Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreactive T cells, which are involved in autoimmune diseases. However, it is unknown whether attenuated act...Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreactive T cells, which are involved in autoimmune diseases. However, it is unknown whether attenuated activated healthy autologous T-cell immunization could increase anti-tumor immune responses. To this end, C57B1/6 mice were immunized with attenuated activated autologous T cells. The splenocytes from immunized mice showed a higher proliferative ability than that from naive mice. The special phenotype analysis showed that there were more CD8+ T cells and CD62L+ T cells in immunized mice after 24 h of culture with 10% fetal calf serum complete medium in vitro (P〈0.01). These results demonstrated that this immunization may activate T cells in vivo. Furthermore, the splenocytes from immunized mice revealed resistance to activation-induced cell death (AICD) in vitro. To further study the relative genes that are responsible for the higher proliferation and resistance to AICD, the expression of Fas/Fas ligand (FasL) and GADD4513 was measured by real-time PCR. The results indicated that GADD45β transcription was higher in the splenocytes from immunized mice than that in the naive mice. In addition, the Fas expression showed a parallel higher, but FasL did not change obviously. To investigate the biologic functions induced by immunization in vivo, a tumor model was established by EL-4 tumor cell inoculation in C57/B1 mice. Mice receiving autologous T-cell immunization had significantly inhibited tumor growth in vivo (P〈0.01). This study implicated that immunization with attenuated activated autologous T cells enhances anti-tumor immune responses that participate in tumor growth inhibition.展开更多
Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have pre...Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.展开更多
Adoptive immunotherapy, the therapeutic infusion of ex vivo activated cancer-fighting white blood cells that was pioneered by Dr. Steven Rosenberg over 30 years ago, has become more widespread due to outstanding publi...Adoptive immunotherapy, the therapeutic infusion of ex vivo activated cancer-fighting white blood cells that was pioneered by Dr. Steven Rosenberg over 30 years ago, has become more widespread due to outstanding published research documenting the clinical efficacy of this strategy. Based on the well-established in vivo functions of NK and NKT cells, their integral role in the efficacy of certain chemotherapeutic and immunomodulatory agents, and their direct therapeutic action as displayed in clinical trials, the use of autologous natural killer cell infusions is an appropriate and warranted therapeutic option for the treatment of malignant diseases, especially in patients whose disease is refractory to standard treatments such as chemotherapy and radiation.展开更多
Background Peripheral T-cell lymphoma （PTCL） is generally characterized by poor prognosis after conventional chemotherapy. The place for high-dose chemotherapy and autologous stem cell transplantation （ASCT） in th...Background Peripheral T-cell lymphoma （PTCL） is generally characterized by poor prognosis after conventional chemotherapy. The place for high-dose chemotherapy and autologous stem cell transplantation （ASCT） in these patients is still not clear. In this study, we presented the outcomes of PTCL patients followed these treatments in our centre. Methods We retrospectively analyzed the outcomes of 39 patients with PTCL received the two treatments between 1999 and 2010. Results The 3-year overall survival （OS） of 61.9% and 3-year progression free survival （PFS） of 35.7% were observed in the 39 patient. Twenty-one patients received Hyper-CVAD chemotherapy with 3-year OS of 46.2% and 3-year PFS of 27.9%. Eighteen patients received ASCT with 3-year OS of 70.3% and 3-year PFS of 44.2%. Further analysis revealed that patients with elevated lactate dehydrogenase, at least 2 international prognostic index （IPI） points, and extranodal involvement had a poorer outcome compared with the control group. Conclusion These findings might suggest that Hyper-CVAD chemotherapy and ASCT could offer a durable survival benefit for patients with aggressive PTCL.展开更多
Background Cancer testis antigens （CTAs） are a novel group of tumor associated antigens.Demethylating agent decitabine was reported to be able to up-regulate CTAs through its hypomethylation mechanism,thus enhance t...Background Cancer testis antigens （CTAs） are a novel group of tumor associated antigens.Demethylating agent decitabine was reported to be able to up-regulate CTAs through its hypomethylation mechanism,thus enhance the immunogenicity of leukemia cells.However,few researches have ever focused on the questions that whether this immunostimulatory effect of decitabine could induce autologous CTA specific cytotoxic T lymphocytes （CTLs） in vivo,and if so,whether this effect contributes to disease control.In this study,we aimed to show that decitabine could induce specific autologous CTLs against some mouse CTAs in leukemia cells in vitro and in vivo.Methods Several mouse CTAs were screened by RT-PCR.CTL specific to one of the CTAs named P1A was detected and sorted by P1A specific dimer by flow cytometry.The activity of specific CTLs was measured by real time RT-PCR.Results We firstly screened expression of some CTAs in mouse leukemia cells before and after decitabine treatment and found that decitabine treatment did up-regulate expression of many CTAs.Then we measured the CTLs＇ activity specific to a mouse CTA P1A in vivo and showed that this activity increased after decitabine treatment.Finally,we sorted these in vivo induced P1A specific CTLs by flow cytometry and demonstrated their cytotoxicity against decitabine treated leukemia cells.Conclusions Our study showed the autologous immune response induced by decitabine in vivo.And more importantly,we firstly proved that this response may contribute to disease control.We believe that this immunostimulatory effect is another anti-cancer mechanism of decitabine,and this special effect would inspire new applications of decitabine in the field of leukemia treatment in the future.展开更多
Objective To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma(PTCL).Methods From July 2007 to July 2014,60 cases of high risk PTCL were analyzed retrospectively...Objective To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma(PTCL).Methods From July 2007 to July 2014,60 cases of high risk PTCL were analyzed retrospectively.Results All 60 patients were at high risk group(carried with IPI≥3),with a median age of展开更多
Objective:To explore the effectiveness of splenic tissue autotransplantation in restoring host defense. Methods: Rabbits were divided into three groups,Sham Operation(SO), Splenic Autotransplantation(SA)and Total Sple...Objective:To explore the effectiveness of splenic tissue autotransplantation in restoring host defense. Methods: Rabbits were divided into three groups,Sham Operation(SO), Splenic Autotransplantation(SA)and Total Splenectomy(TS) ,and dynamic changes in histology and immunology were observed for over 24 weeks. Results: Histologic study shows that the white pulps were poorly developed and central arterioles disappeared in the regenerated splenic tissue. The weight of regenerated spleens recovered six months later in SA was 11% of that in SO, and was significantly reduced comparing with the implanted weight(P<0.05).Tere were no significant difference in the number of T lymphocytes and the levels of serum lysozyme among the three groups. A poor antibody response by the rabbits of SA and TS as compared to those of SO was noted after the primary intravenous administration with sheep red blood cells. After the challenge with type 3 pneumococci intravenously, pneumococcal clearance from bloodstream in SA did not展开更多
目的探讨川芎嗪对自体血回输患者T淋巴细胞免疫功能的保护作用。方法 40例择期行脊柱手术患者,美国麻醉医师协会(American Society of Anesthesiologis,t ASA)分级Ⅰ～Ⅱ级,术前评估出血量>400mL,无血液及内分泌等系统疾病,随机分成...目的探讨川芎嗪对自体血回输患者T淋巴细胞免疫功能的保护作用。方法 40例择期行脊柱手术患者,美国麻醉医师协会(American Society of Anesthesiologis,t ASA)分级Ⅰ～Ⅱ级,术前评估出血量>400mL,无血液及内分泌等系统疾病,随机分成试验组和对照组,每组20例。试验组于术前首次采血后,在收集自体血前30min经静脉滴注川芎嗪2mg/kg,在回收血液的肝素盐水和洗涤盐水内加入川芎嗪,终浓度为0.005%;对照组始终不予川芎嗪,余同试验组。记录术中出血量及回输血量,采集术前、回输自体血后1h、1d、5d的静脉血,使用流式细胞仪测定T淋巴细胞亚群(CD3、CD4、CD8)的水平,并计算CD4/CD8值。结果两组CD3水平在术后1h、1d较术前均明显下降(P<0.05,P<0.01),术后5d对照组较术前仍低(P<0.05),而试验组已恢复至术前水平;在术后各时间点,对照组CD3水平均明显低于试验组(P<0.05,P<0.01)。对照组CD4在术后1h、1d较术前明显下降(P<0.01),至术后5d才基本恢复至术前水平;试验组CD4在回输血后1h较术前明显下降(P<0.01),但术后1d已恢复至术前水平;术后1h、1d对照组CD4水平均低于试验组(P<0.05,P<0.01)。对照组CD4/CD8值在术后1d、5d较术前明显下降,且低于试验组,差异均有统计学意义(P<0.05)。结论试验组T淋巴细胞免疫功能的抑制程度明显较对照组轻,且恢复时间明显比对照组快,表明川芎嗪在自体血回输中对T淋巴细胞免疫功能具有一定的保护作用。展开更多
文摘Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreactive T cells, which are involved in autoimmune diseases. However, it is unknown whether attenuated activated healthy autologous T-cell immunization could increase anti-tumor immune responses. To this end, C57B1/6 mice were immunized with attenuated activated autologous T cells. The splenocytes from immunized mice showed a higher proliferative ability than that from naive mice. The special phenotype analysis showed that there were more CD8+ T cells and CD62L+ T cells in immunized mice after 24 h of culture with 10% fetal calf serum complete medium in vitro (P〈0.01). These results demonstrated that this immunization may activate T cells in vivo. Furthermore, the splenocytes from immunized mice revealed resistance to activation-induced cell death (AICD) in vitro. To further study the relative genes that are responsible for the higher proliferation and resistance to AICD, the expression of Fas/Fas ligand (FasL) and GADD4513 was measured by real-time PCR. The results indicated that GADD45β transcription was higher in the splenocytes from immunized mice than that in the naive mice. In addition, the Fas expression showed a parallel higher, but FasL did not change obviously. To investigate the biologic functions induced by immunization in vivo, a tumor model was established by EL-4 tumor cell inoculation in C57/B1 mice. Mice receiving autologous T-cell immunization had significantly inhibited tumor growth in vivo (P〈0.01). This study implicated that immunization with attenuated activated autologous T cells enhances anti-tumor immune responses that participate in tumor growth inhibition.
基金This work was supported by National Natural Science Foundation of China(No.30671945)Science and Technology Commission of Shanghai Municipality(Nos.06JC14044,05ZR14055,054319928,04DZ14902)+2 种基金Shanghai Municipal Education(No.05BZ26)Shanghai Leading Academic Discipline Project(T0206)Science Foundation of Shanghai Institute of Immunology(No.07-A04,to Ningli Li).
文摘Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.
文摘Adoptive immunotherapy, the therapeutic infusion of ex vivo activated cancer-fighting white blood cells that was pioneered by Dr. Steven Rosenberg over 30 years ago, has become more widespread due to outstanding published research documenting the clinical efficacy of this strategy. Based on the well-established in vivo functions of NK and NKT cells, their integral role in the efficacy of certain chemotherapeutic and immunomodulatory agents, and their direct therapeutic action as displayed in clinical trials, the use of autologous natural killer cell infusions is an appropriate and warranted therapeutic option for the treatment of malignant diseases, especially in patients whose disease is refractory to standard treatments such as chemotherapy and radiation.
文摘Background Peripheral T-cell lymphoma （PTCL） is generally characterized by poor prognosis after conventional chemotherapy. The place for high-dose chemotherapy and autologous stem cell transplantation （ASCT） in these patients is still not clear. In this study, we presented the outcomes of PTCL patients followed these treatments in our centre. Methods We retrospectively analyzed the outcomes of 39 patients with PTCL received the two treatments between 1999 and 2010. Results The 3-year overall survival （OS） of 61.9% and 3-year progression free survival （PFS） of 35.7% were observed in the 39 patient. Twenty-one patients received Hyper-CVAD chemotherapy with 3-year OS of 46.2% and 3-year PFS of 27.9%. Eighteen patients received ASCT with 3-year OS of 70.3% and 3-year PFS of 44.2%. Further analysis revealed that patients with elevated lactate dehydrogenase, at least 2 international prognostic index （IPI） points, and extranodal involvement had a poorer outcome compared with the control group. Conclusion These findings might suggest that Hyper-CVAD chemotherapy and ASCT could offer a durable survival benefit for patients with aggressive PTCL.
基金This work was supported by the grants from the National Basic Research Program of China （No. 2005CB522400）, National Natural Science Foundation of China （Nos. 90919044, 30971297, 81000221 and 81170518）, Capital Medical Development Scientific Research Fund （No. 2007-2040）, National Public Health Grand Research Foundation （No. 201202017） and The Capital of the Public Health Project （No. Z 111107067311070）. Conflict of interest： none.
文摘Background Cancer testis antigens （CTAs） are a novel group of tumor associated antigens.Demethylating agent decitabine was reported to be able to up-regulate CTAs through its hypomethylation mechanism,thus enhance the immunogenicity of leukemia cells.However,few researches have ever focused on the questions that whether this immunostimulatory effect of decitabine could induce autologous CTA specific cytotoxic T lymphocytes （CTLs） in vivo,and if so,whether this effect contributes to disease control.In this study,we aimed to show that decitabine could induce specific autologous CTLs against some mouse CTAs in leukemia cells in vitro and in vivo.Methods Several mouse CTAs were screened by RT-PCR.CTL specific to one of the CTAs named P1A was detected and sorted by P1A specific dimer by flow cytometry.The activity of specific CTLs was measured by real time RT-PCR.Results We firstly screened expression of some CTAs in mouse leukemia cells before and after decitabine treatment and found that decitabine treatment did up-regulate expression of many CTAs.Then we measured the CTLs＇ activity specific to a mouse CTA P1A in vivo and showed that this activity increased after decitabine treatment.Finally,we sorted these in vivo induced P1A specific CTLs by flow cytometry and demonstrated their cytotoxicity against decitabine treated leukemia cells.Conclusions Our study showed the autologous immune response induced by decitabine in vivo.And more importantly,we firstly proved that this response may contribute to disease control.We believe that this immunostimulatory effect is another anti-cancer mechanism of decitabine,and this special effect would inspire new applications of decitabine in the field of leukemia treatment in the future.
文摘Objective To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma(PTCL).Methods From July 2007 to July 2014,60 cases of high risk PTCL were analyzed retrospectively.Results All 60 patients were at high risk group(carried with IPI≥3),with a median age of
文摘Objective:To explore the effectiveness of splenic tissue autotransplantation in restoring host defense. Methods: Rabbits were divided into three groups,Sham Operation(SO), Splenic Autotransplantation(SA)and Total Splenectomy(TS) ,and dynamic changes in histology and immunology were observed for over 24 weeks. Results: Histologic study shows that the white pulps were poorly developed and central arterioles disappeared in the regenerated splenic tissue. The weight of regenerated spleens recovered six months later in SA was 11% of that in SO, and was significantly reduced comparing with the implanted weight(P<0.05).Tere were no significant difference in the number of T lymphocytes and the levels of serum lysozyme among the three groups. A poor antibody response by the rabbits of SA and TS as compared to those of SO was noted after the primary intravenous administration with sheep red blood cells. After the challenge with type 3 pneumococci intravenously, pneumococcal clearance from bloodstream in SA did not
文摘目的探讨川芎嗪对自体血回输患者T淋巴细胞免疫功能的保护作用。方法 40例择期行脊柱手术患者,美国麻醉医师协会(American Society of Anesthesiologis,t ASA)分级Ⅰ～Ⅱ级,术前评估出血量>400mL,无血液及内分泌等系统疾病,随机分成试验组和对照组,每组20例。试验组于术前首次采血后,在收集自体血前30min经静脉滴注川芎嗪2mg/kg,在回收血液的肝素盐水和洗涤盐水内加入川芎嗪,终浓度为0.005%;对照组始终不予川芎嗪,余同试验组。记录术中出血量及回输血量,采集术前、回输自体血后1h、1d、5d的静脉血,使用流式细胞仪测定T淋巴细胞亚群(CD3、CD4、CD8)的水平,并计算CD4/CD8值。结果两组CD3水平在术后1h、1d较术前均明显下降(P<0.05,P<0.01),术后5d对照组较术前仍低(P<0.05),而试验组已恢复至术前水平;在术后各时间点,对照组CD3水平均明显低于试验组(P<0.05,P<0.01)。对照组CD4在术后1h、1d较术前明显下降(P<0.01),至术后5d才基本恢复至术前水平;试验组CD4在回输血后1h较术前明显下降(P<0.01),但术后1d已恢复至术前水平;术后1h、1d对照组CD4水平均低于试验组(P<0.05,P<0.01)。对照组CD4/CD8值在术后1d、5d较术前明显下降,且低于试验组,差异均有统计学意义(P<0.05)。结论试验组T淋巴细胞免疫功能的抑制程度明显较对照组轻,且恢复时间明显比对照组快,表明川芎嗪在自体血回输中对T淋巴细胞免疫功能具有一定的保护作用。
