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首页> 外文期刊>Pathobiology: journal of immunopathology, molecular and cellular biology >Presence of low dose of fludarabine in cultures blocks regulatory T cell expansion and maintains tumor-specific cytotoxic T lymphocyte activity generated with peripheral blood lymphocytes.
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Presence of low dose of fludarabine in cultures blocks regulatory T cell expansion and maintains tumor-specific cytotoxic T lymphocyte activity generated with peripheral blood lymphocytes.

机译：培养物中低剂量氟达拉滨的存在会阻止调节性T细胞扩增，并维持由外周血淋巴细胞产生的肿瘤特异性细胞毒性T淋巴细胞活性。

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BACKGROUND: For tumor vaccine-based immunotherapy of cancer, the expansion of tumor antigen-specific cytotoxic T lymphocytes (CTL) in the patients by blocking induced regulatory T (Treg) cells is the most important objective now. Fludarabine (FLU), a known anticancer drug, has been shown to downregulate Treg cells in vivo in chronic leukemia patients. Melanoma tumor antigen Mart-1(27-35)-specific CD8+ CTLs generated in vitrowith total peripheral blood lymphocytes (PBL) lose their activity within 14-21 days with concomitant expansion of Treg cells. When CD4+ cells are removed from PBL and CTL are generated with purified CD8+ cells, the CTL survive and maintain their activity for a significantly longer period. METHODS: We used a low dose of FLU in the cultures in Mart-1-specific CTL generation assays with total PBL. Blood samples were taken from HLA-A2-positive melanoma patients and normal donors. Autologous matured dendritic cells pulsed with Mart-1(27-35) peptide were used to generate CTL responses using purified CD8+ cells or total PBL. RESULTS: The presence of FLU in the cultures with PBL helped to generate a significantly higher number of antigen-specific CTLs as detected by Mart-1 HLA-A2 tetramer staining. Specificity of such CTLs was determined by IFN-gamma secretion or by cytotoxicity against the target cells bearing the specific antigen. The presence of FLU stopped the expansion of IL-10-producing CD4+ Treg cells in the cultures with PBL. Analyses of expanded CD4+ cells isolated from PBL in vitro cocultures with FLU showed a Th1 type of function. Those cells secreted higher amounts of IFN-gamma and very low levels of IL-10, or no IL-10 at all, upon restimulation. CONCLUSION: The observations of the study are as important for adaptive immunotherapy of cancer as they are for vaccine-based approaches.
机译：背景：对于基于肿瘤疫苗的癌症免疫疗法而言，通过阻断诱导性调节性T（Treg）细胞扩展患者体内肿瘤抗原特异性细胞毒性T淋巴细胞（CTL）是最重要的目标。氟达拉滨（FLU）是一种已知的抗癌药物，已被证明可在慢性白血病患者体内下调Treg细胞。体外产生的黑素瘤肿瘤抗原Mart-1（27-35）特异的CD8 + CTL与总外周血淋巴细胞（PBL）在14-21天之内丧失活性，并伴随Treg细胞的扩增。当从PBL中除去CD4 +细胞并用纯化的CD8 +细胞生成CTL时，CTL存活并在相当长的时间内保持其活性。方法：我们在具有总PBL的Mart-1特异性CTL生成测定中，在培养物中使用了低剂量的FLU。血样取自HLA-A2阳性黑色素瘤患者和正常供体。使用Mart-1（27-35）肽脉冲处理的自体成熟树突细胞，使用纯化的CD8 +细胞或总PBL产生CTL反应。结果：如通过Mart-1 HLA-A2四聚体染色检测到的那样，在含有PBL的培养物中FLU的存在有助于产生大量抗原特异性CTL。此类CTL的特异性是通过IFN-γ分泌或对带有特定抗原的靶细胞的细胞毒性来确定的。 FLU的存在阻止了在含有PBL的培养物中产生IL-10的CD4 + Treg细胞的扩增。从与FLU体外共培养的PBL中分离的扩增CD4 +细胞分析显示Th1型功能。这些细胞在重新刺激后分泌更高水平的IFN-γ和非常低的IL-10，或根本不分泌IL-10。结论：本研究的观察结果与基于疫苗的方法一样，对癌症的适应性免疫治疗同样重要。

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