IFN-γ stimulation of dental follicle mesenchymal stem cells modulates immune response of CD4+ T lymphocytes in Der p1+ asthmatic patients in vitro

Main Article Content

D. Genc
N. Zibandeh
E. Nain
Ü. Arı˘g
K. Göker
E.K. Aydıner
T. Akkoc

Keywords

Dental follicle mesenchymal stem cells, Asthma, House dust mite, Der p1

Abstract

Background: House dust mite (Dermataphagoides pteronyssinus) is a widespread risk factor in the development of asthma. CD4+ T lymphocytes have an important role in the pathogenesis of allergic asthma by polarizing to Th2 cells.


Objective: We aimed to evaluate the immunoregulatory effects of dental follicle mesenchymal stem cells with and without IFN-γ stimulation on peripheral blood mononuclear cells of house dust mite-sensitive asthmatic patients, and compared those with Dexamethasone as a systemic steroid.


Material and methods: PBMC of asthmatic patients and healthy individuals separately cultured with or without DF-MSCs in the presence and absence of IFN-γ or Der p1 or Dexamethasone for 72 h. CD4+ T proliferation, cell viability, CD4+ CD25+ FoxP3+ Treg cell frequency and cytokine profiles of PBMC were evaluated via flow cytometry.


Results: DF-MSCs suppressed proliferation of CD4+ T lymphocytes (pCDmix < 0.01, pDerp1 < 0.01, pIFN < 0.005) by increasing the number of FoxP3 expressing CD4+CD25+ T regulatory cells (pCDmix < 0.005, pDerp1 < 0.01, pIFN < 0.001) and suppressed lymphocyte apoptosis (pCDmix < 0.05, pDerp1 < 0.05, pIFN < 0.05), while Dexamethasone increased the apoptosis and decreased Treg cell frequency in asthmatic patients. IFN-γ stimulation increased the suppressive effect of DF-MSCs and also enhanced the frequency of FoxP3 expressing CD4+ CD25+ T regulatory cells. The cytokine levels were regulated by DF-MSCs by reducing IL-4 cytokine levels (pCDmix < 0.01, pDerp1 < 0.05, pIFN < 0.05) and upregulating IFN- levels (pCDmix < 0.01, pDerp1 < 0.05, pIFN < 0.005) in asthmatic patients.


Conclusion: IFN-γ stimulated DF-MSCs were found to have a high modulatory effect on CD4+ T cell responses, while Dexamethasone had an apoptotic effect on CD4+ T cells in asthmatic patients. DF-MSCs may be a new cell-based therapy option for allergic diseases including asthma.

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References

1. Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469-78.

2. Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol. 2011;128:451---62, quiz 463-4.

3. Phipps S, Benyahia F, Ou TT, Barkans J, Robinson DS, Kay AB. Acute allergen-induced airway remodeling in atopic asthma. Am J Respir Cell Mol Biol. 2004;31:626-32.

4. Lloyd CM, Robinson DS. Allergen-induced airway remodelling. Eur Respir J. 2007;29:1020-32.

5. Stelmach I, Jerzynska J, Stelmach W, Majak P, Chew G, Gorski P, et al. Cockroach allergy and exposure to cockroach allergen in Polish children with asthma. Allergy. 2002;57:701-5.

6. Matsui EC, Wood RA, Rand C, Kanchanaraksa S, Swartz L, CurtinBrosnan J, et al. Cockroach allergen exposure and sensitization in suburban middle-class children with asthma. J Allergy Clin Immunol. 2003;112:87-92.

7. Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med. 2006;100:17-307.

8. Al-Nbaheen M, Vishnubalaji R, Ali D, Bouslimi A, Al-Jassir F, Megges M, et al. 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;56:651-75.

10. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33:136-43.

11. English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP. Cell contact, prostaglandin E(2) and transforming growth factor-beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol. 2009;156:149-60.

12. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, et al. A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 2008;18:846-57.

13. Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming. Stem Cell Rev. 2012;8:98-1188.

14. Gieseke F, Bohringer J, Bussolari R, Dominici M, Handgretinger R, Muller I. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood. 2010;116:9-3770.

15. Mitchell C, Provost K, Niu N, Homer R, Cohn L. IFN- acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease. J Immunol. 2011;187:3815-20.

16. Teixeira LK, Fonseca BP, Barboza BA, Viola JP. The role of interferon-gamma on immune and allergic responses. Mem Inst Oswaldo Cruz. 2005;100 Suppl. 1:137-44.

17. Grosse-Onnebrink J, Werner C, Loges NT, Hörmann K, Blum A, Schmidt R, et al. Effect of TH2 cytokines and interferon-gamma on beat frequency of human respiratory cilia. Pediatr Res. 2016;79:731-5.

18. Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WCW. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. 2016;2016, http://dx.doi.org/10.1155/2016/3924858. Article ID 3924858.

19. Ericson-Neilsen W, Kaye AD. Steroids: pharmacology, complications, and practice delivery issues. Ochsner J. 2014;14:203-7.

20. Shefrin AE, Goldman RD. Use of dexamethasone and prednisone in acute asthma exacerbations in pediatric patients. Can Fam Phys. 2009;55:704-6.

21. Hsu PJ, Liu KJ, Chao YY, Sytwu HK, Yen BL. Assessment of the immunomodulatory properties of human mesenchymal stem cells (MSCs). J Vis Exp. 2015;53265, http://dx.doi.org/10.3791/53265.

22. Randolph C. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014;134 Suppl. 3:9-S178.

23. Urbanek K, De Angelis A, Spaziano G, Piegari E, Matteis M, Cappetta D, et al. Intratracheal administration of mesenchymal stem cells modulates tachykinin system suppresses airway remodeling and reduces airway hyperresponsiveness in an animal model. PLoS ONE. 2016;11:e7460158.

24. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13: 392-402.

25. Chen FM, Sun HH, Lu H, Yu Q. Stem cell-delivery therapeutics for periodontal tissue regeneration. Biomaterials. 2012;33:6320-44.

26. Racz GZ, Kadar K, Foldes A, Kallo K, Perczel-Kovach K, Keremi B, et al. Immunomodulatory and potential therapeutic role of mesenchymal stem cells in periodontitis. J Physiol Pharmacol. 2014;65:327-39.

27. 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. Article ID4682875.

28. 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;10:351-75.

29. 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;24:386-98.

30. Benvenuto F, Ferrari S, Gerdoni E, Gualandi F, Frassoni F, Pistoia V, et al. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells. 2007;25:1753-60.

31. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009;8:110-23.

32. Kikuchi Y, Takai T, Kuhara T, Ota M, Kato T, Hatanaka H, et al. Crucial commitment of proteolytic activity of a purified recombinant major house dust mite allergen Der p1 to sensitization toward IgE and IgG responses. J Immunol. 2006;177:17-609.

33. Pichavant M, Charbonnier AS, Taront S, Brichet A, Wallaert B, Pestel J, et al. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p1 increases selective dendritic cell recruitment. J Allergy Clin Immunol. 2005;115:771-8.

34. Omori M, Ziegler S. Induction of IL-4 expression in CD4+ T cells by thymic stromal lymphopoietin. J Immunol. 2007;178:404-1396.

35. Bonfield TL, Koloze M, Lennon DP, Zuchowski B, Yang SE, Caplan AI. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. Am J Physiol Lung Cell Mol Physiol. 2010;299:L760-70.

36. Boskabady MH, Mehrjardi SS, Rezaee A, Rafatpanah H, Jalali S. The impact of Zataria multiflora Boiss extracton in vitro and in vivo Th1/Th2 cytokine (IFN-/IL4) balance. J Ethnopharmacol. 2013;150:1024-31.

37. Mohammadian M, Boskabady MH, Kashani IR, Jahromi GP, Omidi A, Nejad AK, et al. Effect of bone marrow-derived mesenchymal stem cells on lung pathology and inflammation in ovalbumin-induced asthma in mouse. Iran J Basic Med Sci. 2016;19: 55-63.