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单倍体相合细胞移植治疗小鼠H22实体瘤的实验研究
Study on Haploidentical Transplantation for Treatment of Murine Solid Hepatoma 22
【作者】 李晓峰；
【导师】 叶德富；
【作者基本信息】 福建医科大学 ， 内科学， 2006， 博士
【摘要】 免疫治疗是恶性肿瘤的重要治疗手段之一。由于在异基因造血干细胞移植(Allo-HSCT)中观察到移植物抗白血病(GVL)效应的存在,并发现移植后进行供者淋巴细胞输注(DLI)可以增加抗肿瘤效应,人们开始对这种现象进行研究。目前,异基因造血干细胞移植不仅是一种提高化疗剂量的载体,而且已被作为一种肿瘤免疫治疗的手段。但这种治疗手段具有较高的治疗风险和存在供者来源不足的问题,虽然非清髓造血干细胞移植(NST)的开展在一定程度上降低了治疗的风险,主要组织相容抗原复合物(MHC)不全相合移植的发展解决了供者来源不足的问题,但移植相关并发症和移植相关死亡率(TRM)仍是限制其实际应用的主要障碍。如何保留移植物抗肿瘤(GVT)效应而降低TRM、扩大异基因免疫治疗的实际(特别是在实体瘤方面)应用范围,是临床的一大课题。在本研究中,我们通过动物实验,对单倍体相合细胞移植诱发GVT效应进行观察,并对如何减轻GVHD以及GVT的效应机制进行初步的探索。第一部分:可供单倍体相合移植研究的实体瘤动物模型的建立。实验共进行三次,每次6只F1小鼠。方法:将BABL/C来源的H22肝癌细胞接种于BALB/C×C57BL/6杂交F1代小鼠皮下,通过观察接种H22细胞后F1小鼠肿瘤的形成、生长过程,测量肿瘤大小并计算肿瘤体积的变异系数,探索H22细胞在F1小鼠的成瘤性;以流式细胞仪检测H22细胞的MHC表型;对实体瘤组织进行病理学观察。结果:每只F1小鼠右腋皮下接种2×10~6个H22细胞5、6天后,肿瘤开始长出,成瘤率为100%,肿瘤生长速度尚均匀,接种第14天时,三次实验的肿瘤体积变异系数分别为23%、34%、27%,肿瘤无自发缓解,全部小鼠
【Abstract】 In the last two decades, various immunological strategies have been assessed to stimulate antitumor immunity in cancer patients. In this field, there is a growing perception that the graft-versus-leukemia (GVL) reaction induced by allogeneic hematopoietic stem cell transplantation (HSCT) is the most potent form of cancer immunotherapy in current clinical use, and that the donor lymphocyte infusion (DLI) following HSCT induces effective graft-versus-tumor responses in patients with posttransplantation leukemic relapse. Allogeneic hematopoietic stem cell transplantation is currently being used as a therapy for hematological malignancies and some solid tumors. Nevertheless, its clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. Laying the foundation for the development of novel immunotherapeutic strategies, new concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. Yet the application of this approach is still limited due to the treatment-related complications, transplant-related mortality (TRM), and recurrent malignancy. In the near future the major challenge for investigators in this field will be how to maximize the GVT effect while avoid or minimize GVHD.In this study, the effects of graft-versus-tumor (GVT) induced by the allogeneic