Investigation of Immunological Rejection after Hepatocyte Transplantation for Acute Liver Failure in Animals_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WEI Lingling , DENG Shaoping , HUANG Xiaolun

Center of Cell Transplant， Institute of Organ Transplantation，Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital， Chengdu 610072， Sichuan Province， China;

Corresponding author：

Keywords：

Hepatocyte transplantation; Xenotransplantation; Acute liver failure; Immunological rejection

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Objective 　To investigate the immunological rejection after hepatocyte transplantation for acute liver failure （ALF） in mice．
Methods 　The hepatocytes were isolated from pig，BALB/c and C57BL/6 mice livers were conducted and then transplanted into C57BL/6 mice．CCl4 was used to make ALF mice model．The experimental animals were randomly divided into three groups， including syngenic group，allogeneic group，and xenogenic group．The survival statuses of all the mice were recorded. The alteration of T lymphocyte subsets，immune globulin，and cytokine were determined．
Results ①The survival ratio was 8/10，6/10， and 3/10 in the syngenic group， allogeneic group， and xenogenic group， respectively．The survival ratio in the syngenic group was significantly higher than that in the other two groups （P＜0.05）．②The CD4+ and CD8+ T cells of the peripheral blood in the syngenic group did not change significantly on week one after transplantation．The CD4+ T cells in the allogeneic group reached the peak on day 3 after hepatocyte transplantation （P＜0.05）， while CD8+ T cells did not change much in one week．The CD4+ and CD8+ T cells in the xenogenic group increased and reached the peak on day 3 after transplantation （P＜0.05）．③There were no significantly differences of IgM and IgG in the syngenic group among 0.5， 1， and 3 d after transplantation. IgM of the allogeneic group and xenogenic group reached the peak on day 1 （P＜0.05） and IgG reached the peak on day 3 （P＜0.05） after transplantation．④The concentrations of IFN-γ， TNF-ɑ， and IL-2 in the allogeneic group and xenogenic group were significantly higher than those in the syngenic group （P＜0.05）．The concentration of IL-6 of the xenogenic group was higher than that of the other two groups （P＜0.05）.
Conclusions 　CD4+ and CD8+ T cells play an important role in immune response to both allogeneic and xenogenic hepatocyte transplantation， as well as induce humoral immune response early after hepatocyte transplantation．

Citation： WEI Lingling,DENG Shaoping,HUANG Xiaolun. Investigation of Immunological Rejection after Hepatocyte Transplantation for Acute Liver Failure in Animals. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(2): 135-139. doi: Copy

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2.	Ito M，Nagata H，Miyakawa S，et al．Review of hepatocyte transplantation[J]．J Hepatobiliary Pancreat Surg，2009，16(2)： 97-100．.
3.	Puppi J，Dhawan A．Human hepatocyte transplantation overview[J]．Methods Mol Biol，2009，481：1-16．.
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5.	Zern MA．Cell transplantation to replace whole liver transplantation[J]．Gastroenterology，2009，136(3)：767-769．.
6.	Li WC，Ralphs KL，Tosh D．Isolation and culture of adult mouse hepatocytes[J]．Methods Mol Biol，2010，633：185-196．.
7.	王燕，周露婷，章卫平，等．高活力原代小鼠肝细胞的分离与纯化[ J]．医学研究杂志，2011，40(3)：28-31．.
8.	Song X，Guo Y，Duo S，et al． A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation[J]．Am J Pathol，2009，175(5)：1975-1983．.
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12.	Seppen J，Filali EE，Elferink RO．Small animal models of hepatocyte transplantation[J]．Methods Mol Biol，2009，481：75-82.
13.	Zimmerer JM，Pham TA，Sanders VM，et al．CD8+ T cells negatively regulate IL-4-dependent，IgG1-dominant posttransplant alloantibody production[J]．J Immunol，2010，185(12)：7285-7292．.
14.	Tellides G，Pober JS．Interferon-γ axis in graft arteriosclerosis[J]．Circ Res，2007，100(5)：622-632．.
15.	Jiang X，Kojo S，Harada M，et al．Mechanism of NKT cell-mediated transplant tolerance[J]．Am J Transplant，2007，7(6)： 1482-1490．.
16.	Ekser B，Gridelli B，Veroux M，et al．Clinical pig liver xenotransplantation：how far do we have to go?[J]．Xenotransplantation，2011，18(3)：158-167．.
17.	Ekser B，Ezzelarab M，Hara H，et al．Clinical xenotransplantation：the next medical revolution?[J]．Lancet，2011 Oct 20[Epub ahead of print]．.
18.	Bonavita AG，Quaresma K，Cotta-de-Almeida V，et al．Hepatocyte xenotransplantation for treating liver disease[J]．Xenotransplantation，2010，17(3)：181-187．.
19.	Bartlett DC，Newsome PN．Xenotransplantation：still a bridge too far?[J]．Transplantation，2010，90(5)：481-482．.
20.	Cowan PJ，Robson SC，d’Apice AJ．Controlling coagulation dysregulation in xenotransplantation[J]．Curr Opin Organ Transplant，2011，16(2)：214-221．.
21.	Lytras D，Papalois A，Tsaroucha AK，et al．Xenotransplantation of hepatocytes in rats with acute liver failure using sirolimus for immunosuppression[J]．J Int Med Res，2010，38(2)：546-557.
22.	刘骅，曹晖，吴志勇．不同免疫治疗方案诱导大鼠原位肝移植免疫耐受的实验研究[ J]．中国普通外科杂志， 2009，18(1)： 27-30．.
23.	陈钟，蔡鸿宇，汤飞，等．聚乳酸 -O-羧甲基壳聚糖纳米粒子对大鼠腹腔内猪肝细胞异种移植免疫排斥反应的影响[ J]．中国组织工程研究与临床康复，2008，12(32)：6287-6291．.
24.	Bellizzi AM，Legallo RD，Boyd JC，et al．Hepatocyte cytokeratin 7 expression in chronic allograft rejection[J]．Am J Clin Pathol，2011，135(2)：238-244．.
25.	Landis CS，Yamanouchi K，Zhou H，et al．Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice[J]．Hepatology，2006，44(5)：12501258．.
26.	Shimojima N，Shimazu M，Kikuchi H，et al．Serum alcohol dehydrogenase：a sensitive biomarker of ongoing graft function after liver transplantation[J]．Clin Transplant，2007，21(4)：498-501.
27.	Isobe M，Futamatsu H，Suzuki J．Hepatocyte growth factor： Effects on immune-mediated heart diseases[J]．Trends Cardiovasc Med，2006，16(6)：188-193．.
28.	Suzuki J，Kawauchi M，Ogawa M，et al．Altered expression of hepatocyte growth factor in cardiac allografts of nonhuman primates[J]．Transplant Proc，2006，38(10)：3318-3320．.

1. Hughes RD，Mitry RR，Dhawan A．Current status of hepatocyte transplantation[J]．Transplantation，2011 Nov 11 [Epub ahead of print]．.
2. Ito M，Nagata H，Miyakawa S，et al．Review of hepatocyte transplantation[J]．J Hepatobiliary Pancreat Surg，2009，16(2)： 97-100．.
3. Puppi J，Dhawan A．Human hepatocyte transplantation overview[J]．Methods Mol Biol，2009，481：1-16．.
4. Akhter J，Johnson LA，Gunasegaram A，et al． Hepatocyte transplantation： a review of laboratory techniques and clinical experiences[J]．Surgeon，2007，5(3)：155-164．.
5. Zern MA．Cell transplantation to replace whole liver transplantation[J]．Gastroenterology，2009，136(3)：767-769．.
6. Li WC，Ralphs KL，Tosh D．Isolation and culture of adult mouse hepatocytes[J]．Methods Mol Biol，2010，633：185-196．.
7. 王燕，周露婷，章卫平，等．高活力原代小鼠肝细胞的分离与纯化[ J]．医学研究杂志，2011，40(3)：28-31．.
8. Song X，Guo Y，Duo S，et al． A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation[J]．Am J Pathol，2009，175(5)：1975-1983．.
9. Cho CH，Francois B，Tilles AW，et al．A new technique for primary hepatocyte expansion in vitro[J]．Biotechnol Bioeng， 2008，101(2)：345-356．.
10. Polson J，Lee WM；American Association for the Study of Liver Disease．AASLD position paper：the management of acute liver failure[J]．Hepatology，2005，41(5)：1179-1197．.
11. Weber A，Groyer-Picard MT，Franco D，et al．Hepatocyte transplantation in animal models[J]．Liver Transpl，2009，15(1)：7-14.
12. Seppen J，Filali EE，Elferink RO．Small animal models of hepatocyte transplantation[J]．Methods Mol Biol，2009，481：75-82.
13. Zimmerer JM，Pham TA，Sanders VM，et al．CD8+ T cells negatively regulate IL-4-dependent，IgG1-dominant posttransplant alloantibody production[J]．J Immunol，2010，185(12)：7285-7292．.
14. Tellides G，Pober JS．Interferon-γ axis in graft arteriosclerosis[J]．Circ Res，2007，100(5)：622-632．.
15. Jiang X，Kojo S，Harada M，et al．Mechanism of NKT cell-mediated transplant tolerance[J]．Am J Transplant，2007，7(6)： 1482-1490．.
16. Ekser B，Gridelli B，Veroux M，et al．Clinical pig liver xenotransplantation：how far do we have to go?[J]．Xenotransplantation，2011，18(3)：158-167．.
17. Ekser B，Ezzelarab M，Hara H，et al．Clinical xenotransplantation：the next medical revolution?[J]．Lancet，2011 Oct 20[Epub ahead of print]．.
18. Bonavita AG，Quaresma K，Cotta-de-Almeida V，et al．Hepatocyte xenotransplantation for treating liver disease[J]．Xenotransplantation，2010，17(3)：181-187．.
19. Bartlett DC，Newsome PN．Xenotransplantation：still a bridge too far?[J]．Transplantation，2010，90(5)：481-482．.
20. Cowan PJ，Robson SC，d’Apice AJ．Controlling coagulation dysregulation in xenotransplantation[J]．Curr Opin Organ Transplant，2011，16(2)：214-221．.
21. Lytras D，Papalois A，Tsaroucha AK，et al．Xenotransplantation of hepatocytes in rats with acute liver failure using sirolimus for immunosuppression[J]．J Int Med Res，2010，38(2)：546-557.
22. 刘骅，曹晖，吴志勇．不同免疫治疗方案诱导大鼠原位肝移植免疫耐受的实验研究[ J]．中国普通外科杂志， 2009，18(1)： 27-30．.
23. 陈钟，蔡鸿宇，汤飞，等．聚乳酸 -O-羧甲基壳聚糖纳米粒子对大鼠腹腔内猪肝细胞异种移植免疫排斥反应的影响[ J]．中国组织工程研究与临床康复，2008，12(32)：6287-6291．.
24. Bellizzi AM，Legallo RD，Boyd JC，et al．Hepatocyte cytokeratin 7 expression in chronic allograft rejection[J]．Am J Clin Pathol，2011，135(2)：238-244．.
25. Landis CS，Yamanouchi K，Zhou H，et al．Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice[J]．Hepatology，2006，44(5)：12501258．.
26. Shimojima N，Shimazu M，Kikuchi H，et al．Serum alcohol dehydrogenase：a sensitive biomarker of ongoing graft function after liver transplantation[J]．Clin Transplant，2007，21(4)：498-501.
27. Isobe M，Futamatsu H，Suzuki J．Hepatocyte growth factor： Effects on immune-mediated heart diseases[J]．Trends Cardiovasc Med，2006，16(6)：188-193．.
28. Suzuki J，Kawauchi M，Ogawa M，et al．Altered expression of hepatocyte growth factor in cardiac allografts of nonhuman primates[J]．Transplant Proc，2006，38(10)：3318-3320．.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Investigation of Immunological Rejection after Hepatocyte Transplantation for Acute Liver Failure in Animals

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