同种异基因白细胞输注治疗肿瘤的实验研究
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摘要
目的:恶性肿瘤已成为我国死亡率最高的疾病,近年来发病率有显著增高趋势。除了三大常规疗法,生物疗法为肿瘤治疗带来了新的希望。细胞因子、单克隆抗体及其他生物治疗手段已逐渐成为临床上重要而有效的辅助治疗手段。众所周知,恶性肿瘤患者的免疫功能普遍处于低下状态;而对于同种异体器官移植,移植物通常会刺激宿主产生强烈的细胞免疫反应。因此,如果利用同种抗原作为生物反应调节剂治疗肿瘤,打破肿瘤患者的免疫无反应状态,也许能找到一条有效的治疗恶性肿瘤的新途径。本研究探讨了MHC不相合同种异基因白细胞输注(Allogeneic LeukocyteInfusion,ALI)的抗肿瘤效应及其相关机制。
方法:丝裂霉素C(MMC)灭活的同种异基因白细胞输注治疗弱免疫原性黑色素瘤(B16-F10)和路易斯肺癌(LLC)的荷瘤小鼠。细胞毒及淋巴细胞亚群删除实验鉴定ALI抗肿瘤中的效应细胞;小鼠血清细胞因子检测分析ALI治疗后在宿主体内产生的免疫效应;流式细胞术分析治疗过程中小鼠脾淋巴细胞绝对/相对数变化。另外,观察了环磷酰胺(Cyclophophamide,Cy)清除CD4~+CD25~+调节T细胞(Regulatory Tcell,Treg)对ALI治疗产生的协同作用。
结果:灭活同种异基因白细胞输注可以诱导荷瘤小鼠体内CD4~+、CD8~+ T和NK细胞活化、增殖,释放大量IFN-γ和IL-2;相反,B淋巴细胞及Th2细胞因子IL-4和IL-10无明显变化;ALI诱导宿主产生了特异性和非特异性抗肿瘤免疫反应;小鼠肿瘤生长延缓、生存期延长。30mg/kg Cy可以有效清除CD4~+CD25~+调节性T细胞,因而增强了ALI诱导的抗肿瘤效应。在LLC自发肺转移模型中,手术切除肿瘤后小鼠外周血中TGF-B和VEGF显著升高并促进肿瘤的转移。给予ALI治疗后诱导IFN-γ和IL-2大量释放,同时减少了抑制性细胞因子IL-10和TGF-β的产生,并激发了特异性和非特异性抗肿瘤免疫反应。该疗法有效清除了小鼠肺转移灶,使62.5%的小鼠获得了长期生存。
结论:灭活同种异基因白细胞输注可以诱发宿主体内大量淋巴细胞活化、增殖,释放大量Th1细胞因子。这些细胞因子促进宿主产生了特异性和非特异性抗肿瘤免疫反应,进而导致小鼠肿瘤生长延缓、生存期延长。清除CD4~+CD25~+调节性T细胞可显著增强ALI诱导的免疫反应,提高抗肿瘤效应。灭活同种白细胞输注可以有效抑制肿瘤自发肺转移,使多数小鼠获得长期生存。该方法简单、安全、有效,有望成为一种新犁的抗肿瘤疗法。
Purpose:Cytokines,mAb and other biologic-based therapies are being developed as antineoplastic agents.As is well known,cancer patients are always with immune function defects.On the other hand,an intensive cell-mediated immunity wilt be initiated by a graft in the circumstances of allogeneic organ transplantation.Therefore,using the allogeneic antigen as a biological responding modifier to break the immune non-response condition could be an effective antitumor approach.This study tests the tolerance and antineoplastic activity of infusion of MHC-mismatched allogeneic leukocytes.The cells are mitotically inactivated to prevent graft-versus-host disease.
Methods:After inoculation of B16-F10 or LLC tumor cells,C57BL/6 mice were treated i.v.with mitomycin C inactivated allogeneic leukocytes either alone,or combination with cyclophosphamide(Cy).Antitumor effects were evaluated by measuring tumor volume and animal survival time as well as lung weight in a spontaneous metastases model.The mechanisms of antitumor effect were analyzed by Th1,Th2 cytokines detection;CD4~+, CD8~+ T or NK cells depletion;cell-mediated cytotoxicity assay and relative/absolute number of splenocytes measurement during the treatment.
Results:The infusion of inactivated allogeneic leukocytes was found to be able to induce activation and proliferation of CD4~+,CD8~+ T and NK cells and release type-1 cytokines (including IL-2 and IFN-γ) in a tumor-bearing mouse.It may in turn initiate a specific and non-specific antitumor immune response.Of note,allogeneic leukocyte infusion(ALI) caused a delayed tumor growth and a prolonged survival time in an established B16-F10 melanoma model.In addition,the therapeutic responses to ALl were potentiated by elimination of CD4~+CD25~+ regulatory T cells with injection of 30mg/Kg Cy intraperitoneally.In an LLC pulmonary spontaneous metastases model,serum concentration of TGF-B and VEGF were upregulated and thus may promote the metastases when a primary tumor has been resected.After ALl treatment,the large amount of IFN-γand IL-2 were released,and the inhibitory cytokines such as IL-10 and TGF-βwere decreased.This immune stimulation evoked a specific and non-specific antitumor immune response.As the result of these responses,lung metastases were eradicated effectively and 62.5%mice had a long-term survival.
Conclusion:Administration of mitotically inactivated allogeneic leukocytes may induce activation and proliferation of enormous lymphocytes which then release large amounts of cytokines.These cytokines promoted specific and non-specific antitumor responses in mice with established or metastatic malignancies and the therapeutic responses induced by ALl were potentiated by Cy-mediated elimination of CD4~+CD25~+ regulatory T cells. In a word,transfusion of mitotically allogeneic leukocytes is a simple,safe and effective therapeutic antineoplastic approach which should be developed further as a novel antitumor strategy.
方法:丝裂霉素C(MMC)灭活的同种异基因白细胞输注治疗弱免疫原性黑色素瘤(B16-F10)和路易斯肺癌(LLC)的荷瘤小鼠。细胞毒及淋巴细胞亚群删除实验鉴定ALI抗肿瘤中的效应细胞;小鼠血清细胞因子检测分析ALI治疗后在宿主体内产生的免疫效应;流式细胞术分析治疗过程中小鼠脾淋巴细胞绝对/相对数变化。另外,观察了环磷酰胺(Cyclophophamide,Cy)清除CD4~+CD25~+调节T细胞(Regulatory Tcell,Treg)对ALI治疗产生的协同作用。
结果:灭活同种异基因白细胞输注可以诱导荷瘤小鼠体内CD4~+、CD8~+ T和NK细胞活化、增殖,释放大量IFN-γ和IL-2;相反,B淋巴细胞及Th2细胞因子IL-4和IL-10无明显变化;ALI诱导宿主产生了特异性和非特异性抗肿瘤免疫反应;小鼠肿瘤生长延缓、生存期延长。30mg/kg Cy可以有效清除CD4~+CD25~+调节性T细胞,因而增强了ALI诱导的抗肿瘤效应。在LLC自发肺转移模型中,手术切除肿瘤后小鼠外周血中TGF-B和VEGF显著升高并促进肿瘤的转移。给予ALI治疗后诱导IFN-γ和IL-2大量释放,同时减少了抑制性细胞因子IL-10和TGF-β的产生,并激发了特异性和非特异性抗肿瘤免疫反应。该疗法有效清除了小鼠肺转移灶,使62.5%的小鼠获得了长期生存。
结论:灭活同种异基因白细胞输注可以诱发宿主体内大量淋巴细胞活化、增殖,释放大量Th1细胞因子。这些细胞因子促进宿主产生了特异性和非特异性抗肿瘤免疫反应,进而导致小鼠肿瘤生长延缓、生存期延长。清除CD4~+CD25~+调节性T细胞可显著增强ALI诱导的免疫反应,提高抗肿瘤效应。灭活同种白细胞输注可以有效抑制肿瘤自发肺转移,使多数小鼠获得长期生存。该方法简单、安全、有效,有望成为一种新犁的抗肿瘤疗法。
Purpose:Cytokines,mAb and other biologic-based therapies are being developed as antineoplastic agents.As is well known,cancer patients are always with immune function defects.On the other hand,an intensive cell-mediated immunity wilt be initiated by a graft in the circumstances of allogeneic organ transplantation.Therefore,using the allogeneic antigen as a biological responding modifier to break the immune non-response condition could be an effective antitumor approach.This study tests the tolerance and antineoplastic activity of infusion of MHC-mismatched allogeneic leukocytes.The cells are mitotically inactivated to prevent graft-versus-host disease.
Methods:After inoculation of B16-F10 or LLC tumor cells,C57BL/6 mice were treated i.v.with mitomycin C inactivated allogeneic leukocytes either alone,or combination with cyclophosphamide(Cy).Antitumor effects were evaluated by measuring tumor volume and animal survival time as well as lung weight in a spontaneous metastases model.The mechanisms of antitumor effect were analyzed by Th1,Th2 cytokines detection;CD4~+, CD8~+ T or NK cells depletion;cell-mediated cytotoxicity assay and relative/absolute number of splenocytes measurement during the treatment.
Results:The infusion of inactivated allogeneic leukocytes was found to be able to induce activation and proliferation of CD4~+,CD8~+ T and NK cells and release type-1 cytokines (including IL-2 and IFN-γ) in a tumor-bearing mouse.It may in turn initiate a specific and non-specific antitumor immune response.Of note,allogeneic leukocyte infusion(ALI) caused a delayed tumor growth and a prolonged survival time in an established B16-F10 melanoma model.In addition,the therapeutic responses to ALl were potentiated by elimination of CD4~+CD25~+ regulatory T cells with injection of 30mg/Kg Cy intraperitoneally.In an LLC pulmonary spontaneous metastases model,serum concentration of TGF-B and VEGF were upregulated and thus may promote the metastases when a primary tumor has been resected.After ALl treatment,the large amount of IFN-γand IL-2 were released,and the inhibitory cytokines such as IL-10 and TGF-βwere decreased.This immune stimulation evoked a specific and non-specific antitumor immune response.As the result of these responses,lung metastases were eradicated effectively and 62.5%mice had a long-term survival.
Conclusion:Administration of mitotically inactivated allogeneic leukocytes may induce activation and proliferation of enormous lymphocytes which then release large amounts of cytokines.These cytokines promoted specific and non-specific antitumor responses in mice with established or metastatic malignancies and the therapeutic responses induced by ALl were potentiated by Cy-mediated elimination of CD4~+CD25~+ regulatory T cells. In a word,transfusion of mitotically allogeneic leukocytes is a simple,safe and effective therapeutic antineoplastic approach which should be developed further as a novel antitumor strategy.
引文
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