目的了解肿瘤抗原肽的HLA限制性以及其诱导的T细胞能否杀伤肿瘤细胞,探索无关供者来源细胞用于过继性抗肿瘤T细胞治疗。方法使用16个肿瘤抗原肽诱导18名无关供者外周血单个核细胞(PBMC)分化为反应性T细胞,并分析HLA型别;利用NetMHC数据...目的了解肿瘤抗原肽的HLA限制性以及其诱导的T细胞能否杀伤肿瘤细胞,探索无关供者来源细胞用于过继性抗肿瘤T细胞治疗。方法使用16个肿瘤抗原肽诱导18名无关供者外周血单个核细胞(PBMC)分化为反应性T细胞,并分析HLA型别;利用NetMHC数据库预测肽和HLA分子亲和力;选择HLA-A2限制性的肿瘤抗原肽诱导第二组17名无关供者的PBMC进行杀瘤实验,反应性T细胞作为效应细胞,T2细胞及肿瘤抗原肽同源的肿瘤细胞作为靶细胞,测量LDH(乳酸脱氢酶)释放量或者RTCA(实时无标记细胞分析仪)检测效应细胞杀瘤效率,比较HLA-A2+和A2-T细胞杀瘤效率。结果筛出和HLA-A2具有高亲和力的肿瘤抗原肽LM7,可诱导5/11 HLA-A2+为反应性T细胞,其中HLA-A2+纯合子则为3/3,而HLA-A2-者则为2/7。LM7诱导反应性T细胞杀伤肿瘤百分比A2+组明显强于A2-组(60.72±11.28 vs 47.2±4.46,P=0.03)。结论本研究显示NetMHC预测对于纯合子样品更有帮助,肿瘤抗原肽LM7具有HLA-A2限制性,可诱导部分HLAA2+PBMC分化为反应性T细胞,可杀伤肿瘤,应对供者进行HLA筛选并分析其细胞功能,其诱导的反应性T细胞可作为过继性T细胞抗肿瘤治疗的细胞来源。展开更多
Objective: To study the protective and therapeutic antitumor immunity against hepatocellular carcinoma (HCC) with the fixed-tumor vaccine.Methods: A tumor vaccine consisting of fixed tumor cells or fixed tumor fragmen...Objective: To study the protective and therapeutic antitumor immunity against hepatocellular carcinoma (HCC) with the fixed-tumor vaccine.Methods: A tumor vaccine consisting of fixed tumor cells or fixed tumor fragments combined with sustained-releasers of cytokines and a non-toxic adjuvant was developed. C57BL/6J mice were immunized intra-dermally with the vaccine on day 0 and 7, followed by intrahepatic challenge with live Hepa 1–6 cells.Results: All of 15 nonimmunized control mice developed the hepatoma. Protection of mice immunized with fixed Hepa 1–6 cells and both of IL-2/GM-CSF microspheres or further mixed with TiterMax Gold reached 80% and 87%, respectively. Mass growth of the established tumors, vaccinated twice at 5 mm in diameter, the tumor of control animals continued to grow. However, 7–10 days after the second injection of the tumor vaccine, the tumor growth was suppressed in 9 of 10 mice and then markedly reduced. Complete tumor regression was observed in 60% (6/10) of mice. Splenocytes from the control mice were not able to lyse target Hepa 1–6 cells and other tumor cells. In contrast splenocytes from the vaccinated mice exhibited a 41% lytic activity against the Hepa 1–6 cells tested at an effector/target (E/T) ratio of 5, whereas they did not exhibited such activity against the melanoma cells (B16-F1), Lewis lung carcinoma cells (LLC), renal carcinoma cells (Renca), and bladder carcinoma cells (MBT-2). The cytotoxic activity was inhibited by the treatment with anti-CD3, anti-CD8, and anti-MHC-class I monoclonal antibodies but not with anti-CD4 and anti-MHC-class II antibodies. In the Phase-I clinical trial, vaccination of HCC patients with the autologous vaccine is a well-tolerated treatment and induces fixed tumor fragment-specific immunity.Conclusion: Fixed HCC vaccination elicited protective and therapeutic antitumor immunity against HCC. The tumor vaccine elicited antigen specific CTL response lysis of the target HCC was mediated by the typical MHC-class I restricted CD8+ T cells. Key words cancer vaccine - cytotoxic T lymphocyte - immunotherapy - hepatoma展开更多
Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly,T cells not only destroy hepatocytes infected by hepatitis B virus(HBV),but also control HBV ...Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly,T cells not only destroy hepatocytes infected by hepatitis B virus(HBV),but also control HBV replication or eradicate HBV in a noncytolytic manner.Therefore,analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control,which could lead to immunotherapy for terminating persistent HBV infection.There have been many attempts at immunotherapy for chronic HBV infection,and some have shown promising results.High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore,viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response,and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.展开更多
The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, li...The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.展开更多
文摘目的了解肿瘤抗原肽的HLA限制性以及其诱导的T细胞能否杀伤肿瘤细胞,探索无关供者来源细胞用于过继性抗肿瘤T细胞治疗。方法使用16个肿瘤抗原肽诱导18名无关供者外周血单个核细胞(PBMC)分化为反应性T细胞,并分析HLA型别;利用NetMHC数据库预测肽和HLA分子亲和力;选择HLA-A2限制性的肿瘤抗原肽诱导第二组17名无关供者的PBMC进行杀瘤实验,反应性T细胞作为效应细胞,T2细胞及肿瘤抗原肽同源的肿瘤细胞作为靶细胞,测量LDH(乳酸脱氢酶)释放量或者RTCA(实时无标记细胞分析仪)检测效应细胞杀瘤效率,比较HLA-A2+和A2-T细胞杀瘤效率。结果筛出和HLA-A2具有高亲和力的肿瘤抗原肽LM7,可诱导5/11 HLA-A2+为反应性T细胞,其中HLA-A2+纯合子则为3/3,而HLA-A2-者则为2/7。LM7诱导反应性T细胞杀伤肿瘤百分比A2+组明显强于A2-组(60.72±11.28 vs 47.2±4.46,P=0.03)。结论本研究显示NetMHC预测对于纯合子样品更有帮助,肿瘤抗原肽LM7具有HLA-A2限制性,可诱导部分HLAA2+PBMC分化为反应性T细胞,可杀伤肿瘤,应对供者进行HLA筛选并分析其细胞功能,其诱导的反应性T细胞可作为过继性T细胞抗肿瘤治疗的细胞来源。
文摘Objective: To study the protective and therapeutic antitumor immunity against hepatocellular carcinoma (HCC) with the fixed-tumor vaccine.Methods: A tumor vaccine consisting of fixed tumor cells or fixed tumor fragments combined with sustained-releasers of cytokines and a non-toxic adjuvant was developed. C57BL/6J mice were immunized intra-dermally with the vaccine on day 0 and 7, followed by intrahepatic challenge with live Hepa 1–6 cells.Results: All of 15 nonimmunized control mice developed the hepatoma. Protection of mice immunized with fixed Hepa 1–6 cells and both of IL-2/GM-CSF microspheres or further mixed with TiterMax Gold reached 80% and 87%, respectively. Mass growth of the established tumors, vaccinated twice at 5 mm in diameter, the tumor of control animals continued to grow. However, 7–10 days after the second injection of the tumor vaccine, the tumor growth was suppressed in 9 of 10 mice and then markedly reduced. Complete tumor regression was observed in 60% (6/10) of mice. Splenocytes from the control mice were not able to lyse target Hepa 1–6 cells and other tumor cells. In contrast splenocytes from the vaccinated mice exhibited a 41% lytic activity against the Hepa 1–6 cells tested at an effector/target (E/T) ratio of 5, whereas they did not exhibited such activity against the melanoma cells (B16-F1), Lewis lung carcinoma cells (LLC), renal carcinoma cells (Renca), and bladder carcinoma cells (MBT-2). The cytotoxic activity was inhibited by the treatment with anti-CD3, anti-CD8, and anti-MHC-class I monoclonal antibodies but not with anti-CD4 and anti-MHC-class II antibodies. In the Phase-I clinical trial, vaccination of HCC patients with the autologous vaccine is a well-tolerated treatment and induces fixed tumor fragment-specific immunity.Conclusion: Fixed HCC vaccination elicited protective and therapeutic antitumor immunity against HCC. The tumor vaccine elicited antigen specific CTL response lysis of the target HCC was mediated by the typical MHC-class I restricted CD8+ T cells. Key words cancer vaccine - cytotoxic T lymphocyte - immunotherapy - hepatoma
文摘Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly,T cells not only destroy hepatocytes infected by hepatitis B virus(HBV),but also control HBV replication or eradicate HBV in a noncytolytic manner.Therefore,analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control,which could lead to immunotherapy for terminating persistent HBV infection.There have been many attempts at immunotherapy for chronic HBV infection,and some have shown promising results.High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore,viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response,and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.
文摘The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.
