Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells
Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells
复制标题
DOI：
10.1158/1078-0432.ccr-06-0053
复制
发表时间：
2006-07-15
影响因子：
11.5
通讯作者：
Sampson, John H.
中科院分区：
文献类型：
--
作者：
Fecci, Peter E.;Sweeney, Alison E.;Sampson, John H.
目的：调节性T细胞（T-reg）的比例升高存在于患有多种癌症（包括恶性胶质瘤）的患者中，但需要重演性小鼠模型。实验设计：在携带恶性胶质瘤的小鼠的外周血、脾、颈淋巴结和骨髓中定量CD 4（+）CD 25（+）Foxp 3（+）GITR（+）T-T细胞。评估了全身性抗CD 25治疗消除T细胞亚群、增强淋巴细胞功能和产生抗胶质瘤CTL应答的能力。最后，生存和实验性过敏性脑炎的风险进行了评估时，抗CD 25与树突状细胞为基础的免疫靶向共享肿瘤和中枢神经系统antigens.Results：类似的恶性胶质瘤患者，胶质瘤荷瘤小鼠表现出CD 4淋巴细胞减少症。此外，CD 4（+）CD 25（+）Foxp 3（+）GITR（+）T细胞代表剩余外周血CD 4（+）T细胞的增加部分，尽管它们本身的数量减少。在颈淋巴结和脾脏中观察到类似的趋势，但在骨髓中未观察到。全身性抗CD 25给药阻碍了CD 25（+）细胞的检测，但未能完全消除T细胞，仅适度减少其数量，但消除了其抑制功能。这种T-reg功能的消除允许增强的淋巴细胞增殖和IFN-γ应答以及体外高达80%的胶质瘤细胞靶特异性裂解。当与树突状细胞免疫相结合，抗CD 25 elephant肿瘤排斥反应，在100%的挑战小鼠没有沉淀实验过敏性encephalitis.Conclusions：全身抗CD 25管理不完全消除T细胞，但防止T-reg功能。这导致在鼠神经胶质瘤模型中安全增强肿瘤免疫，该模型重现了恶性神经胶质瘤患者中观察到的肿瘤诱导的CD 4和T-reg区室变化。
Purpose: Elevated proportions of regulatory T cells (T-reg) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T-regs in mice bearing malignant glioma an devaluated anti-CD25 as an immunotherapeutic adjuncts.Experimental Design: CD4(+)CD25(+)Foxp3(+)GITR(+) T-regs were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T-regs, enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell - based immunization targeting shared tumor and central nervous system antigens.Results: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4(+)CD25(+)Foxp3(+)GITR(+) T-regs represent an increased fraction of the remaining peripheral blood CD4(+) T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25(+) cells but fails to completely eliminate T-regs, reducing their number only moderately, yet eliminating their suppressive function. This elimination of T-reg function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis.Conclusions: Systemic anti-CD25 administration does not entirely eliminate T-regs, but does prevent T-reg function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T-reg compartments seen in patients with malignant glioma.