TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma.
TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma.
复制标题
来自恶性细胞的Th2细胞因子抑制了Th1反应并在白血病皮肤T细胞淋巴瘤中抑制全球Th2偏置。
DOI：
10.1158/1078-0432.ccr-12-3488
复制
发表时间：
2013-07-15
期刊：
影响因子：
--
通讯作者：
Clark RA
中科院分区：
文献类型：
--
作者：
Guenova E;Watanabe R;Teague JE;Desimone JA;Jiang Y;Dowlatshahi M;Schlapbach C;Schaekel K;Rook AH;Tawa M;Fisher DC;Kupper TS;Clark RA
在白血病CTCL（L-CTCL）中，恶性T细胞在血液中积聚并引起广泛的皮肤炎症。患者有强烈的瘙痒，IgE升高，Th 1应答降低，大多数死于感染。在保持正常免疫力的同时耗尽恶性T细胞是一项临床挑战。L-CTCL被认为是调节性Th 2和Th 17细胞的恶性肿瘤。我们分析了恶性和良性L-CTCL T细胞的表型和细胞因子产生，表征了恶性T细胞对健康T细胞的影响，并研究了L-CTCL患者治疗方式的免疫调节作用。12/12例L-CTCL患者过度产生Th 2细胞因子。剩余的良性T细胞也强烈Th 2偏向，表明T细胞库的整体Th 2偏斜。良性T细胞培养远离恶性克隆减少Th 2和增强Th 1反应，但单独培养对恶性T细胞没有影响。健康T细胞与L-CTCL T细胞的共培养减少了IFNγ的产生，并且针对IL-4和IL-13的中和抗体恢复了Th 1应答。在患者中，观察到增强的Th 1反应后，各种治疗方式，减少恶性T细胞负荷。在L-CTCL中，良性和恶性T细胞均存在整体Th 2偏倚，可能是患者感染易感性的基础。来自恶性肿瘤细胞的Th 2细胞因子强烈抑制Th 1应答。我们的研究结果表明，抑制Th 2细胞因子活性的疗法，凭借其改善Th 1应答的能力，可能具有增强抗癌和抗病原体应答的潜力。
In leukemic CTCL (L-CTCL) malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased IgE, decreased Th1 responses and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, Th2 and Th17 cells. We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells and studied the immunomodulatory effects of treatment modalities in L-CTCL patients. 12/12 L-CTCL patients overproduced Th2 cytokines. Remaining benign T cells were also strongly Th2 biased, suggesting a global Th2 skewing of the T cell repertoire. Culture of benign T cells away from the malignant clone reduced Th2 and enhanced Th1 responses but separate culture had no effect on malignant T cells. Co-culture of healthy T cells with L-CTCL T cells reduced IFNγ production and neutralizing antibodies to IL-4 and IL-13 restored Th1 responses. In patients, enhanced Th1 responses were observed following a variety of treatment modalities that reduced malignant T cell burden. A global Th2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. Th2 cytokines from malignant cells strongly inhibited Th1 responses. Our results suggest therapies that inhibit Th2 cytokine activity, by virtue of their ability to improve Th1 responses, may have the potential to enhance both anti-cancer and anti-pathogen responses.