Impact of CD4+CD25+ Regulatory T Cells in Maintenance of Spontaneous Immunotolerance in Mouse Liver Transplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

JIANG Xiaofeng , WANG Xuefan , CUI Zheming , ZHU Lei , GUO Dawei , SUN Wenyu , LIN Lin , TANG Yufu , LIANG Jian.

Department of Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, Liaoning Province, China;

Corresponding author：

Keywords：

CD4+CD25+ regulatory T cell; Mouse; Liver transplantation; Transplantation immunotolerance

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ObjectiveTo approach the role of CD4+CD25+ regulatory T cells in the maintenance of immunotolerance in mouse liver allograft. MethodsThe mouse orthotopic liver transplantation was performed. After the liver transplantation immunotolerance induction, antiCD25 monoclonal antibody (PC61) was injected into the recipients with a delayed timing to remove the CD4+CD25+ T cells. The percentage of CD4+CD25+ T cells and the expression of forkhead/winged helix transcription factor (Foxp3) in the recipients were examined. Furthermore, the survival time of the recipient was observed. ResultsC3H/HeJ recipients receiving DBA/2 hepatic allografts survived over 70 d as in the syngeneic liver transplantation (C3H/HeJ recipients receiving C3H/HeJ hepatic grafts). With various protocols of the delayed PC61 treatment, the CD4+CD25+ T cell was completely disappeared as observed. However, the removal of CD4+CD25+ regulatory T cells after the induction of transplantation immunotolerance did not affect the survival of hepatic allografts. ConclusionCD4+CD25+ regulatory T cells are not essential for the maintenance of spontaneous mouse liver transplantation immunotolerance.

Citation： JIANG Xiaofeng,WANG Xuefan,CUI Zheming,ZHU Lei,GUO Dawei,SUN Wenyu,LIN Lin,TANG Yufu,LIANG Jian.. Impact of CD4+CD25+ Regulatory T Cells in Maintenance of Spontaneous Immunotolerance in Mouse Liver Transplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(4): 366-369. doi: Copy

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12.	Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivationmediated apoptosis of effector CD4+ T cells [J]. Nat Immunol, 2007, 8(12): 13531362.
13.	Kearley J, Robinson DS, Lloyd CM. CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling [J]. J Allergy Clin Immunol, 2008, 122(3): 617624.
14.	Curiel TJ. Tregs and rethinking cancer immunotherapy [J]. J Clin Invest, 2007, 117(5): 11671174.
15.	Morse MA, Hobeika AC, Osada T, et al. Depletion of human regulatory T cells specifically enhances antigenspecific immune responses to cancer vaccines [J]. Blood, 2008, 112(3): 610618.
16.	Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease [J]. Nat Immunol, 2005, 6(4): 353360.
17.	Xue F, Chen W, Wang X, et al. Regulatory T cells contribute to the immunoregulatory effect on graft versus host reaction after liver transplantation in donordominant oneway MHC matching rats [J]. Transpl Immunol, 2009, 20(4): 232237.
18.	Nguyen VH, Shashidhar S, Chang DS, et al. The impact of regulatory T cells on Tcell immunity following hematopoietic cell transplantation [J]. Blood, 2008, 111(2): 945953.
19.	Kang SM, Tang Q, Bluestone JA. CD4+CD25+ regulatory T cells in transplantation: progress, challenges and prospects [J]. Am J Transplant, 2007, 7(6): 14571463.
20.	Iwami D, Zhang Q, Aramaki O, et al. Purified eicosapentaenoic acid induces prolonged survival of cardiac allografts and generates regulatory T cells [J]. Am J Transplant, 2009, 9(6): 12941307.
21.	Yoshizawa A, Ito A, Li Y, et al. The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation [J]. Transplant Proc, 2005, 37(1): 3739.
22.	Takatsuki M, Uemoto S, Inomata Y, et al. Weaning of immunosuppression in living donor liver transplant recipients [J]. Transplantation, 2001 , 72(3): 449454.
23.	Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3dependent programme of regulatory Tcell differentiation [J]. Nature, 2007, 445(7129): 771775.

1. Sugioka A, Morita M, Fujita J, et al. Graft acceptance and tolerance induction in mouse liver transplantation using wild mice [J]. Transplant Proc, 2001, 33(12): 137139.
2. Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes [J]. Nat Med, 2008, 14(1): 8892.
3. Jiang X, Sun W, Guo D, et al. Cardiac allograft acceptance induced by blockade of CD40CD40L costimulation is dependent on CD4(+)CD25(+) regulatory T cells [J]. Surgery, 2011, 149(3): 336346.
4. Waldmann H, Graca L, Cobbold S, et al. Regulatory T cells and organ transplantation [J]. Semin Immunol, 2004, 16(2): 119126.
5. Sugioka A, Morita M, Esaki T, et al. Evaluation of microchimerism after orthotopic liver transplantation between allogeneic mice [J]. Transplant Proc, 1997, 29(12): 11891192.
6. Harada M, Seino K, Wakao H, et al. Downregulation of the invariant Valpha14 antigen receptor in NKT cells upon activation [J]. Int Immunol, 2004, 16(2): 241247.
7. Roncarolo MG, Battaglia M. Regulatory Tcell immunotherapy for tolerance to self antigens and alloantigens in humans [J]. Nat Rev Immunol, 2007, 7(8): 585598.
8. Trzonkowski P, Szaryńska M, My＇sliwska J, et al. Ex vivo expansion of CD4(+)CD25(+) T regulatory cells for immunosuppressive therapy [J]. Cytometry A, 2009, 75(3): 175188.
9. Tarbell KV, Yamazaki S, Steinman RM. The interactions of dendritic cells with antigenspecific, regulatory T cells that suppress autoimmunity [J]. Semin Immunol, 2006, 18(2): 93102.
10. Sakaguchi S. Naturally arising Foxp3expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and nonself [J]. Nat Immunol, 2005, 6(4): 345352.
11. Webster KE, Walters S, Kohler RE, et al. In vivo expansion of T reg cells with IL2mAb complexes: induction of resistance to EAE and longterm acceptance of islet allografts without immunosuppression [J]. J Exp Med, 2009, 206(4): 751760.
12. Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivationmediated apoptosis of effector CD4+ T cells [J]. Nat Immunol, 2007, 8(12): 13531362.
13. Kearley J, Robinson DS, Lloyd CM. CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling [J]. J Allergy Clin Immunol, 2008, 122(3): 617624.
14. Curiel TJ. Tregs and rethinking cancer immunotherapy [J]. J Clin Invest, 2007, 117(5): 11671174.
15. Morse MA, Hobeika AC, Osada T, et al. Depletion of human regulatory T cells specifically enhances antigenspecific immune responses to cancer vaccines [J]. Blood, 2008, 112(3): 610618.
16. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease [J]. Nat Immunol, 2005, 6(4): 353360.
17. Xue F, Chen W, Wang X, et al. Regulatory T cells contribute to the immunoregulatory effect on graft versus host reaction after liver transplantation in donordominant oneway MHC matching rats [J]. Transpl Immunol, 2009, 20(4): 232237.
18. Nguyen VH, Shashidhar S, Chang DS, et al. The impact of regulatory T cells on Tcell immunity following hematopoietic cell transplantation [J]. Blood, 2008, 111(2): 945953.
19. Kang SM, Tang Q, Bluestone JA. CD4+CD25+ regulatory T cells in transplantation: progress, challenges and prospects [J]. Am J Transplant, 2007, 7(6): 14571463.
20. Iwami D, Zhang Q, Aramaki O, et al. Purified eicosapentaenoic acid induces prolonged survival of cardiac allografts and generates regulatory T cells [J]. Am J Transplant, 2009, 9(6): 12941307.
21. Yoshizawa A, Ito A, Li Y, et al. The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation [J]. Transplant Proc, 2005, 37(1): 3739.
22. Takatsuki M, Uemoto S, Inomata Y, et al. Weaning of immunosuppression in living donor liver transplant recipients [J]. Transplantation, 2001 , 72(3): 449454.
23. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3dependent programme of regulatory Tcell differentiation [J]. Nature, 2007, 445(7129): 771775.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Impact of CD4+CD25+ Regulatory T Cells in Maintenance of Spontaneous Immunotolerance in Mouse Liver Transplantation

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