Inflammation

, Volume 41, Issue 2, pp 485–495 | Cite as

Adoptive Induced Antigen-Specific Treg Cells Reverse Inflammation in Collagen-Induced Arthritis Mouse Model

  • Guangzhi Sun
  • Yanfeng Hou
  • Wang Gong
  • Sai Liu
  • Jia Li
  • Yao Yuan
  • Dunfang Zhang
  • Qianming Chen
  • Xinfeng Yan
ORIGINAL ARTICLE
  • 243 Downloads

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that may cause bone damage and worsening disability. Manipulating antigen-specific Treg cells is a promising approach to treat autoimmune disease since the immune suppressive function of Treg cells has the feature of antigen specificity which could avoid overall immune suppression. It has been known that the function of Treg cells is impaired in RA, and adoptive transfer of Treg cells is effective in suppressing RA. Here, we designed a new approach to generate antigen-specific Treg cells by culturing CD4+ T cells from mice with RA onset, and we also proved that the adoptive transfer of these antigen-specific Treg cells reversed the collagen-induced arthritis (CIA) progression by suppressing the key inflammatory cytokine TNF-α. Further analysis showed that the transferred Treg cells were stable in vivo. These findings suggest this novel approach may have clinical applications for treatment of autoimmunity, including RA and other autoimmune disorders.

Key Words

RA Treg cells Foxp3 TNF-α CIA antigen-specific autoimmunity 

Notes

Compliance with Ethical Standards

All animal studies were approved by the Subcommittee on Research and Animal Care (SRAC) of Shandong University and Sichuan University, and were performed by following the guidelines of Experimental Animal Center of Shandong University and Sichuan University for the use and care of live animals.

Conflict of Interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Smolen, J.S., D. Aletaha, and I.B. McInnes. 2016. Rheumatoid arthritis. The Lancet. 388: 2023–2038.CrossRefGoogle Scholar
  2. 2.
    Saag, K.G., G.G. Teng, N.M. Patkar, J. Anuntiyo, C. Finney, J.R. Curtis, et al. 2008. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis and Rheumatism 59: 762–784.CrossRefPubMedGoogle Scholar
  3. 3.
    Shi, W., Y.M. Wang, L.S. Li, M. Yan, D. Li, N.N. Chen, et al. 2004. Safety and efficacy of oral nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis : A six-month randomised study. Clinical drug investigation. 24: 89–101.CrossRefPubMedGoogle Scholar
  4. 4.
    Feldmann, M., and S.R. Maini. 2008. Role of cytokines in rheumatoid arthritis: An education in pathophysiology and therapeutics. Immunological Reviews 223: 7–19.CrossRefPubMedGoogle Scholar
  5. 5.
    Tung, C.H., M.C. Lu, N.S. Lai, and S.F. Wu. 2017. Tumor necrosis factor-alpha blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis. PLoS One 12: e0183726.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rein, P., and R.B. Mueller. 2017. Treatment with biologicals in rheumatoid arthritis: An overview. Rheumatology and Therapy.Google Scholar
  7. 7.
    Zhang, D., E. Tu, S. Kasagi, P. Zanvit, Q. Chen, and W. Chen. 2015. Manipulating regulatory T cells: A promising strategy to treat autoimmunity. Immunotherapy 7: 1201–1211.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Li, M.O., and A.Y. Rudensky. 2016. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nature reviews Immunology. 16: 220–233.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chen, W., W. Jin, N. Hardegen, K.J. Lei, L. Li, N. Marinos, et al. 2003. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of experimental medicine. 198: 1875–1886.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Malek, T.R., and A.L. Bayer. 2004. Tolerance, not immunity, crucially depends on IL-2. Nature reviews Immunology. 4: 665–674.CrossRefPubMedGoogle Scholar
  11. 11.
    Mucida, D., Y. Park, G. Kim, O. Turovskaya, I. Scott, M. Kronenberg, et al. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.CrossRefPubMedGoogle Scholar
  12. 12.
    Wing, K., and S. Sakaguchi. 2010. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunology 11: 7–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Leipe, J., A. Skapenko, P.E. Lipsky, and H. Schulze-Koops. 2005. Regulatory T cells in rheumatoid arthritis. Arthritis research & therapy. 7: 93.CrossRefGoogle Scholar
  14. 14.
    Boissier, M.C., E. Assier, J. Biton, A. Denys, G. Falgarone, and N. Bessis. 2009. Regulatory T cells (Treg) in rheumatoid arthritis. Joint, bone, spine : revue du rhumatisme. 76: 10–14.CrossRefGoogle Scholar
  15. 15.
    Morgan, M.E., R. Flierman, L.M. van Duivenvoorde, H.J. Witteveen, W. van Ewijk, J.M. van Laar, et al. 2005. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis and Rheumatism 52: 2212–2221.CrossRefPubMedGoogle Scholar
  16. 16.
    Kong, N., Q. Lan, M. Chen, J. Wang, W. Shi, D.A. Horwitz, et al. 2012. Antigen-specific transforming growth factor beta-induced Treg cells, but not natural Treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance. Arthritis and Rheumatism 64: 2548–2558.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hill, J.A., D.A. Bell, W. Brintnell, D. Yue, B. Wehrli, A.M. Jevnikar, et al. 2008. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. The Journal of experimental medicine. 205: 967–979.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Inglis, J.J., E. Simelyte, F.E. McCann, G. Criado, and R.O. Williams. 2008. Protocol for the induction of arthritis in C57BL/6 mice. Nature protocols. 3: 612–618.CrossRefPubMedGoogle Scholar
  19. 19.
    Brand, D.D., K.A. Latham, and E.F. Rosloniec. 2007. Collagen-induced arthritis. Nature protocols. 2: 1269–1275.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang, D., C. Chia, X. Jiao, W. Jin, S. Kasagi, R. Wu, et al. 2017. D-mannose induces regulatory T cells and suppresses immunopathology. Nature Medicine.Google Scholar
  21. 21.
    Placek, K., G. Hu, K. Cui, D. Zhang, Y. Ding, J.E. Lee, et al. 2017. MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping. Nature Immunology 18: 1035–1045.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Fang, Z.Z., D. Zhang, Y.F. Cao, C. Xie, D. Lu, D.X. Sun, et al. 2016. Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression. Toxicology and applied pharmacology. 291: 21–27.CrossRefPubMedGoogle Scholar
  23. 23.
    La Paglia, G.M.C., M.C. Leone, G. Lepri, R. Vagelli, E. Valentini, A. Alunno, et al. 2017. One year in review 2017: Systemic lupus erythematosus. Clinical and experimental rheumatology. 35: 551–561.PubMedGoogle Scholar
  24. 24.
    Konkel, J.E., D. Zhang, P. Zanvit, C. Chia, T. Zangarle-Murray, W. Jin, et al. 2017. Transforming growth factor-beta signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 46: 660–674.CrossRefPubMedGoogle Scholar
  25. 25.
    Kasagi, S., P. Zhang, L. Che, B. Abbatiello, T. Maruyama, H. Nakatsukasa, et al. 2014. In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Science Translational Medicine 6: 241ra78.CrossRefPubMedGoogle Scholar
  26. 26.
    Zanvit, P., J.E. Konkel, X. Jiao, S. Kasagi, D. Zhang, R. Wu, et al. 2015. Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. Nature Communications 6: 8424.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang, D., J. Wang, Z. Li, M. Zhou, Q. Chen, X. Zeng, et al. 2015. The activation of NF-kappaB in infiltrated mononuclear cells negatively correlates with Treg cell frequency in oral lichen planus. Inflammation 38: 1683–1689.CrossRefPubMedGoogle Scholar
  28. 28.
    Tang, Q., K.J. Henriksen, M. Bi, E.B. Finger, G. Szot, J. Ye, et al. 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. The Journal of experimental medicine. 199: 1455–1465.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tarbell, K.V., L. Petit, X. Zuo, P. Toy, X. Luo, A. Mqadmi, et al. 2007. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. The Journal of experimental medicine. 204: 191–201.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nguyen, T.L., N.L. Sullivan, M. Ebel, R.M. Teague, and R.J. DiPaolo. 2011. Antigen-specific TGF-beta-induced regulatory T cells secrete chemokines, regulate T cell trafficking, and suppress ongoing autoimmunity. Journal of immunology. 187: 1745–1753.CrossRefGoogle Scholar
  31. 31.
    Stephens, L.A., K.H. Malpass, and S.M. Anderton. 2009. Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg. European Journal of Immunology 39: 1108–1117.CrossRefPubMedGoogle Scholar
  32. 32.
    Jaeckel, E., H. von Boehmer, and M.P. Manns. 2005. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes 54: 306–310.CrossRefPubMedGoogle Scholar
  33. 33.
    Tu, E., D. Bourges, P.A. Gleeson, D.K. Ang, and I.R. van Driel. 2013. Pathogenic T cells persist after reversal of autoimmune disease by immunosuppression with regulatory T cells. European Journal of Immunology 43: 1286–1296.CrossRefPubMedGoogle Scholar
  34. 34.
    Thomas, R. 2013. Dendritic cells and the promise of antigen-specific therapy in rheumatoid arthritis. Arthritis research & therapy. 15: 204.CrossRefGoogle Scholar
  35. 35.
    Corrigall, V.M., and G.S. Panayi. 2002. Autoantigens and immune pathways in rheumatoid arthritis. Critical Reviews in Immunology. 22: 281–293.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Guangzhi Sun
    • 1
  • Yanfeng Hou
    • 2
  • Wang Gong
    • 3
  • Sai Liu
    • 3
  • Jia Li
    • 4
  • Yao Yuan
    • 3
  • Dunfang Zhang
    • 3
  • Qianming Chen
    • 3
  • Xinfeng Yan
    • 1
  1. 1.Department of Orthopaedics, Shandong Provincial Qianfoshan HospitalShandong UniversityJinanChina
  2. 2.Department of Rheumatology, Shandong Provincial Qianfoshan HospitalShandong UniversityJinanChina
  3. 3.State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral Medicine of West China Hospital of StomatologySichuan UniversityChengduChina
  4. 4.Viral Oncology Program, Center for Cancer and MetabolismSRI InternationalMenlo ParkUSA

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