Recent data suggest that activation of aryl hydrocarbon receptor （AhR） by its high-affinity ligand 2,3,7,8-tetrachlorodihenzo-p-dioxin （TCDD） results in expansion of regulatory T （Treg） cells and suppresses the ...Recent data suggest that activation of aryl hydrocarbon receptor （AhR） by its high-affinity ligand 2,3,7,8-tetrachlorodihenzo-p-dioxin （TCDD） results in expansion of regulatory T （Treg） cells and suppresses the development of autoimmune and allergic diseases in several models. Treg cells have been increasingly documented to suppress allograft rejection and even to establish stable long-term graft acceptance. However, the involvement of TCDD in the regulation of solid organ transplantation rejec- tion is largely unknown. Here, we examined whether activation of AhR with TCDD altered cardiac al- lograft rejection in an allogeneic heart transplant model. Recipient C57BL/6 （H-2b） mice were adminis- trated with a single intraperitoneal injection of TCDD, and the murine cardiac transplant models from BALB/c （H-2d） to C57BL/6 （H-2b） were built 24 h later. The complete cessation of cardiac contractility was defined as the observation endpoint. The effect of TCDD on T-cell proliferation was assessed by mixed lymphocyte reaction （MLR）. Histological and immunohistochemical analyses were performed to estimate the severity of rejection. The phenotype and cytokine profile of lymphocytes were analyzed by flow cytometry and enzyme-linked immunosorbent assay （ELISA）. Activation of AhR remarkably pro- longed the survival of cardiac allografts to more than 20 days. In vitro, TCDD ugregulated the fre- quency of CD4＋CD25＋Foxp3＋ Treg cells and suppressed the proliferation of T lymphocytes. In vivo, the prolonged survival time was associated with increased number of Treg cells in allografls and spleens Furthermore, the secretion of interferon-3, （IFN-3,） and interleukin-17 （IL-17） was reduced to less than 50% of that of the PBS treatment control group by TCDD treatment, whereas IL-10 was elevated to 10-fold of that of the PBS treatment control group. Collectively, our data indicate that activation of AhR with a single dose of TCDD significantly prolonged the survival of fully allogeneic cardiac grafts, and the mechanism underlying this effect might be involved in the induction of Treg cells.展开更多
To identify acute renal allograft rejection biomarkers in human serum, two-dimensional differential in-gel electrophoresis （2-D DIGE） and reversed phase high-performance liquid chromatography （RP-HPLC） followed by...To identify acute renal allograft rejection biomarkers in human serum, two-dimensional differential in-gel electrophoresis （2-D DIGE） and reversed phase high-performance liquid chromatography （RP-HPLC） followed by electrospray ionization mass spectrometry （ESI-MS） were used. Serum samples from renal allograft patients and normal volunteers were divided into three groups： acute rejec- tion （AR）, stable renal function （SRF） and normal volunteer （N）. Serum samples were firstly processed using Multiple Affinity Removal Column to selectively remove the highest abundance proteins. Differentially expressed proteins were analyzed using 2-D DIGE. These differential protein spots were excised, digested by trypsin, and identified by RP-HPLC-ESI/MS. Twenty-two differentially expressed proteins were identified in serum from AR group. These proteins included complement C9 precursor, apolipoprotein A-IV precursor, vitamin D-binding protein precursor, beta-2-glycoprotein 1 precursor, etc. Vitamin D-binding protein, one of these proteins, was confirmed by ELISA in the independent set of serum samples. In conclusion, the differentially expressed proteins as serum biomarker candidates may provide the basis of acute rejection noninvasive diagnosis. Confirmed vitamin D-binding protein may be one of serum biomarkers of acute rejection. Furthermore, it may provide great insights into understanding the mechanisms and potential treatment strategy of acute rejection.展开更多
基金supported by the grants from the Special Funds for State Key Development Program for Basic Research of China(973Program)(No.2009CB522407)National Natural Science Foundation of China(No.30972794)
文摘Recent data suggest that activation of aryl hydrocarbon receptor （AhR） by its high-affinity ligand 2,3,7,8-tetrachlorodihenzo-p-dioxin （TCDD） results in expansion of regulatory T （Treg） cells and suppresses the development of autoimmune and allergic diseases in several models. Treg cells have been increasingly documented to suppress allograft rejection and even to establish stable long-term graft acceptance. However, the involvement of TCDD in the regulation of solid organ transplantation rejec- tion is largely unknown. Here, we examined whether activation of AhR with TCDD altered cardiac al- lograft rejection in an allogeneic heart transplant model. Recipient C57BL/6 （H-2b） mice were adminis- trated with a single intraperitoneal injection of TCDD, and the murine cardiac transplant models from BALB/c （H-2d） to C57BL/6 （H-2b） were built 24 h later. The complete cessation of cardiac contractility was defined as the observation endpoint. The effect of TCDD on T-cell proliferation was assessed by mixed lymphocyte reaction （MLR）. Histological and immunohistochemical analyses were performed to estimate the severity of rejection. The phenotype and cytokine profile of lymphocytes were analyzed by flow cytometry and enzyme-linked immunosorbent assay （ELISA）. Activation of AhR remarkably pro- longed the survival of cardiac allografts to more than 20 days. In vitro, TCDD ugregulated the fre- quency of CD4＋CD25＋Foxp3＋ Treg cells and suppressed the proliferation of T lymphocytes. In vivo, the prolonged survival time was associated with increased number of Treg cells in allografls and spleens Furthermore, the secretion of interferon-3, （IFN-3,） and interleukin-17 （IL-17） was reduced to less than 50% of that of the PBS treatment control group by TCDD treatment, whereas IL-10 was elevated to 10-fold of that of the PBS treatment control group. Collectively, our data indicate that activation of AhR with a single dose of TCDD significantly prolonged the survival of fully allogeneic cardiac grafts, and the mechanism underlying this effect might be involved in the induction of Treg cells.
基金supported by a grant from National Basic Research 973 Program of China (No.2009CB522407)
文摘To identify acute renal allograft rejection biomarkers in human serum, two-dimensional differential in-gel electrophoresis （2-D DIGE） and reversed phase high-performance liquid chromatography （RP-HPLC） followed by electrospray ionization mass spectrometry （ESI-MS） were used. Serum samples from renal allograft patients and normal volunteers were divided into three groups： acute rejec- tion （AR）, stable renal function （SRF） and normal volunteer （N）. Serum samples were firstly processed using Multiple Affinity Removal Column to selectively remove the highest abundance proteins. Differentially expressed proteins were analyzed using 2-D DIGE. These differential protein spots were excised, digested by trypsin, and identified by RP-HPLC-ESI/MS. Twenty-two differentially expressed proteins were identified in serum from AR group. These proteins included complement C9 precursor, apolipoprotein A-IV precursor, vitamin D-binding protein precursor, beta-2-glycoprotein 1 precursor, etc. Vitamin D-binding protein, one of these proteins, was confirmed by ELISA in the independent set of serum samples. In conclusion, the differentially expressed proteins as serum biomarker candidates may provide the basis of acute rejection noninvasive diagnosis. Confirmed vitamin D-binding protein may be one of serum biomarkers of acute rejection. Furthermore, it may provide great insights into understanding the mechanisms and potential treatment strategy of acute rejection.
基金国家自然科学基金资助项目（30671989,30800524）国家重点基础研究发展规划（973计划）（2009CB522407）
志谢：感谢Toshiro Niki博士（GalPharma Ltd,Japan）提供pBKC-MV-mG9质粒和大鼠抗小鼠galectin-9单抗,以及Ritter Thomas教授（National University of Ireland,Galway,Ireland）提供腺病毒质粒pENTRlA DualSelection和pAd/CMV/V5-DEST.
