Insights into gene modulation by therapeutic TNF and IFNγ antibodies:: TNF regulates IFNγ production by T cells and TNF-regulated genes linked to psoriasis transcriptome
Insights into gene modulation by therapeutic TNF and IFNγ antibodies:: TNF regulates IFNγ production by T cells and TNF-regulated genes linked to psoriasis transcriptome
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DOI：
10.1038/sj.jid.5701064
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发表时间：
2008-03-01
影响因子：
6.5
通讯作者：
Krueger, James G.
中科院分区：
文献类型：
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作者：
Haider, Asifa S.;Cohen, Jules;Krueger, James G.
针对肿瘤坏死因子（TNF）（英夫利昔单抗）和IFN γ (fontolizumab)的治疗性抗体已被开发用于治疗自身免疫性疾病。虽然这些抗体的主要靶点是明确的，但炎性分子的集合，通过使用这些抑制剂被改变，知之甚少。我们从健康志愿者的活化人外周血单核细胞中阐明这些抗体的靶基因。虽然fontolizumab抑制的基因与已知的IFN γ诱导基因重叠，但英夫利昔单抗抑制的大多数基因以前并未追踪到TNF信号。通过这种方法，我们能够推断新的TNF相关基因在寻常型牛皮癣中上调，这是一种用TNF拮抗剂有效治疗的“自身免疫性”疾病。这些基因代表了TNF拮抗剂在银屑病中的潜在治疗靶点。此外，这些数据建立了TNF阻断对T细胞合成IFN γ的意想不到的影响。IFN γ是th1极化T细胞的一种细胞因子，其合成受到8.1倍（P60%）单个T细胞的抑制。这些数据表明，用英夫利昔单抗阻断TNF可以抑制适应性免疫反应的主要途径，这一观察结果为靶向TNF治疗“1型”t细胞介导的自身免疫性疾病提供了关键的理论依据。
Therapeutic antibodies against tumor necrosis factor (TNF) (infliximab) and IFN gamma (fontolizumab) have been developed to treat autoimmune diseases. While the primary targets of these antibodies are clearly defined, the set of inflammatory molecules, which is altered by use of these inhibitors, is poorly understood. We elucidate the target genes of these antibodies in activated human peripheral blood mononuclear cells from healthy volunteers. While genes suppressed by fontolizumab overlap with known IFN gamma-induced genes, majority of genes suppressed by infliximab have previously not been traced to TNF signaling. With this approach we were able to extrapolate new TNF-associated genes to be upregulated in psoriasis vulgaris, an "autoimmune" disease effectively treated with TNF antagonists. These genes represent potential therapeutic targets of TNF antagonists in psoriasis. Furthermore, these data establish an unexpected effect of TNF blockade on IFN gamma synthesis by T cells. Synthesis of IFN gamma, a cytokine of Th1-polarized T cells, is suppressed by 8.1-fold (P60% of individual T cells. These data suggest that TNF blockade with infliximab can suppress a major pathway of the adaptive immune response and this observation provides a key rationale for targeting TNF in "Type-1" T-cell-mediated autoimmune diseases.