Anti-Rejection Effect of Triptolide on Islet Allografts in Chemically Induced Diabetic Mice_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIANG Kuo ¹ , LIU Shuang ¹ , CUI Yeqing ¹ , SUN Haichen ¹ , LUO Bin ¹ , WAN Suigui ² , SUN Xuejing ² , GUO Duo ³ ,  LI Fei ¹

1.Department of General Surgery， Xuanwu Hospital of Capital Medical University， Beijing 100053， China;;
2.Flow Cytometry Laboratory， Department of Hematology， Xuanwu Hospital of Capital Medical University， Beijing 100053， China;;
3.Department of Anatomy， Histology and Embryology， Capital Medical University， Beijing 100054， China.;

Corresponding author：

LI Fei, Email: fli36@hotmail.com

Keywords：

Islet transplantation; Immunosuppression; Triptolide; Regulatory T cell

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Objective 　To investigate the anti-rejection effect and the mechanism of triptolide （TPT） on islet allo- grafts in a murine model.
Methods 　BALB/c mice were used as islet donor. C57BL/6 mice were rendered diabetic by streptozotocin （STZ） injection， and transplanted with islets under the left kidney capsule. The recipients were randomly （method of random digits table） divided into three groups （n=8）. The mice in the treatment groups were injected intrap-
eritoneally with TPT at 50 μg/kg （low-dose TPT group， L-TPT group） or 100 μg/kg （high-dose TPT group， H-TPT group） daily in the first 5 days and then on alternate days until 14 days；while the mice in control group were given vehicles （1% tween 80）. Blood glucose after operation were monitored. The grafts were defined as rejection when two consecutive reading of blood glucose＞20 mmol/L. The left kidney of three recipients in each group were resected for pathological examination. The proportion of CD4＋CD25＋Foxp3＋ regulatory T cells in spleen tissues were tested by flow cytometry.
Results 　The median survival time of islet allografts from the control group， L-TPT group， and H-TPT group were 12.6 days （9-16 days）， 21.4 days （14-27 days）， and 27.6 days （19-34 days）， respectivly. The percentage
of CD4＋CD25＋Foxp3＋regulatory T cells in spleen tissues of three groups were （5.2±0.6）%，（12.0±1.3）%， and
（15.7±1.8）%， respectivly. Compared with control group， the median survival time of islet transplantation in mice exte-
nded and the proportion of CD4＋CD25＋Foxp3＋ regulatory T cells in spleen tissues increased （P＜0.05）.
Conclusions　 TPT could increase the percentage of CD4＋CD25＋Foxp3＋ regulatory T cells， reduce the rejection after islet transplanta-tion， and prolong the survival time of islet transplantation in mice. The immunosuppressive effect of TPT shows a dose-dependent.

Citation： LIANG Kuo,LIU Shuang,CUI Yeqing,SUN Haichen,LUO Bin,WAN Suigui,SUN Xuejing,GUO Duo,LI Fei. Anti-Rejection Effect of Triptolide on Islet Allografts in Chemically Induced Diabetic Mice. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(7): 737-741. doi: Copy

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2.	Ryan EA， Paty BW， Senior PA， et al. Five-year follow-up after clinical islet transplantation[J]. Diabetes， 2005， 54(7)：2060-2069.
3.	Larsen JL， Bennett RG， Burkman T， et al. Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats[J]. Transplantation， 2006， 82(4)： 466-470.
4.	Wang J， Xu R， Jin R， et al. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. Ⅰ. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine[J]. Transplantation， 2000， 70(3)： 447-455.
5.	Li R， Takazawa K， Suzuki H， et al. Synergistic effect of triptolideand tacrolimus on rat cardiac allotransplantation[J]. Jpn Heart J， 2004， 45(4)：657-665.
6.	Liu Y， Chen Y， Liu FQ， et al. Combined treatment with triptolideand rapamycin prolongs graft survival in a mouse model of cardiactransplantation[J]. Transpl Int， 2008， 21(5)：483-494.
7.	Zhang G， Liu Y， Guo H， et al. Triptolide promotes generation of FoxP3＋ T regulatory cells in rats[J]. J Ethnopharmacol， 2009， 125(1)： 41-46.
8.	郑树森，郭华，俞军，等. 雷公藤多甙抑制大鼠异种肝移植急性排斥的研究[J]. 中华器官移植杂志， 2003， 24 (6)：223-225.
9.	刘爽，崔士华，孙海晨，等. 一种改良的小鼠胰岛分离和移植模型[J]. 首都医科大学学报， 2009， 30(2)：259-261.
10.	Xin MJ， Cui SH， Liu S， et al. Triptolide prolonged allogeneic islet graft survival in chemically induced and spontaneously diabeticmice without impairment of islet function[J]. Hepatobiliary Pancreat Dis Int， 2010， 9(3)：312-318.
11.	Liang K， Du W， Zhu W， et al. Contribution of different mecha-nisms to pancreatic beta-cell hyper-secretion in non-obese diabetic(NOD) mice during pre-diabetes[J]. J Biol Chem， 2011， 286(45)：39537-39545.
12.	徐泽宽，苗毅. 胰腺移植和胰岛移植的现状[J]. 中国普外基础与临床杂志， 2003， 10(6)： 532-534.
13.	张剑，陈规划，翁建平，等. 抗CD40L 单克隆抗体在异种胰岛移植排斥反应中的作用[J]. 中国普外基础与临床杂志， 2008， 15(5)： 329-332.
14.	李柏峰，刘永锋，程颖，等. 氨基胍对大鼠胰岛保护作用的实验研究[J]. 中国普外基础与临床杂志， 2009， 16(9)： 729-733.
15.	Lo DJ， Anderson DJ， Weaver TA， et al. Belatacept and sirolimusprolong nonhuman primate renal allograft survival without arequirement for memory T cell depletion[J]. Am J Transplant， 2013， 13(2)： 320-328.
16.	Lowe M， Badell IR， Thompson P， et al. A novel monoclonal antibody to CD40 prolongs islet allograft survival[J]. Am J Transplant， 2012， 12(8)： 2079-2087.
17.	Yin N， Zhang N， Xu J， et al. Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival[J]. Transplantation， 2011， 92(1) ：25-30.
18.	Nataraju A， Saini D， Ramachandran S， et al. Oleanolic acid， a plant triterpenoid， significantly improves survival and function of islet allograft[J]. Transplantation， 2009， 88(8)：987-994.
19.	Zhou R， Zhang F， He PL， et al. (5R)-5-hydroxytriptolide (LLDT-8)， a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo[J]. Int Immunopharmacol， 2005， 5(13-14)：1895-1903.
20.	Liu Q， Chen T， Chen G， et al. Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-kappaB pathways[J]. Mol Immunol， 2007，44(10)： 2686-2696.
21.	Hong Y， Zhou W， Li K， et al. Triptolide is a potent suppressant of C3， CD40 and B7h expression in activated human proximaltubular epithelial cells[J]. Kidney Int， 2002， 62(4)：1291-1300.
22.	Liu Y， Chen Y， Lamb JR， et al. Triptolide， a component of Chinese herbal medicine， modulates the functional phenotype of dendritic cells[J]. Transplantation， 2007， 84(11)： 1517-1526.
23.	Hoffmann P， Ermann J， Edinger M， et al. Donor-type CD4＋CD25＋T regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation[J]. J Exp Med， 2002， 196(3)： 389-399.
24.	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.
25.	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.
26.	Sakaguchi S. Naturally arising CD4＋ regulatory T cells for immu-nologic self tolerance and negative control of immune responses[J]. Annu Rev Immunol， 2004， 22： 531-562.
27.	Shevach EM， McHugh RS， Piccirillo CA， et al. Control of T cell activation by CD4＋CD25＋T suppressor T cells[J]. ImmunolRev， 2001， 182：58-67.
28.	Cobbokl SP， Graca L， Lin CY， et al. Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance[J]. Transpl Int， 2003， 16(2) ： 66-75.
29.	Zorn E， Kim HT， Lee SJ， et al． Reduced frequency of FOXP3＋CD4＋CD25＋regulatory T cells in patients with chronic graft-versus-host disease[J]. Blood， 2005， 106(8) ： 2903-2911.
30.	Hori S， Nomura T， Sakaguchi S. Control of regulatory T cell development by the transcription factor FoxP3[J]. Science， 2003， 299(5609)：1057-1061.

1. Shapiro AM， Lakey JR， Ryan EA， et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen[J]. N Engl J Med， 2000， 343(4)：230-238.
2. Ryan EA， Paty BW， Senior PA， et al. Five-year follow-up after clinical islet transplantation[J]. Diabetes， 2005， 54(7)：2060-2069.
3. Larsen JL， Bennett RG， Burkman T， et al. Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats[J]. Transplantation， 2006， 82(4)： 466-470.
4. Wang J， Xu R， Jin R， et al. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. Ⅰ. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine[J]. Transplantation， 2000， 70(3)： 447-455.
5. Li R， Takazawa K， Suzuki H， et al. Synergistic effect of triptolideand tacrolimus on rat cardiac allotransplantation[J]. Jpn Heart J， 2004， 45(4)：657-665.
6. Liu Y， Chen Y， Liu FQ， et al. Combined treatment with triptolideand rapamycin prolongs graft survival in a mouse model of cardiactransplantation[J]. Transpl Int， 2008， 21(5)：483-494.
7. Zhang G， Liu Y， Guo H， et al. Triptolide promotes generation of FoxP3＋ T regulatory cells in rats[J]. J Ethnopharmacol， 2009， 125(1)： 41-46.
8. 郑树森，郭华，俞军，等. 雷公藤多甙抑制大鼠异种肝移植急性排斥的研究[J]. 中华器官移植杂志， 2003， 24 (6)：223-225.
9. 刘爽，崔士华，孙海晨，等. 一种改良的小鼠胰岛分离和移植模型[J]. 首都医科大学学报， 2009， 30(2)：259-261.
10. Xin MJ， Cui SH， Liu S， et al. Triptolide prolonged allogeneic islet graft survival in chemically induced and spontaneously diabeticmice without impairment of islet function[J]. Hepatobiliary Pancreat Dis Int， 2010， 9(3)：312-318.
11. Liang K， Du W， Zhu W， et al. Contribution of different mecha-nisms to pancreatic beta-cell hyper-secretion in non-obese diabetic(NOD) mice during pre-diabetes[J]. J Biol Chem， 2011， 286(45)：39537-39545.
12. 徐泽宽，苗毅. 胰腺移植和胰岛移植的现状[J]. 中国普外基础与临床杂志， 2003， 10(6)： 532-534.
13. 张剑，陈规划，翁建平，等. 抗CD40L 单克隆抗体在异种胰岛移植排斥反应中的作用[J]. 中国普外基础与临床杂志， 2008， 15(5)： 329-332.
14. 李柏峰，刘永锋，程颖，等. 氨基胍对大鼠胰岛保护作用的实验研究[J]. 中国普外基础与临床杂志， 2009， 16(9)： 729-733.
15. Lo DJ， Anderson DJ， Weaver TA， et al. Belatacept and sirolimusprolong nonhuman primate renal allograft survival without arequirement for memory T cell depletion[J]. Am J Transplant， 2013， 13(2)： 320-328.
16. Lowe M， Badell IR， Thompson P， et al. A novel monoclonal antibody to CD40 prolongs islet allograft survival[J]. Am J Transplant， 2012， 12(8)： 2079-2087.
17. Yin N， Zhang N， Xu J， et al. Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival[J]. Transplantation， 2011， 92(1) ：25-30.
18. Nataraju A， Saini D， Ramachandran S， et al. Oleanolic acid， a plant triterpenoid， significantly improves survival and function of islet allograft[J]. Transplantation， 2009， 88(8)：987-994.
19. Zhou R， Zhang F， He PL， et al. (5R)-5-hydroxytriptolide (LLDT-8)， a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo[J]. Int Immunopharmacol， 2005， 5(13-14)：1895-1903.
20. Liu Q， Chen T， Chen G， et al. Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-kappaB pathways[J]. Mol Immunol， 2007，44(10)： 2686-2696.
21. Hong Y， Zhou W， Li K， et al. Triptolide is a potent suppressant of C3， CD40 and B7h expression in activated human proximaltubular epithelial cells[J]. Kidney Int， 2002， 62(4)：1291-1300.
22. Liu Y， Chen Y， Lamb JR， et al. Triptolide， a component of Chinese herbal medicine， modulates the functional phenotype of dendritic cells[J]. Transplantation， 2007， 84(11)： 1517-1526.
23. Hoffmann P， Ermann J， Edinger M， et al. Donor-type CD4＋CD25＋T regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation[J]. J Exp Med， 2002， 196(3)： 389-399.
24. 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.
25. 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.
26. Sakaguchi S. Naturally arising CD4＋ regulatory T cells for immu-nologic self tolerance and negative control of immune responses[J]. Annu Rev Immunol， 2004， 22： 531-562.
27. Shevach EM， McHugh RS， Piccirillo CA， et al. Control of T cell activation by CD4＋CD25＋T suppressor T cells[J]. ImmunolRev， 2001， 182：58-67.
28. Cobbokl SP， Graca L， Lin CY， et al. Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance[J]. Transpl Int， 2003， 16(2) ： 66-75.
29. Zorn E， Kim HT， Lee SJ， et al． Reduced frequency of FOXP3＋CD4＋CD25＋regulatory T cells in patients with chronic graft-versus-host disease[J]. Blood， 2005， 106(8) ： 2903-2911.
30. Hori S， Nomura T， Sakaguchi S. Control of regulatory T cell development by the transcription factor FoxP3[J]. Science， 2003， 299(5609)：1057-1061.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Anti-Rejection Effect of Triptolide on Islet Allografts in Chemically Induced Diabetic Mice

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