Background Blocking the 4-1BB/4-1BB ligand （4-1BBL） signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of...Background Blocking the 4-1BB/4-1BB ligand （4-1BBL） signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody （mAB） in acute rejection of rat orthotopic liver transplantation. Methods The orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase （AST）, alanine aminotransferase （ALT）, and bilirubin （BIL）, was assayed. The concentrations of interleukin （IL）-2, IL-10 and interferon （IFN）-γ in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope. Results Isotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver ailografts, and a mean graft survival time （MST） of 10.9 days. Administration of anti 4-1BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-γ. The histological grade of rejection on day 7 decreased and MST （17.3 days） increased substantially. Conclusions These results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.展开更多
The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand(4-1BBL)plays an important role in the activation,proliferation and differentiation of T lymphocytes.The function of 4-1BB/4-1BBL expressed by the immu...The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand(4-1BBL)plays an important role in the activation,proliferation and differentiation of T lymphocytes.The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts.In this study,4-1BBL was expressed in non-immune cells and non-tumor cells,and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated.The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed,and the plasmid was transfected into baby hamster kidney(BHK)cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly.The study demonstrated that the molecule 4-1BBL expressed by BHK cells in vitro could enhance the proliferation and cytotoxicity of lymphocytes,and it could increase the expression level of IL-2 and IFN-γ.The treatment with plasmid p4-1BBL in vivo revealed that the number of CD8+Tcells in the peri-tumoral tissue increased markedly,and the growth rate of the tumor was significantly lower than that of control group.Thesefindings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes.This therapeutic method may provide a promising approach for tumor immunotherapy.展开更多
文摘Background Blocking the 4-1BB/4-1BB ligand （4-1BBL） signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody （mAB） in acute rejection of rat orthotopic liver transplantation. Methods The orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase （AST）, alanine aminotransferase （ALT）, and bilirubin （BIL）, was assayed. The concentrations of interleukin （IL）-2, IL-10 and interferon （IFN）-γ in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope. Results Isotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver ailografts, and a mean graft survival time （MST） of 10.9 days. Administration of anti 4-1BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-γ. The histological grade of rejection on day 7 decreased and MST （17.3 days） increased substantially. Conclusions These results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.
基金supported in part by the National Natural Science Foundation of China(No.30600735)the Special Funds for Major State Basic Research Program of China(973 Program)(No.2002CB513100).
文摘The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand(4-1BBL)plays an important role in the activation,proliferation and differentiation of T lymphocytes.The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts.In this study,4-1BBL was expressed in non-immune cells and non-tumor cells,and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated.The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed,and the plasmid was transfected into baby hamster kidney(BHK)cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly.The study demonstrated that the molecule 4-1BBL expressed by BHK cells in vitro could enhance the proliferation and cytotoxicity of lymphocytes,and it could increase the expression level of IL-2 and IFN-γ.The treatment with plasmid p4-1BBL in vivo revealed that the number of CD8+Tcells in the peri-tumoral tissue increased markedly,and the growth rate of the tumor was significantly lower than that of control group.Thesefindings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes.This therapeutic method may provide a promising approach for tumor immunotherapy.
