In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: Implications for adoptive immunotherapy
In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: Implications for adoptive immunotherapy
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DOI：
10.4049/jimmunol.172.9.5338
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Adler, AJ
中科院分区：
文献类型：
--
作者：
Mihalyo, MA;Doody, ADH;Adler, AJ
针对肿瘤相关抗原的 T 细胞耐受性的发展会限制功能性肿瘤反应性 T 细胞的全部功能，从而削弱疫苗引发有效抗肿瘤免疫的能力。使用离体扩增的肿瘤反应性效应T细胞的过继免疫治疗策略可以绕过这个问题；然而，效应 T 细胞对耐受的敏感性表明耐受也可能对过继免疫疗法产生负面影响。尽管如此，过继免疫治疗策略可能是有效的，特别是那些使用药物环磷酰胺 (CY) 和/或外源性 IL-2 的策略。在当前的研究中，我们使用TCR转基因小鼠过继转移系统来评估CY加IL-2治疗是否可以在面对耐受Ag（即同源实质自身Ag）时挽救效应CD4细胞功能。 CY加IL-2治疗不仅增强效应CD4细胞的增殖和积累，而且还保留这些细胞表达效应细胞因子IFN-γ（以及较小程度的TNF-α）的能力，其与实质自身Ag表达水平成比例。当单独给药时，CY 而不是 IL-2 可以显着阻碍耐受性，尽管它们的组合是最有效的。虽然 CY 加 IL-2 处理的自身 Ag 表达小鼠中的效应 CD4 细胞最终屈服于耐受，但这种延迟导致同源 Ag 表达的实质组织中原位 IFN-γ 表达水平增加，并通过需要直接实质 Ag 呈递的机制导致死亡。这些结果表明，CY 和 IL-2 增强过继性免疫治疗策略治疗癌症的一种潜在机制是阻碍肿瘤反应性效应 T 细胞的耐受。
The development of T cell tolerance directed toward tumor-associated Ags can limit the repertoire of functional tumor-reactive T cells, thus impairing the ability of vaccines to elicit effective antitumor immunity. Adoptive immunotherapy strategies using ex vivo expanded tumor-reactive effector T cells can bypass this problem; however, the susceptibility of effector T cells to undergoing tolerization suggests that tolerance might also negatively impact adoptive immunotherapy. Nonetheless, adoptive immunotherapy strategies can be effective, particularly those utilizing the drug cyclophosphamide (CY) and/or exogenous IL-2. In the current study, we used a TCR-transgenic mouse adoptive transfer system to assess whether CY plus IL-2 treatment rescues effector CD4 cell function in the face of tolerizing Ag (i.e., cognate parenchymal self-Ag). CY plus IL-2 treatment not only enhances proliferation and accumulation of effector CD4 cells, but also preserves the ability of these cells to express the effector cytokine IFN-gamma (and to a lesser extent TNF-alpha) in proportion to the level of parenchymal self-Ag expression. When administered individually, CY but not IL-2 can markedly impede tolerization, although their combination is the most effective. Although effector CD4 cells in CY plus IL-2-treated self-Ag-expressing mice eventually succumb to tolerization, this delay results in an increased level of in situ IFN-gamma expression in cognate Ag-expressing parenchymal tissues as well as death via a mechanism that requires direct parenchymal Ag presentation. These results suggest that one potential mechanism by which CY and IL-2 augment adoptive immunotherapy strategies to treat cancer is by impeding the tolerization of tumor-reactive effector T cells.