Cyclosporine A Suppresses the Activation of the Th17 Cells in Patients with Primary Sjögren's Syndrome
-
Kaiwen Wang
,
Lei Shi
,
Zongliang Yu
,
Zhiyong Deng
,
AoLin He
,
Shasha Li
,
Lei Liu
Abstract
Primary Sjögren's syndrome (pSS) is a common autoimmune disease involving abnormal Th17 activation. The aim of the current study was to investigate the immunosuppression effect of Cyclosporine A (Cys A), a potent immunosuppressor on the proliferation and activation of T cells, on the activation of Th17 cells. Blood samples from both inactive and active pSS patients as well as healthy controls were collected and serum and peripheral blood mononuclear cells (PBMCs) were collected and tested for IL-17 and RORγt expression. Subsequently, PBMCs were treated in vitro with Cys A in a series of doses and incubation time and the effect of Cys A on inhibiting Th17 activation was tested by measuring IL-17 and RORγt expression. IL-17 in both serum and PBMCs as well as RORγt in PBMCs from active pSS patients were significantly elevated on both the mRNA and protein levels comparing to those from both inactive pSS patients and healthy controlCys A in the final concentration of 80ng/ml and the treatment time of 24h showed strong inhibition effect on the expression of IL-17 and RORγt in PBMCs from active pSS patients. However, Cys A in various doses and incubation times did not show much impact on inhibiting IL-17 as well as RORγt expression in PBMCs from healthy donors and inactive pSS patients. Cys A possesses the capability in immunosuppressing the activation of Th17 cells, suggesting that Cys A may be a potential treatment for pSS and maybe other autoimmune diseases.
1. Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ.Sjogren's syndrome. A clinical, pathological, and serological study of sixty-two cases. 1965. Medicine 1992; 71(6):386-401.
2. Fox RI. Clinical features, pathogenesis, and treatment of Sjogren's syndrome. Curr Opin Rheumatol 1996;8(5):438-45.
3. Ramos-Casals M, Tzioufas AG, Stone JH, Siso A, Bosch X. Treatment of primary Sjogren syndrome: a systematic review. JAMA 2010; 304(4):452-60.
4. Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjogren's syndrome. Nat Rev Rheumatol 2010; 6(9):529-37.
5. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV.Sjogren's syndrome. Proposed criteria for classification. Arthritis Rheum 1986; 29(5):577-85.
6. Talal N, Bunim JJ. The development of malignant lymphoma in the course of Sjögren's syndrome. Am J Med 1964; 36(4):529-40.
7. Van de Merwe J, Kamerling R, Arendsen E, Mulder D,Hooijkaas H. Sjogren's syndrome in patients with interstitial cystitis. J Rheumatol 1993; 20(6):962-6.
8. Burke JF, Jr., Pirsch JD, Ramos EL, Salomon DR,Stablein DM, Van Buren DH, et al. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med 1994; 331(6):358-63.
9. Brito-Zeron P, Siso-Almirall A, Bove A, Kostov BA, Ramos-Casals M. Primary Sjogren syndrome: an update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 2013; 14(3):279-89.
10. Jain AK, Sukhija J, Dwedi S, Sood A. Effect of topical cyclosporine on tear functions in tear-deficient dry eyes. Ann Ophthalmol (Skokie) 2007; 39(1):19-25.
11. Bedoya SK, Lam B, Lau K, Larkin J. Th17 Cells in Immunity and Autoimmunity. Clin Dev Immunol 2013;2013: 986789.
12. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 2000; 288(5475):2369-73.
13. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008; 8(5):337-48.
14. Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, et al. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A 2000;97(18):10132-7.
15. Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, et al.Th17 cells play a critical role in the development of experimental Sjogren's syndrome. Ann Rheum Dis 2014.
16. Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S. Identification of IL-18 and Th17 cells in salivary glands of patients with Sjogren's syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol 2008; 181(4):2898-906.
17. Sudzius G, Mieliauskaite D, Butrimiene I, Siaurys A, Mackiewicz Z, Dumalakiene I. Activity of T-helper cells in patients with primary Sjogren's syndrome. In vivo 2013; 27(2):263-8.
18. Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM. Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis. Am J Pathol 2009; 175(3):1167-77.
19. Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A, et al. IL-17-producing CD4-CD8- T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patie nts with primary Sjogren's syndrome. Ann Rheum Dis 2013; 72(2):286-92.
20. Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB.IL17: potential therapeutic target in Sjogren's syndrome using adenovirus-mediated gene transfer. Lab Invest 2011; 91(1):54-62.
21. Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, et al. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol 2009; 158(2):199-204.
22. Yamada H. Current perspectives on the role of IL-17 in autoimmune disease. J Inflamm Res 2010; 3:33-44.
23. Zhang F, Meng G, Strober W. Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17 -producing T cells. Nat Immunol 2008; 9(11):1297-306.
24. Zhou L, Lopes JE, Chong MM, Ivanov, II, Min R, Victora GD, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008; 453(7192):236-40.
25. Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular Helper T Cells: Lineage and Location. Immunity 2009; 30(3):324 -35.
26. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatmentof patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000; 118(11):1489-96.
27. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol 2002; 120(3):330-7.
28. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science 2009;325(5943):1001-5.
29. World Medical Association. Declaration of Helsinki, ethical principles for medical research involving human subjects. Bull World Health Organ 2001; 79(4): 373-374.
30. Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjogren's syndrome: a data-driven, expert consensus approach in the Sjogren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64(4):475-87.
31. Vitali C, Palombi G, Baldini C, Benucci M, Bombardieri S, Covelli M, et al. Sjogren's Syndrome Disease Damage Index and disease activity index: scoring systems for the assessment of disease damage and disease activity in Sjogren's syndrome, derived from an analysis of a cohort of Italian patients. Arthritis Rheum 2007; 56(7):2223-31.
32. Ciccia F, Alessandro R, Rodolico V, Guggino G, Raimondo S, Guarnotta C, et al. IL-34 is overexpressed in the inflamed salivary glands of patients with Sjogren's syndrome and is associated with the local expansion of pro-inflammatory CD14(bright)CD16+ monocytes. Rheumatology (Oxford) 2013; 52(6):1009 -17.
33. Shi Y, Sandoghchian Shotorbani S, Su Z, Liu Y, Tong J, Zheng D, et al. Enhanced HMGB1 expression may contribute to Th17 cells activation in rheumatoid arthritis. Clin Dev Immunol 2012; 2012:295081.
34. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell - mediated tissue damage. Nat Med 2007; 13(2):139-45.
35. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17- producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6(11):1123-32.
36. Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol 2007; 19(3):281-6.
37. Cantrell DA, Smith KA. The interleukin-2 T-cell system: a new cell growth model. Science 1984;224(4655):1312-6.
38. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4(2):481-508.
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| Issue | Vol 14, No 2 (2015) | |
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