腹水来源的外来体用于卵巢癌免疫治疗的实验研究
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摘要
外来体(exosomes)是一种膜性脂类囊泡，直径30nm～90nm，可由多种细胞分泌，如B淋巴细胞、肥大细胞、不成熟DC、血小板、CTL、纤维原细胞、上皮细胞和肿瘤细胞。这些小囊泡来源于具有细胞膜的晚期多囊性的内涵体或溶酶体，这些细胞以胞吞的方式摄取外来抗原在细胞内形成多囊体(MVBs)，MVBs是一种复杂的胞内细胞器，由胞吞作用产生。细胞膜先内陷形成吞饮泡，吞饮泡的界膜再向内出芽，形成许多小泡，这种胞吞腔室即为MVB。胞吞的主要功能是对内化的大分子和膜蛋白进行分类，一部分经过MVB被转运到溶酶体降解。另一部分移向质膜，MVB的泡膜与质膜融合后释放小泡到胞外空间，这种小泡便是外来体。目前，从囊泡的形态、生化特点(蛋白、磷脂)和纯化过程来定义外来体。
最近发现，肿瘤细胞也可释放外来体，同时在肿瘤患者的腹水中也能分离出外来体，推测其来源于肿瘤细胞。肿瘤细胞释放的外来体能够包含和转移抗原给树突状细胞，提呈给T淋巴细胞，引起CTL效应。研究发现，外来体含有的成分如下：①抗原呈递相关分子：MHC-Ⅰ和Ⅱ类分子、HSC73、HSP70等；②免疫粘附及信号转导相关分子：ICAM-Ⅰ、CD58、CD9、CD86／B7．2、Mac-l、MFG-E8等：③其它功能蛋白：AnnexinⅡ、TfR、CD55、CD59、Gi2等。因此，外来体可能具有细胞毒性效应、免疫调节、诱导凋亡和免疫耐受诱导等作用。将其用于肿瘤免疫治疗的优点是：非细胞成分、体积小易清除、稳定性高、可按照GMP标准制备、可冷冻储藏等。
目前国内外关于卵巢癌患者的腹水中分离出外来体作为特异性抗原用于免疫治疗的研究较为少见，而运用脐血来源树突状细胞(DC)作为抗原
Exosomes are membrane lipid vesicles in density at 1.13~1.21g/ml. These vesicles are released by numerous cells such as B lymphocytes, mastocytes, immature DCs, platelets, cytotoxic T lymphocytes, fibroblasts, epithelial cells, and tumor cells. Exosomes originate from late endosomes with membrane, i.e. multivesiclear bodies(MVB) and form by inward budding from the limiting membrand of MVBs into the endosomal lumen. Exosomes accumulate inside MVBs and can be released in the extracellular milieu following fusion of the external membrane of MVBs with plasma membrane. Exosomes can be defined according to morphological, biochemical and purification process criteria.
Tumor cell can also secrete exosomes. Exosomes, in addition, can be separated from ascites of the patients with malignant tumors. Some researchers presumed and proved that they are secreted by tumor cells. Tumour-derived exosomes can be utilised as a source of tumour antigen for cross-priming to T-cells for CTL effect and are thus of interest for use in anti-tumour immunotherapy. The composition of exosomes are as follows: ① molecules associated with antigen presentation: MHC class I molecule, MHC class II molecule, HSC70 and HSP70. ② molecules associated with immune adhesion and signal transduction: ICAM-1, CD58, CD9, CD86/B7.2, Mac-1, MFG-E8 and so on. ③ other functional proteins: Annexin II ,TfR, CD55, CD59, Gi2 and so on. Exosomes, therefore, may be in possession of CTL effect, immune regulation, inducing apoptosis immune enduring and so on. The advantage of exosomes in cancer therapy are non-cell character, being freezed for storage, high stability, being seperated according to GMP criterion, little size and easy to be eliminated.
At present, it is rare that exosomes derived from ascites of patients with
Department o/Gynecology and Obstetrics, Xijing Hospital, FMMU
最近发现，肿瘤细胞也可释放外来体，同时在肿瘤患者的腹水中也能分离出外来体，推测其来源于肿瘤细胞。肿瘤细胞释放的外来体能够包含和转移抗原给树突状细胞，提呈给T淋巴细胞，引起CTL效应。研究发现，外来体含有的成分如下：①抗原呈递相关分子：MHC-Ⅰ和Ⅱ类分子、HSC73、HSP70等；②免疫粘附及信号转导相关分子：ICAM-Ⅰ、CD58、CD9、CD86／B7．2、Mac-l、MFG-E8等：③其它功能蛋白：AnnexinⅡ、TfR、CD55、CD59、Gi2等。因此，外来体可能具有细胞毒性效应、免疫调节、诱导凋亡和免疫耐受诱导等作用。将其用于肿瘤免疫治疗的优点是：非细胞成分、体积小易清除、稳定性高、可按照GMP标准制备、可冷冻储藏等。
目前国内外关于卵巢癌患者的腹水中分离出外来体作为特异性抗原用于免疫治疗的研究较为少见，而运用脐血来源树突状细胞(DC)作为抗原
Exosomes are membrane lipid vesicles in density at 1.13~1.21g/ml. These vesicles are released by numerous cells such as B lymphocytes, mastocytes, immature DCs, platelets, cytotoxic T lymphocytes, fibroblasts, epithelial cells, and tumor cells. Exosomes originate from late endosomes with membrane, i.e. multivesiclear bodies(MVB) and form by inward budding from the limiting membrand of MVBs into the endosomal lumen. Exosomes accumulate inside MVBs and can be released in the extracellular milieu following fusion of the external membrane of MVBs with plasma membrane. Exosomes can be defined according to morphological, biochemical and purification process criteria.
Tumor cell can also secrete exosomes. Exosomes, in addition, can be separated from ascites of the patients with malignant tumors. Some researchers presumed and proved that they are secreted by tumor cells. Tumour-derived exosomes can be utilised as a source of tumour antigen for cross-priming to T-cells for CTL effect and are thus of interest for use in anti-tumour immunotherapy. The composition of exosomes are as follows: ① molecules associated with antigen presentation: MHC class I molecule, MHC class II molecule, HSC70 and HSP70. ② molecules associated with immune adhesion and signal transduction: ICAM-1, CD58, CD9, CD86/B7.2, Mac-1, MFG-E8 and so on. ③ other functional proteins: Annexin II ,TfR, CD55, CD59, Gi2 and so on. Exosomes, therefore, may be in possession of CTL effect, immune regulation, inducing apoptosis immune enduring and so on. The advantage of exosomes in cancer therapy are non-cell character, being freezed for storage, high stability, being seperated according to GMP criterion, little size and easy to be eliminated.
At present, it is rare that exosomes derived from ascites of patients with
Department o/Gynecology and Obstetrics, Xijing Hospital, FMMU
引文
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