. Sci Rep 2007; 7: 18019.