Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Gastroenterology. 2011 Jan;140(1):221-30. doi: 10.1053/j.gastro.2010.10.008. Epub 2010 Oct 16.
BACKGROUND & AIMS: Anti-tumor necrosis factor (TNF)α antibodies are effective in treating patients with Crohn's disease whereas soluble TNFα receptors have not shown clinical efficacy; the mechanism that underlies these different effects is not clear. We examined the immunosuppressive effects of different anti-TNFα reagents on activated T cells.
We studied the effects of anti-TNFα antibodies infliximab and adalimumab, the soluble TNFα receptor etanercept, the pegylated F(ab') fragment certolizumab, and certolizumab-immunoglobulin (Ig)G on primary activated T cells. T cells were grown in isolation or in a mixed lymphocyte reaction (MLR). Proliferation was measured by (3)H thymidine incorporation and apoptosis was examined using Annexin V labeling and a colorimetric assay for activated caspase-3. Macrophage phenotypes were assayed by flow cytometry and cytokine secretion.
Infliximab and adalimumab reduced T-cell proliferation in an MLR whereas etanercept and certolizumab did not; this effect was lost after Fc receptors were blocked. The infliximab F(ab')2 fragment did not inhibit proliferation whereas certolizumab-IgG did inhibit proliferation. In the MLR, the antibodies against TNF induced formation of a new population of macrophages in an Fc region-dependent manner; these macrophages had an immunosuppressive phenotype because they inhibit proliferation of activated T cells, produce anti-inflammatory cytokines, and express the regulatory macrophage marker CD206.
Regulatory macrophages have immunosuppressive properties and an important role in wound healing. Antibodies against TNF induce regulatory macrophages in an Fc region-dependent manner. These functions of anti-TNFs might contribute to the resolution of inflammation.
抗肿瘤坏死因子（TNF）α 抗体在治疗克罗恩病患者方面非常有效，而可溶性 TNFα 受体则没有显示出临床疗效；这些不同效果的机制尚不清楚。我们研究了不同抗 TNFα 试剂对激活的 T 细胞的免疫抑制作用。
我们研究了抗 TNFα 抗体英夫利昔单抗和阿达木单抗、可溶性 TNFα 受体依那西普、聚乙二醇化 F(ab') 片段 certolizumab 以及 certolizumab-IgG 对原代激活 T 细胞的影响。T 细胞在分离或混合淋巴细胞反应（MLR）中生长。通过[3H]胸苷掺入测量增殖，并用 Annexin V 标记和激活的 caspase-3 的比色测定法检查细胞凋亡。通过流式细胞术和细胞因子分泌测定巨噬细胞表型。
英夫利昔单抗和阿达木单抗在 MLR 中减少了 T 细胞增殖，而依那西普和 certolizumab 则没有；在阻断 Fc 受体后，这种作用消失了。英夫利昔单抗 F(ab')2 片段不抑制增殖，而 certolizumab-IgG 则抑制增殖。在 MLR 中，抗 TNF 抗体以 Fc 区域依赖性方式诱导形成新的巨噬细胞群体；这些巨噬细胞具有免疫抑制表型，因为它们抑制激活的 T 细胞增殖、产生抗炎细胞因子，并表达调节性巨噬细胞标记物 CD206。
调节性巨噬细胞具有免疫抑制特性，在伤口愈合中具有重要作用。抗 TNF 抗体以 Fc 区域依赖性方式诱导调节性巨噬细胞。这些抗 TNF 的功能可能有助于炎症的消退。
