人化嵌合T细胞受体修饰T淋巴细胞对慢性粒细胞白血病细胞的体外杀伤效应
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摘要
目的：慢性粒细胞白血病（Chronic Myelogenous Leukemia，CML）是一种起源于造血干细胞的恶性血液系统疾病，目前常用的CML治疗方法包括放射性治疗、化学药物治疗、异基因造血干细胞移植和BCR/ABL酪氨酸激酶抑制剂治疗。虽然可用于CML治疗方法较多，但上述各种方法都有其一定的局限性。本研究结合嵌合T细胞受体(chimeric T cell receptors，chTCR)和慢性粒细胞白血病免疫学研究成果，以人化单克隆抗体单链可变区片段、人CD8分子铰链区、人CD28分子跨膜及胞内结构域和人CD3ζ链胞内信号转导域为基础，构建可表达人化嵌合TCR（humanized chrimeric T cell receptors，hchTCR）的逆转录病毒，并以其修饰健康供者T淋巴细胞，验证修饰T淋巴细胞对CML白血病细胞的体外杀伤效应，为将该方法应用于CML的过继性免疫治疗奠定理论基础。
方法：以临床CML患者来源的白血病细胞为抗原免疫BALB/c小鼠，杂交瘤技术制备分泌CML白血病细胞特异性单克隆抗体的杂交瘤细胞株；应用生物信息学技术分析单克隆抗体编码序列，确定抗体重链及轻链可变区片段中的互补决定簇，通过与基因库中的已知人源抗体序列进行比对，获得与所制备抗体具有较高同源性的人源抗体序列，以鼠源抗体的CDR取代人源抗体中的CDR，构建人化scFv；将人化scFv、人CD8分子铰链区、人CD28分子跨膜及胞内结构域和人CD3ζ链胞内信号转导域的编码序列依次连接，构建可表达hchTCR的逆转录病毒；用所构建的逆转录病毒转染健康供者来源的T淋巴细胞，检测修饰T淋巴细胞的蛋白表达，及其在CML白血病细胞刺激下的细胞毒性作用、细胞增殖能力和细胞因子分泌功能。
结果：成功构建稳定分泌CML白血病细胞特异性单克隆抗体的杂交瘤细胞株CMA1,抗体效价在1:1500以上。对CMA1细胞中抗体重链及轻链可变区的编码序列进行生物信息学分析，得到了鼠源抗体的CDR编码序列及与鼠源抗体可变区具有高度同源性的人源抗体编码序列。以序列分析结果为基础，用逆转录病毒空载质粒pBABEpuro成功构建了hchCMLTCR的逆转录病毒载体pBCT；同时成功构建了只含有人CD8分子铰链区、人CD28分子跨膜及胞内结构域和人CD3ζ链胞内信号转导域的质粒pB8283。通过将逆转录病毒载体转入PHA细胞中，构建了逆转录病毒pBABEpuro-hchCMLTCR和pBABEpuro-8283包装细胞株PHA-hchCMLTCR和PHA-8283。上述两种逆转录病毒转染健康供者外周血T淋巴细胞，通过体外试验证实经hchTCR修饰的T淋巴细胞具有CML白血病细胞特异性的细胞杀伤效应、细胞因子分泌效应和增殖效应。
结论：通过体外试验，证实经人化嵌合TCR修饰的健康供者外周血T淋巴细胞具有CML白血病细胞特异性生物学活性，为进一步将该方法用于CML患者的过继性细胞免疫治疗奠定了基础。
Objectives: Chronic Myelogenous Leukemia （CML）is a clonalmalignant disease of hematopoietic stem cells. The commonly usedtreatments of CML include radiation therapy, chemotherapy, allogeneichematopoietic stem cell transplantation and BCR/ABL tyrosine kinasespecific inhibitors. Almost all of these therapies have certain limitations.This study is based on the development of scientific research aboutchimeric T cell receptors (chTCR) and immunological characteristics ofCML, utilizing humanized single chain variable fragment, hinge region ofCD8molecule, transmembrane and intracellular domain of human CD28molecule and intracellular signal transduction domain of human CD3ζchain to construct retrovirus, which can expressing humanized chimericTCR (hchTCR) molecules. In vitro killing effects of T lymphocytes fromhealthy donors, modified with the retrovirus, is then detected to verify theusage of this method to treat CML by adoptive immunotherapy.
Methods: Leukemia cells from CML patients are used to immunizeBALB/c mice. Cell lines secreting monoclonal antibody specific for CMLleukemia cells are produced by hybridoma technology. CDR regions of the monoclonal antibody are confirmed by bioinfromation methods and linkedwith fragment regions from human antibody, which is highly homologouswith the murine monoclonal antibody, to construct humanized scFv.Retrovirus is constructed by fusing humanized scFv, hinge region of CD8molecule, transmembrane and intracellular domain of human CD28molecule and intracellular signal transduction domain of human CD3ζchain. T-lymphocytes from healthy donors are detected of the expressing ofhumanized chimeric TCR（hchTCR）, after infected by retrovirus. Also, thecytotoxic effects, proliferation and cytokine secreting of T-lymphocytes,modified by humanized chimeric TCR and stimulated with CML leukemiacells are analyzed.
Results: Cell line CMA1, which can constantly secreting monoclonalantibody specific for CML leukemia cells, was produced and the titre ofthis monoclonal antibody is more than1:1500. CDR regions of thismonoclonal antibody and humanized scFv sequence were obtained. Twocell lines PHA-hchCMLTCR and PHA-8283that can persistently produceretrovirus pBABEpuro-hchCMLTCR and pBABEpuro-8283are obtained.The cytotoxicity effects, cytokine secreting of IFN-γand proliferation ofT-lymphocytes from healthy donors, infected by pBABEpuro-hchCMLTCRand stimulated with CML leukemia cells, were confirmed by in vitroanalysis.
Conclusions: T-lymphocytes from healthy donors, modified by humanized chimeric TCR can killing CML leukemia cells, secreting IFN-γand proliferation in vitro. This achievement indicates that this method canbe utilized to treat CML patients with adoptive immunotherapy.
方法：以临床CML患者来源的白血病细胞为抗原免疫BALB/c小鼠，杂交瘤技术制备分泌CML白血病细胞特异性单克隆抗体的杂交瘤细胞株；应用生物信息学技术分析单克隆抗体编码序列，确定抗体重链及轻链可变区片段中的互补决定簇，通过与基因库中的已知人源抗体序列进行比对，获得与所制备抗体具有较高同源性的人源抗体序列，以鼠源抗体的CDR取代人源抗体中的CDR，构建人化scFv；将人化scFv、人CD8分子铰链区、人CD28分子跨膜及胞内结构域和人CD3ζ链胞内信号转导域的编码序列依次连接，构建可表达hchTCR的逆转录病毒；用所构建的逆转录病毒转染健康供者来源的T淋巴细胞，检测修饰T淋巴细胞的蛋白表达，及其在CML白血病细胞刺激下的细胞毒性作用、细胞增殖能力和细胞因子分泌功能。
结果：成功构建稳定分泌CML白血病细胞特异性单克隆抗体的杂交瘤细胞株CMA1,抗体效价在1:1500以上。对CMA1细胞中抗体重链及轻链可变区的编码序列进行生物信息学分析，得到了鼠源抗体的CDR编码序列及与鼠源抗体可变区具有高度同源性的人源抗体编码序列。以序列分析结果为基础，用逆转录病毒空载质粒pBABEpuro成功构建了hchCMLTCR的逆转录病毒载体pBCT；同时成功构建了只含有人CD8分子铰链区、人CD28分子跨膜及胞内结构域和人CD3ζ链胞内信号转导域的质粒pB8283。通过将逆转录病毒载体转入PHA细胞中，构建了逆转录病毒pBABEpuro-hchCMLTCR和pBABEpuro-8283包装细胞株PHA-hchCMLTCR和PHA-8283。上述两种逆转录病毒转染健康供者外周血T淋巴细胞，通过体外试验证实经hchTCR修饰的T淋巴细胞具有CML白血病细胞特异性的细胞杀伤效应、细胞因子分泌效应和增殖效应。
结论：通过体外试验，证实经人化嵌合TCR修饰的健康供者外周血T淋巴细胞具有CML白血病细胞特异性生物学活性，为进一步将该方法用于CML患者的过继性细胞免疫治疗奠定了基础。
Objectives: Chronic Myelogenous Leukemia （CML）is a clonalmalignant disease of hematopoietic stem cells. The commonly usedtreatments of CML include radiation therapy, chemotherapy, allogeneichematopoietic stem cell transplantation and BCR/ABL tyrosine kinasespecific inhibitors. Almost all of these therapies have certain limitations.This study is based on the development of scientific research aboutchimeric T cell receptors (chTCR) and immunological characteristics ofCML, utilizing humanized single chain variable fragment, hinge region ofCD8molecule, transmembrane and intracellular domain of human CD28molecule and intracellular signal transduction domain of human CD3ζchain to construct retrovirus, which can expressing humanized chimericTCR (hchTCR) molecules. In vitro killing effects of T lymphocytes fromhealthy donors, modified with the retrovirus, is then detected to verify theusage of this method to treat CML by adoptive immunotherapy.
Methods: Leukemia cells from CML patients are used to immunizeBALB/c mice. Cell lines secreting monoclonal antibody specific for CMLleukemia cells are produced by hybridoma technology. CDR regions of the monoclonal antibody are confirmed by bioinfromation methods and linkedwith fragment regions from human antibody, which is highly homologouswith the murine monoclonal antibody, to construct humanized scFv.Retrovirus is constructed by fusing humanized scFv, hinge region of CD8molecule, transmembrane and intracellular domain of human CD28molecule and intracellular signal transduction domain of human CD3ζchain. T-lymphocytes from healthy donors are detected of the expressing ofhumanized chimeric TCR（hchTCR）, after infected by retrovirus. Also, thecytotoxic effects, proliferation and cytokine secreting of T-lymphocytes,modified by humanized chimeric TCR and stimulated with CML leukemiacells are analyzed.
Results: Cell line CMA1, which can constantly secreting monoclonalantibody specific for CML leukemia cells, was produced and the titre ofthis monoclonal antibody is more than1:1500. CDR regions of thismonoclonal antibody and humanized scFv sequence were obtained. Twocell lines PHA-hchCMLTCR and PHA-8283that can persistently produceretrovirus pBABEpuro-hchCMLTCR and pBABEpuro-8283are obtained.The cytotoxicity effects, cytokine secreting of IFN-γand proliferation ofT-lymphocytes from healthy donors, infected by pBABEpuro-hchCMLTCRand stimulated with CML leukemia cells, were confirmed by in vitroanalysis.
Conclusions: T-lymphocytes from healthy donors, modified by humanized chimeric TCR can killing CML leukemia cells, secreting IFN-γand proliferation in vitro. This achievement indicates that this method canbe utilized to treat CML patients with adoptive immunotherapy.
引文
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[2]Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structuralmechanism for STI-571inhibition of abelson tyrosine kinase[J].Science,2000;289:1938-1942.
[3]Savage D, Antman K. Imatinib mesylate: a new oral targeted therapy[J]. N Engl JMed,2002;346:683–93.
[4]Pricl S, Fermeglia M, Ferrone M, et al. T315I-mutated Bcr-Abl in chronic myeloidleukemia and imatinib: insights from a computational study[J]. MolCancer,Ther,2005;4:1167–1174.
[5] Helga Bernhard, Julia Neudorfer, Kerstin Gebhard et al. Adoptive transfer ofautologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer[J]. Cancer Immunology,Immunotherapy,2008;57(2):271-280
[6] Agnieszka Morgenroth, Marc Cartellieri, Marc Schmitz, Serap Günes et al.Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) usinggenetically engineered T-cells[J]. Prostate,2007;67:1121-31.
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