Au-ACRAMTU-PEt3 Alters Redox Balance To Inhibit T Cell Proliferation and Function.
Au-ACRAMTU-PEt3 Alters Redox Balance To Inhibit T Cell Proliferation and Function.
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DOI：
10.4049/jimmunol.1400391
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发表时间：
2015-09-01
期刊：
影响因子：
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通讯作者：
Grayson JM
中科院分区：
文献类型：
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作者：
Langston PK;Yang M;Bierbach U;Parsonage D;Poole LB;Price MJ;Grayson JM
尽管T细胞在抵御病毒、细菌和肿瘤方面发挥着关键作用，但它们也会引起自身免疫性疾病，如系统性红斑狼疮（SLE）、类风湿性关节炎（RA）和多发性硬化症（MS）。器官移植、移植物抗宿主病（GVHD）和过敏过程中不需要的T细胞反应也是主要的临床问题。虽然有药物可以抑制不想要的免疫反应，但它们的疗效有限，副作用严重。因此，限制T细胞活化、增殖和功能的新疗法可以立即产生临床影响。为了寻找新的淋巴细胞活化、增殖和功能抑制因子，我们检测了铂-吖啶类抗肿瘤药物的金(I)类似物的免疫抑制活性。我们发现金络合物Au-ACRAMTU-PEt3是小鼠和人类T细胞激活的有效抑制因子。预孵育Au-ACRAMTU-PEt3可抑制CD4+和CD8+ T细胞的增殖，其浓度与药物级环孢素a相似。Au-ACRAMTU-PEt3预处理可降低人和小鼠CD4+和CD8+ T细胞IFNγ、TNFα、IL-2和IL-17的产生。在病毒感染期间用Au-ACRAMTU-PEt3处理小鼠，病毒特异性CD8+ T细胞的扩增减少10倍，病毒载量升高。综上所述，这些结果表明Au-ACRAMTU-PEt3具有有效的免疫抑制活性，可用于抑制移植和自身免疫期间的免疫反应。
Although T cells play a critical role in protection from viruses, bacteria and tumors, they also cause autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Unwanted T cell responses during organ transplant, graft versus host disease (GVHD), and allergies are also major clinical problems. While drugs are available to suppress unwanted immune responses they have limited efficacy with serious side effects. Thus new therapeutics limiting T cell activation, proliferation and function can make an immediate clinical impact. To identify new suppressors of lymphocyte activation, proliferation and function, we examined the immunosuppressive activity of gold(I) analogues of platinum-acridine antitumor agents. We found that the gold complex, Au-ACRAMTU-PEt3 is a potent suppressor of murine and human T cell activation. Preincubation with Au-ACRAMTU-PEt3 suppresses the proliferation of CD4+ and CD8+ T cells at a similar concentration as pharmaceutical grade cyclosporine A. Au-ACRAMTU-PEt3 pretreatment decreases the production of IFNγ, TNFα, IL-2, and IL-17 by human and murine CD4+ and CD8+ T cells. When mice were treated with Au-ACRAMTU-PEt3 during viral infection the expansion of virus-specific CD8+ T cells was decreased 10-fold and viral load was elevated. Taken together these results demonstrate that Au-ACRAMTU-PEt3 has potent immunosuppressive activity that could be used to suppress immune responses during transplantation and autoimmunity.