Mechanism of Immune Hyporesponsiveness Induced by Recipient-Derived Immature Dendritic Cells in Rat Liver Transplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Li , ZHANG Shengning , RAN Jianghua , LIU Jing , LI Zhu , ZHAO Yongheng , LI Laibang

*The First Department of Hepatobiliaropancreatic Surgery, The Affiliated Ganmei Hospital of Kunming Medical College and The First Peoples Hospital of Kunming City, Liver Transplantation Center of Organ Transplantation Institute of Yunnan Province, Kunming 650011, ChinaCorresponding Author： LI Li, E-mail： ynkmlili@yahoo.com.cn;

Corresponding author：

Keywords：

Rat; Liver transplantation; Rejection; Immature dendritic cell; Immune hyporesponsiveness【Foundation item】 Science and Technology Plan of Yunnan Province (No.2007CA007)

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Objective To study the mechanism of immune hyporesponsiveness of allograft rejection induced by transfusion nonpufsed allopeptide syngeneic immature dendritic cell (imDC) generated from recipient bone marrow progenitors and to explore a possible strategy for liver allograft protection in clinic. Methods Forty experimental rats were randomly divided into 4 group: control group, cyclosporine A (CsA) group, mature DC (mDC) group and imDC group. In control group, Wistar rats only received liver transplantation. In CsA group, Wistar rats underwent liver transplantation plus CsA treatment 〔10 mg/（kg·d)〕. In mDC group, recipient-derived mDC 1×106 were infused intravenously through the penile vein to Wistar rats. In imDC group, ImDC with the dose of 1×106 were injected into Wistar rats via the dorsum vein of penile. In each group, five recipients were killed on the 10th day after transplantation, the other five recipients were left to observe survival time. The levels of ALT, AST, TBIL, IL-2, IFN-γ, IL-4 and IL-10 were detected. The acute rejection and the expression of FasL/Fas in the grafts were detected by HE and immunohistochemical staining. Western blot was used to detect Scurfin protein expression of CD4+ CD25+ T cells. Results The median survival time of the liver allografts in CsA group and imDC group were significantly longer than that in control group and mDC group ( P ＜ 0.05). The levels of ALT and TBIL in control group and mDC group were significantly higher than those in CsA group and imDC group ( P ＜ 0.05). Compared with CsA group and imDC group, the levels of IL-2 and IFN-γ were higher but the levels of IL-4 and IL-10 were lower in control group and mDC group ( P ＜ 0.01). Slightly or no rejection reaction was found in CsA group and imDC group ( P ＜ 0.05). The Scurfin protein expressions of CD4+ CD25+ T cells of imDC group were significantly higher than those of other three groups. Conclusion Application of nonpufsed allopeptide syngeneic recipient-derived imDC is an effective way to induce immune hyporesponsiveness by blocking indirect recognition in rat liver transplantation model. Survival span is significantly prolonged by its protective effect. The mechanism of immune hyporesponsiveness induced by imDC transfusion might be involved in some aspects: T cell apoptosis, immune deviation of Thl/Th2 cytokine net and inhibition of T lymphocytes responsiveness by regulatory T cells.

Citation： LI Li,ZHANG Shengning,RAN Jianghua,LIU Jing,LI Zhu,ZHAO Yongheng,LI Laibang,.. Mechanism of Immune Hyporesponsiveness Induced by Recipient-Derived Immature Dendritic Cells in Rat Liver Transplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2009, 16(1): 32-38. doi: Copy

1.	Barratt-Boyes SM, Thomson AW. Dendritic cells: tools and targets for transplant tolerance [Ｊ] . Am J Transplant, 2005; 5(12)： 2807.
2.	李纪鹏，黄怡，王为忠，等. TGF-β1基因修饰的未成熟树突状细胞对小肠移植大鼠外周血及移植肠浸润T细胞的影响 [Ｊ] . 中国普外基础与临床杂志， 2008； 15(2)： 96.
3.	Chen-Woan M, Delaney CP, Fournier V, et al . A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM-CSF, and their quantification using the mAb OX-62 [Ｊ] . J Immunol Methods， 1995; 178(2)： 157 4 Sun JH, Zeng QH, Wu MC. Experience with orthotopic rat liver transplantation [Ｊ] . Chin Med J (Engl), 1990; 103(2)： 142.
4.	Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage [Ｊ] . Transplantation, 1979; 28(1)： 47.
5.	Kashfi A, Mehrabi A, Pahlavan PS, et al . A review of various techniques of orthotopic liver transplantation in the rat [Ｊ] . Transplant Proc, 2005; 37(1)： 185.
6.	张升宁，白建华，刘静，等. 大鼠原位肝移植模型的手术改进及体会 [Ｊ] . 肝胆外科杂志， 2008； 16(3)： 210.
7.	Pêche H, Trinité B, Martinet B, et al . Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors [Ｊ] . Am J Transplant, 2005; 5(2)： 255.
8.	Bériou G, Pêche H, Guillonneau C, et al . Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression [Ｊ] . Transplantation, 2005; 79(8)： 969.
9.	Demetrius AJ, Batts KP, Dhillon AP, et al . Banff schema for grading liver allograft rejection: An international consensus document [Ｊ] . Hepatology, 1997; 25(3)： 658.
10.	Hübscher S. Diagnosis and grading of liver allograft rejection: a European perspective [Ｊ] . Transplant Proc, 1996; 28(1)： 504.
11.	Hroldt BS, Burattin M, Gunson BK, et al . Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? [Ｊ] . Liver Transpl, 2006; 12(7)： 1144.
12.	Pompili M, Mirante VG, Rapaccini GL, et al . Liver transplantation [Ｊ] . Ann Ital Med Int, 2004; 19(1)： 20.
13.	Tiao MM, Lu L, Tao R, et al . Application of recipient-derived dendritic cells to induce donor-specific T-cell hyporesponsiveness [Ｊ] . Transplant Proc, 2004; 36(5)： 1592.
14.	Gould DS, Auchincloss H Jr. Direct and indirect recognition: the role of MHC antigens in graft rejection [Ｊ] . Immunol Today, 1999; 20(2)： 77.
15.	Game DS, Lechler RI. Pathways of allorecognition: implications for transplantation tolerance [Ｊ] . Transpl Immunol, 2002; 10(2-3)： 101.
16.	Benham AM, Sawyer GJ, Fabre JW. Indirect T cell allorecognition of donor antigens contributes to the rejection of vascularized kidney allografts [Ｊ] . Transplantation, 1995; 59(7)： 1028.
17.	Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more [Ｊ] . Immunol Today, 1996; 17(3)： 138.
18.	Chen Y, Chen J, Liu Z, et al . Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats [Ｊ] . Transplant Proc, 2008; 40(8)： 2691.
19.	韩方海，张肇达，李月春，等. 监测Th1/Th2细胞因子变化对猪胰腺移植急性排斥反应早期诊断的意义 [Ｊ] . 四川大学学报（医学版）， 2006； 37(4)： 587.
20.	Mariotti J, Foley J, Ryan K, et al . Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway [Ｊ] . Blood, 2008; 112(12)： 4765.
21.	Wang YL, Tang ZQ, Gao W, et al . Influence of Th1, Th2, and Th3 cytokines during the early phase after liver transplantation [Ｊ] . Transplant Proc, 2003; 35(8)： 3024.
22.	Gibelli NE, Pinho-Apezzato ML, Miyatani HT, et al . Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study [Ｊ] . Transplant Proc, 2004; 36(4)： 956.
23.	Pellegrini P, Totaro R, Contasta I, et al . CD30 antigen and multiple sclerosis: CD30, an important costimulatory molecule and marker of a regulatory subpopulation of dendritic cells, is involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. The role of IFNbeta-1a in the treatment of multiple sclerosis [Ｊ] . Neuroimmunomodulation, 2005; 12(4)： 220.
24.	Min MP, Zhou D, Ichim TE, et al . Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance [Ｊ] . Immunol, 2003; 170(3)： 1304.
25.	Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3 [Ｊ] . Science, 2003; 299(5609)： 1057.
26.	Albert MH, Liu Y, Anasetti C, et al . Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation [Ｊ] . Eur J Immunol, 2005; 35(9)： 2598.
27.	吕凌，张峰，张伟，等. 转录因子Foxp3在自发免疫耐受大鼠移植肝内的表达 [Ｊ] . 中国普外基础与临床杂志， 2007； 14(2)： 138.
28.	Fontenot JD, Rasmussen JP, Williams LM, et al . Regulatory T cell lineage specification by the forkhead transcription factor foxp3 [Ｊ] . Immunity, 2005; 22(3)： 329.
29.	Wang H, Zhao L, Sun Z, et al . A potential side effect of cyclosporine A: inhibition of CD4+CD25+ regulatory T cells in mice [Ｊ] . Transplantation, 2006; 82 (11)： 1484.

1. Barratt-Boyes SM, Thomson AW. Dendritic cells: tools and targets for transplant tolerance [Ｊ] . Am J Transplant, 2005; 5(12)： 2807.
2. 李纪鹏，黄怡，王为忠，等. TGF-β1基因修饰的未成熟树突状细胞对小肠移植大鼠外周血及移植肠浸润T细胞的影响 [Ｊ] . 中国普外基础与临床杂志， 2008； 15(2)： 96.
3. Chen-Woan M, Delaney CP, Fournier V, et al . A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM-CSF, and their quantification using the mAb OX-62 [Ｊ] . J Immunol Methods， 1995; 178(2)： 157 4 Sun JH, Zeng QH, Wu MC. Experience with orthotopic rat liver transplantation [Ｊ] . Chin Med J (Engl), 1990; 103(2)： 142.
4. Kamada N, Calne RY. Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage [Ｊ] . Transplantation, 1979; 28(1)： 47.
5. Kashfi A, Mehrabi A, Pahlavan PS, et al . A review of various techniques of orthotopic liver transplantation in the rat [Ｊ] . Transplant Proc, 2005; 37(1)： 185.
6. 张升宁，白建华，刘静，等. 大鼠原位肝移植模型的手术改进及体会 [Ｊ] . 肝胆外科杂志， 2008； 16(3)： 210.
7. Pêche H, Trinité B, Martinet B, et al . Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors [Ｊ] . Am J Transplant, 2005; 5(2)： 255.
8. Bériou G, Pêche H, Guillonneau C, et al . Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression [Ｊ] . Transplantation, 2005; 79(8)： 969.
9. Demetrius AJ, Batts KP, Dhillon AP, et al . Banff schema for grading liver allograft rejection: An international consensus document [Ｊ] . Hepatology, 1997; 25(3)： 658.
10. Hübscher S. Diagnosis and grading of liver allograft rejection: a European perspective [Ｊ] . Transplant Proc, 1996; 28(1)： 504.
11. Hroldt BS, Burattin M, Gunson BK, et al . Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? [Ｊ] . Liver Transpl, 2006; 12(7)： 1144.
12. Pompili M, Mirante VG, Rapaccini GL, et al . Liver transplantation [Ｊ] . Ann Ital Med Int, 2004; 19(1)： 20.
13. Tiao MM, Lu L, Tao R, et al . Application of recipient-derived dendritic cells to induce donor-specific T-cell hyporesponsiveness [Ｊ] . Transplant Proc, 2004; 36(5)： 1592.
14. Gould DS, Auchincloss H Jr. Direct and indirect recognition: the role of MHC antigens in graft rejection [Ｊ] . Immunol Today, 1999; 20(2)： 77.
15. Game DS, Lechler RI. Pathways of allorecognition: implications for transplantation tolerance [Ｊ] . Transpl Immunol, 2002; 10(2-3)： 101.
16. Benham AM, Sawyer GJ, Fabre JW. Indirect T cell allorecognition of donor antigens contributes to the rejection of vascularized kidney allografts [Ｊ] . Transplantation, 1995; 59(7)： 1028.
17. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more [Ｊ] . Immunol Today, 1996; 17(3)： 138.
18. Chen Y, Chen J, Liu Z, et al . Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats [Ｊ] . Transplant Proc, 2008; 40(8)： 2691.
19. 韩方海，张肇达，李月春，等. 监测Th1/Th2细胞因子变化对猪胰腺移植急性排斥反应早期诊断的意义 [Ｊ] . 四川大学学报（医学版）， 2006； 37(4)： 587.
20. Mariotti J, Foley J, Ryan K, et al . Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway [Ｊ] . Blood, 2008; 112(12)： 4765.
21. Wang YL, Tang ZQ, Gao W, et al . Influence of Th1, Th2, and Th3 cytokines during the early phase after liver transplantation [Ｊ] . Transplant Proc, 2003; 35(8)： 3024.
22. Gibelli NE, Pinho-Apezzato ML, Miyatani HT, et al . Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study [Ｊ] . Transplant Proc, 2004; 36(4)： 956.
23. Pellegrini P, Totaro R, Contasta I, et al . CD30 antigen and multiple sclerosis: CD30, an important costimulatory molecule and marker of a regulatory subpopulation of dendritic cells, is involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. The role of IFNbeta-1a in the treatment of multiple sclerosis [Ｊ] . Neuroimmunomodulation, 2005; 12(4)： 220.
24. Min MP, Zhou D, Ichim TE, et al . Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance [Ｊ] . Immunol, 2003; 170(3)： 1304.
25. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3 [Ｊ] . Science, 2003; 299(5609)： 1057.
26. Albert MH, Liu Y, Anasetti C, et al . Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation [Ｊ] . Eur J Immunol, 2005; 35(9)： 2598.
27. 吕凌，张峰，张伟，等. 转录因子Foxp3在自发免疫耐受大鼠移植肝内的表达 [Ｊ] . 中国普外基础与临床杂志， 2007； 14(2)： 138.
28. Fontenot JD, Rasmussen JP, Williams LM, et al . Regulatory T cell lineage specification by the forkhead transcription factor foxp3 [Ｊ] . Immunity, 2005; 22(3)： 329.
29. Wang H, Zhao L, Sun Z, et al . A potential side effect of cyclosporine A: inhibition of CD4+CD25+ regulatory T cells in mice [Ｊ] . Transplantation, 2006; 82 (11)： 1484.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Mechanism of Immune Hyporesponsiveness Induced by Recipient-Derived Immature Dendritic Cells in Rat Liver Transplantation

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