Collagen II-primed Foxp3 Transduced T Cells Ameliorate Collagen-induced Arthritis in Rats: The Effect of Antigenic Priming on T Regulatory Cell Function

  • Mahdi Zavvar Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Mohsen Abdolmaleki Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Hamid Farajifard Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Farshid Noorbakhsh Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • kayhan Azadmanesh Department of Virology, Pasteur Institute of Iran, Tehran, Iran
  • Mohammad Vojgani Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammad Hossein Nikcnam Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Molecular Immunology Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
Keywords: Collagen-induced arthritis, Retroviral vectors, Rheumatoid arthritis, T regulatory cells


Regulatory T cells (Tregs) play a major role in the prevention of autoimmune diseases. Transfer of Foxp3 gene into conventional T cells converts their phenotype to regulatory T cells. Therefore, the question arises as to whether adoptively transferred in vitro differentiated Treg cells specific for a locally expressed antigen might have better inhibitory effects on the progression of the disease as compared with antigen-nonspecific T reg cells. Herein, we investigated the therapeutic potential of primed and unprimed retrovirus mediated Foxp3-overexpression T cells following intravenously injected of these cells into affected rats with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Our analyses demonstrate that systemic administration of collagen II primed Foxp3-transduced T cells could markedly ameliorate CIA inflammatory responses at clinical (p<0.0014) and pathological exchanges including cellular infiltration (p=0.002), bone erosion (p=0.0013) and synovial hyperplasia (p=0.002). In contrast, collagen II unprimed Foxp3-transduced T cells like as collagen II primed or unprimed GFP-transduced T cells did not reveal any beneficial effects on arthritis features as compared with untreated group (p>0.05). Therefore, we believe that collagen II primed Foxp3-transduced T cells are interacting locally and systemically with immune cells which reveled with decreasing of T cells infiltration into joints along with specific CII IgG production. Considering the results described here, it appears that the using patients' T cells which previously exposed to specific antigens may have more effective therapeutic advantage in the production of induced regulatory T cells in the treatment of arthritis.

Author Biography

kayhan Azadmanesh, Department of Virology, Pasteur Institute of Iran, Tehran, Iran

Department of Virology


style='font-size:10.0pt;font-family:"Times New Roman","serif";mso-ascii-theme-font:



style='mso-spacerun:yes'> ADDIN EN.REFLIST


1. Tengvall S, Eneljung T, Jirholt P, Turesson O, Wing K, Holmdahl R, et al. Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis. PloS one 2016; 11(5):e0154630.

2. Wang F, Yu J, Wang Y, Jiang Y, Guo N, Zhang W. Combination therapy with TNFR-Fc and CTLA4-FasL using the recombinant adeno-associated virus potently suppresses adjuvant-induced arthritis in rats. Appl Microbiol Biotechnol 2015; 99(15):6327-37.

3. Steiner G. Auto-antibodies and autoreactive T-cells in rheumatoid arthritis: pathogenetic players and diagnostic tools. Clin Rev Allergy Immunol 2007; 32(1):23-36.

4. Bugatti S, Vitolo B, Caporali R, Montecucco C, Manzo A. B cells in rheumatoid arthritis: from pathogenic players to disease biomarkers. BioMed Res Int 2014; 2014:681678.

5. Rezaiemanesh AR, Abdolmaleki M, Abdolmohammadi K, Aghaei H, DadgarPakdel F, Fatahi Y, et al. Immune cells involved in the pathogenesis of ankylosing spondylitis. Biomed. Pharmacother 2018:198-204.

6. Williams RO. Collagen-induced arthritis as a model for rheumatoid arthritis. Methods Mol Med 2004; 98:207-16.

7. Ria F, Penitente R, De Santis M, Nicolo C, Di Sante G, Orsini M, et al. Collagen-specific T-cell repertoire in blood and synovial fluid varies with disease activity in early rheumatoid arthritis. Arthritis Res Ther 2008; 10(6):R135.

8. Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007; 19(3):284-8.

9. Daryabor G, Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N, et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Netw 2014; 25(1):24-9.

10. Gol-Ara M, Jadidi-Niaragh F, Sadria R, Azizi G, Mirshafiey A. The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis. Arthritis 2012; 2012:805875.

11. Yu Q, Xu M, Yu F, Jin Y. CD4(+) CD25(+) regulatory T cells as a therapeutic target in rheumatoid arthritis. Cent Eur J Immunol 2014; 39(1):100-3.

12. Lan Q, Fan H, Quesniaux V, Ryffel B, Liu Z, Zheng SG. Induced Foxp3(+) regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases J Mol Cell Biol 2012; 4(1):22-8.

13. Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C. In vitro generation of CD4+ CD25+ regulatory cells from murine naive T cells. Nat. Protoc 2007; 2(7):1789-94.

14. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299(5609):1057-61.

15. Marta Kisgati Æ Reto Asmis. Generation of retroviruses for the overexpression of cytosolic and mitochondrial glutathione reductase in macrophages in vivo. Cytotechnology 2007; 54:5-14. Pmid:1900301314.

16 Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 2005; 52(7):2212-21.

17. Lee J, Lee J, Park MK, Lim MA, Park EM, Kim EK, et al. Interferon gamma suppresses collagen-induced arthritis by regulation of Th17 through the induction of indoleamine-2,3-deoxygenase. PloS one 2013; 8(4):e60900.

18. Haque R, Lei F, Xiong X, Wu Y, Song J. FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development. Arthritis Res Ther 2010; 12(2):R66.

19. Catchpole B, Staines NA, Hamblin AS. Antigen presentation of Type II collagen in rats. Clin Exp Immunol 2001; 125(3):478-84.

20. Andersen KG, Butcher T, Betz AG. Specific Immunosuppression with InducibleFoxp3-Transduced Polyclonal T cells. PLoS Biol 2008; 6(11):e276.

21. Baeke F, Korf H, Overbergh L, Verstuyf A, Thorrez L, Van Lommel L, et al. The vitamin D analog, TX527, promotes a human CD4+CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation. J Immunol 2011; 186(1):132-42.

22. Yao Y, Vent-Schmidt J, McGeough MD, Wong M, Hoffman HM, Steiner TS, et al. Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism. J. Immunol 2015; 195(2):488-97.

23. Asnagli H, Martire D, Belmonte N, Quentin J, Bastian H, Boucard-Jourdin M, et al. Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis. Arthritis Res Ther 2014; 16(3):R115.

24. Chen SY, Wu CL, Lai MD, Lin CC, Yo YT, Jou IM, et al. Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy. Hum Gene Ther 2011; 22(2):145-54.

25. Wang Q, Wang L, Wu L, Zhang M, Hu S, Wang R, et al. Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis. Sci. Rep 2017; 7:45364.

26. Porporatto C, Canali MM, Bianco ID, Correa SG. The biocompatible polysaccharide chitosan enhances the oral tolerance to type II collagen. Clin Exp Immunol 2009; 155(1):79-87.

27. Wang X, Ma Y, Yoder A, Crandall H, Zachary JF, Fujinami RS, et al. T cell infiltration is associated with increased Lyme arthritis in TLR2-/- mice. F FEMS Immunol Med Microbiol 2008; 52(1):124-33.

28. Vremec D, Pooley J, Hochrein H, Wu L, Shortman K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J Immunol 2000; 164(6):2978-86.

29. Ellis SD, McGovern JL, van Maurik A, Howe D, Ehrenstein MR, Notley CA. Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor alpha and CD86. Arthritis Rheum 2014; 66(10):2694-705.

30. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003; 170(8):3939-43.

31. Wing JB, Sakaguchi S. TCR diversity and Treg cells, sometimes more is more. Eur J Immunol 2011; 41(11):3097-100.

32. Pietrosimone KM, Jin M, Poston B, Liu P. Collagen-Induced Arthritis: A model for Murine Autoimmune Arthritis. Bio Protoc 2015; 5(20).

33. Song HP, Li X, Yu R, Zeng G, Yuan ZY, Wang W, et al. Phenotypic characterization of type II collagen-induced arthritis in Wistar rats. Exp Ther Med 2015; 10(4):1483-8.

34. L Dai, A Claxson, SL Marklund, R Feakins, N Yousaf, Y Chernajovsky and PG Winyard. Amelioration of antigen-induced arthritis in rats by transfer of extracellular superoxide dismutase and catalase genes. Gene Ther 2003; 10,550-8. PMID:12646860

35. Ganesan K, Selvam R, Abhirami R, Raju KV, Manohar BM, Puvanakrishnan R. Gender differences and protective effects of testosterone in collagen induced arthritis in rats. Rheumatol Int 2008; 28(4):345-53.

36. Charbonnier LM, Han WG, Quentin J, Huizinga TW, Zwerina J, Toes RE, et al. Adoptive transfer of IL-10-secreting CD4+CD49b+ regulatory T cells suppresses ongoing arthritis. J Autoimmun 2010; 34(4):390-9.

37. Zhang W, Wang F, Wang B, Zhang J, Yu JY. Intraarticular gene delivery of CTLA4-FasL suppresses experimental arthritis. Int Immunol 2012; 24(6):379-88.

38. Boissier MC, Feng XZ, Carlioz A, Roudier R, Fournier C. Experimental autoimmune arthritis in mice. I. Homologous type II collagen is responsible for self-perpetuating chronic polyarthritis. Ann Rheum Dis 1987; 46(9):691-700.

font-family:"Times New Roman","serif";mso-ascii-theme-font:major-bidi;




How to Cite
Zavvar M, Abdolmaleki M, Farajifard H, Noorbakhsh F, Azadmanesh kayhan, Vojgani M, Nikcnam MH. Collagen II-primed Foxp3 Transduced T Cells Ameliorate Collagen-induced Arthritis in Rats: The Effect of Antigenic Priming on T Regulatory Cell Function. Iran J Allergy Asthma Immunol. 17(4):361-371.
Original Article(s)