Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification.
Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification.
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人类同种异体反应性 CTL 与神经胶质瘤和那些因外源 IFN-γ 或 IFN-γ 基因修饰而上调 HLA 表达的细胞相互作用。
DOI：
10.1089/107999003322226032
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Kruse,CarolA
中科院分区：
文献类型：
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作者：
Read,SusanaB;Kulprathipanja,NishaV;Gomez,GermanG;Paul,DavidB;Winston,KenR;Robbins,JoanM;Kruse,CarolA
通过流式细胞术，一组18个原代胶质瘤细胞外植体显示I类HLA-A、B、C的高表达，但II类HLA-DR表达缺失。新鲜分离的正常脑细胞几乎没有 或没有HLA抗原。在单向混合淋巴细胞反应（MLR）中产生对患者的HLA致敏的同种异体反应性细胞毒性T淋巴细胞（aCTL）。证实了aCTL的特异性 靶向表达相关HLA抗原的靶细胞（患者神经胶质瘤细胞或成淋巴细胞）。然而，非肿瘤患者特异性aCTL不裂解正常脑细胞。HLA抗体滴定 I类抗原的细胞毒性试验阻断了aCTL对神经胶质瘤的溶解，证实了aCTL T细胞受体（TCR）与神经胶质瘤上的I类抗原的相互作用。此外，aCTL与胶质瘤细胞的相互作用 导致了细胞凋亡。aCTL与胶质瘤的共孵育导致细胞因子分泌上调。重要的是，地塞米松，一种用于脑水肿的免疫抑制类固醇， 对肿瘤的溶解功能，表明类固醇依赖性患者可能受益于免疫治疗。我们还探索了使用干扰素-γ（IFN-γ）来增加aCTL肿瘤识别。 胶质瘤与外源性IFN-γ共孵育（500 U/ml，48 h）导致HLA I类抗原表达上调3倍，并轻微诱导II类抗原表达。基因修饰的胶质瘤细胞产生 IFN-γ类似地显示上调的HLA表达。与外源性IFN-γ或IFN-γ转导的胶质瘤细胞孵育的胶质瘤细胞比其亲本细胞更容易被aCTL裂解 因此，支持IFN-γ细胞因子基因疗法与过继性aCTL免疫疗法组合用于脑肿瘤治疗的概念。
By flow cytometry, a panel of 18 primary glioma cell explants exhibited high expression of class I HLA-A, B, C, but class II HLA-DR expression was absent. Freshly isolated normal brain cells displayed little or no HLA antigens. Alloreactive cytotoxic T lymphocytes (aCTL), sensitized to the HLA of the patient, were generated in a one-way mixed lymphocyte response (MLR). The specificity of aCTL was confirmed to be to target cells (patient glioma cells or lymphoblasts) expressing the relevant HLA antigens. However, nontumor patient-specific aCTL did not lyse normal brain cells. Titration of antibodies to HLA class I into cytotoxicity assays blocked lysis of gliomas by aCTL, confirming aCTL T cell receptor (TCR) interactions with the class I antigen on gliomas. Furthermore, aCTL interactions with glioma cells caused their apoptosis. Coincubations of aCTL with gliomas resulted in upregulated cytokine secretion. Importantly, dexamethasone, an immunosuppressive steroid used for brain edema, did not affect aCTL lytic function against tumor, indicating that steroid-dependent patients may benefit from the immunotherapy. We also explored the use of interferon-γ (IFN-γ) to increase aCTL tumor recognition. Coincubation of gliomas with exogenous IFN-γ (500 U/ml, 48 h) caused a 3-fold upregulation of HLA class I and a slight induction of class II antigen expression. Gene-modified glioma cells producing IFN-γ similarly displayed upregulated HLA expression. Glioma cells incubated with exogenous IFN-γ or IFN-γ-transduced glioma cells were more susceptible to lysis by aCTL than their parental counterparts, thus supporting the concept of combining IFN-γ cytokine gene therapy with adoptive aCTL immunotherapy for brain tumor treatment.