Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplan...Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody （mAb） daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Ra. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by dacllzumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ra ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL- 2Ra ectodomain. The antigen-binding site of daclizumab is mainly composed of live complementarity determining regions （CDRs） that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Ru ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2Ra and the subsequent formation of the IL-2fIL-2Ra[~/c complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Ra.展开更多
AIM: To investigate the efficacy and safety of a singledose daclizumab induction therapy in orthotopic liver transplantation (OLTx).METHODS: A retrospective study was made for 54 cases of OLTx in recent three years. T...AIM: To investigate the efficacy and safety of a singledose daclizumab induction therapy in orthotopic liver transplantation (OLTx).METHODS: A retrospective study was made for 54 cases of OLTx in recent three years. The daclizumab group consisted of 23 cases of OLTx who received single-dose of 2 mg/kg intravenously after postoperative 24 hours. The control group consisted of the remaining 31 patients. Additional immunosuppressors included steroids, mycomphenolate mofetil, facrolimus or microemulsion cyclosporine used in all patients. Meta-statistical analysis was made for general data,incidence of acute rejection and infection, postoperative clinical course, complications and prognosis between two groups.RESULTS: Pretransplant demographies were not significantly different between two groups. In the induction group there were significantly less acute rejection episodes (5 of 23, 21.74 %) than those in the control group (12 of 31, 38.71%), which were proved by pathologic diagnosis (P＜0.05). The incidence of infection at the early stage was not significantly different between two groups.CONCLUSION: Induction therapy with single-dose of daclizumab is safe and effective and appears to be able to reduce the incidence of acute rejection.展开更多
AIM: To investigate the use of Daclizumab (Dmab) as an immunosuppressive agent in an experimental model of hepatocyte xenotransplantation (XenoTx) in rats with fulminant hepatic failure (FHF). METHODS: Two white male ...AIM: To investigate the use of Daclizumab (Dmab) as an immunosuppressive agent in an experimental model of hepatocyte xenotransplantation (XenoTx) in rats with fulminant hepatic failure (FHF). METHODS: Two white male New Zealand rabbits were used as donors and 68 Wistar rats as recipients. FHF was induced by intravenous application of dimethylnitrosamine (DMNA). The isolated hepatocytes of the rabbits were xenotransplanted into the spleen of the rats 24 h after FHF induction. Group A (n = 13): no treatment; Group B (n = 14): FHF and XenoTx; Group C (n = 14): FHF and XenoTx and cyclosporin (CsA); Group D (n = 14): FHF and XenoTx and Dmab; Group E (n = 13): FHF and XenoTx and CsA and Dmab. The rats were followed for 15 d. RESULTS: Statistical analysis showed better survival among groups D (92.86%) and E (76.92%) compared to group A (all rats died after 72 h), group B (28.57%) or group C (71.43%), although the differences were not statistically significant. Biochemical evaluation of the liver enzymes and histology confirmed satisfactory function and engraftment, respectively. CONCLUSION: This experimental model has shown the safe, effective and beneficial use of Dmab in a xenotransplantation model of rabbit hepatocytes in rats.展开更多
目的总结本组8例心脏移植受者应用免疫诱导方案治疗的临床经验。方法8例终末期扩张型心肌病患者接受同种异体原位心脏移植术,免疫诱导采用术前12 h内及术后第14天2剂赛尼哌1.0 mg/kg(抗白介素-2受体抗体)结合术后前5 d 5剂抗胸腺细胞球...目的总结本组8例心脏移植受者应用免疫诱导方案治疗的临床经验。方法8例终末期扩张型心肌病患者接受同种异体原位心脏移植术,免疫诱导采用术前12 h内及术后第14天2剂赛尼哌1.0 mg/kg(抗白介素-2受体抗体)结合术后前5 d 5剂抗胸腺细胞球蛋白(ATG)100 mg/d的方法,免疫抑制维持治疗采用环孢素A(或他克莫司)+骁悉(或硫唑嘌呤)+泼尼松三联方案。结果全组无死亡,移植后早期心内膜心肌活检无明显急性排斥反应,无移植物功能不全,无明显急性肾功能不全;3例发生机会性感染,1例远期发生急性排斥反应。结论心脏移植围术期采用2剂赛尼哌结合5剂ATG进行免疫诱导治疗方案能有效预防移植心脏急性排斥反应和减少器官功能损害,但可能增加感染的发生率。展开更多
基金Acknowledgments We are grateful to the staff members at Shanghai Synchrotron Radiation Facility for support in diffraction data collection and other members of our group for helpful discussion. This work was supported by grants from the Ministry of Science and Technology of China （2010CB833601, 2006AA02A313, and 2009ZX09503- 009）, the National Natural Science Foundation of China （30730028 and 90713046）, and the Chinese Academy of Sciences （KSCX2-YW-R- 107 and SIBS2008002）.
文摘Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody （mAb） daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Ra. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by dacllzumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ra ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL- 2Ra ectodomain. The antigen-binding site of daclizumab is mainly composed of live complementarity determining regions （CDRs） that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Ru ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2Ra and the subsequent formation of the IL-2fIL-2Ra[~/c complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Ra.
文摘AIM: To investigate the efficacy and safety of a singledose daclizumab induction therapy in orthotopic liver transplantation (OLTx).METHODS: A retrospective study was made for 54 cases of OLTx in recent three years. The daclizumab group consisted of 23 cases of OLTx who received single-dose of 2 mg/kg intravenously after postoperative 24 hours. The control group consisted of the remaining 31 patients. Additional immunosuppressors included steroids, mycomphenolate mofetil, facrolimus or microemulsion cyclosporine used in all patients. Meta-statistical analysis was made for general data,incidence of acute rejection and infection, postoperative clinical course, complications and prognosis between two groups.RESULTS: Pretransplant demographies were not significantly different between two groups. In the induction group there were significantly less acute rejection episodes (5 of 23, 21.74 %) than those in the control group (12 of 31, 38.71%), which were proved by pathologic diagnosis (P＜0.05). The incidence of infection at the early stage was not significantly different between two groups.CONCLUSION: Induction therapy with single-dose of daclizumab is safe and effective and appears to be able to reduce the incidence of acute rejection.
文摘AIM: To investigate the use of Daclizumab (Dmab) as an immunosuppressive agent in an experimental model of hepatocyte xenotransplantation (XenoTx) in rats with fulminant hepatic failure (FHF). METHODS: Two white male New Zealand rabbits were used as donors and 68 Wistar rats as recipients. FHF was induced by intravenous application of dimethylnitrosamine (DMNA). The isolated hepatocytes of the rabbits were xenotransplanted into the spleen of the rats 24 h after FHF induction. Group A (n = 13): no treatment; Group B (n = 14): FHF and XenoTx; Group C (n = 14): FHF and XenoTx and cyclosporin (CsA); Group D (n = 14): FHF and XenoTx and Dmab; Group E (n = 13): FHF and XenoTx and CsA and Dmab. The rats were followed for 15 d. RESULTS: Statistical analysis showed better survival among groups D (92.86%) and E (76.92%) compared to group A (all rats died after 72 h), group B (28.57%) or group C (71.43%), although the differences were not statistically significant. Biochemical evaluation of the liver enzymes and histology confirmed satisfactory function and engraftment, respectively. CONCLUSION: This experimental model has shown the safe, effective and beneficial use of Dmab in a xenotransplantation model of rabbit hepatocytes in rats.
