Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis
Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis
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DOI：
10.4049/jimmunol.174.7.4316
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Burrows, GG
中科院分区：
文献类型：
--
作者：
Chou, YK;Edwards, DM;Burrows, GG
CD4(+)T细胞在慢性铍病患者肺部肉芽肿炎症中起关键作用。这项研究的目的是描述慢性铍病患者对铍反应的支气管肺泡灌洗(BAL)CD4(+)T细胞的激活途径，以确定可能的治疗干预策略。我们的结果表明，在AM存在的情况下，铍诱导了BAL CD4(+)T细胞的强烈增殖反应，产生了超适浓度的分泌性促炎细胞因子、干扰素-γ、肿瘤坏死因子-α和IL-2，并上调了许多T细胞表面标志物，从而促进了T-T抗原的提呈。AB阻断实验显示，抗HLADP或抗LFA-1Ab可显著降低BAL CD4(+)T细胞的增殖反应和细胞因子的分泌。相反，抗HLADR或抗OX40配体抗体主要影响绿柱石诱导的增殖反应，对IL-2以外的细胞因子影响很小，提示非增殖的BAL CD4(+)T细胞仍可能参与炎症反应。CTLA4-Ig阻断对细胞增殖和细胞因子反应的影响最小，证实激活不依赖于B7/CD28共刺激。这些结果表明，HLADP和LFA-1在BAL CD4(+)T细胞活化中起着重要作用，并进一步提示针对这些分子的特异性抗体可能成为治疗慢性铍病的一种可能。
CD4(+) T cells play a key role in granulornatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the presence of AM, beryllium induced strong proliferation responses of BAL CD4(+) T cells, production of superoptimal concentrations of secreted proinflammatory cytokines, IFN-gamma, TNF-alpha,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4(+) T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryl lium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4(+) T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4(+) T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease.