Dearman R J, Warbrick E V, Humphreys I R, Kimber I
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK.
J Appl Toxicol. 2000 May-Jun;20(3):221-30. doi: 10.1002/(sici)1099-1263(200005/06)20:3<221::aid-jat651>3.0.co;2-#.
Occupational exposure to certain acid anhydrides, including trimellitic anhydride (TMA), maleic anhydride (MA), phthalic anhydride (PA), hexahydrophthalic anhydride (HHPA) and methyltetrahydrophthalic anhydride (MTHPA), has been associated with the development of respiratory allergy or asthma. There is considerable debate about the mechanisms through which such chemicals may cause respiratory sensitization, particularly concerning a universal requirement for specific IgE antibody. Despite the controversy regarding an obligatory role for IgE, there is a growing consensus that chemical respiratory hypersensitivity is associated with the selective development of T lymphocytes with a type 2 (Th2) phenotype. In the current investigations we have characterized in mice the nature of immune responses provoked by prolonged topical exposure to five acid anhydrides. Under application conditions where similar overall immunogenicity was achieved, we have compared cytokine responses induced by PA, MA, HHPA and MTHPA with those provoked by concurrent exposure to TMA or to the reference contact allergen 2, 4-dinitrochlorobenzene (DNCB). Lymph node cells (LNC) draining the site of topical exposure to DNCB invariably expressed high levels of the type 1 cytokines interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), but only low levels of the type 2 cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). In each experiment, TMA-activated LNC displayed the converse, type 2, phenotype of cytokine production. The other acid anhydrides in each case provoked a type 2 cytokine secretion profile, with comparable IL-10 expression but somewhat less vigorous IL-4 production compared with that observed following exposure to the reference respiratory allergen TMA. In every experiment relatively low levels of IFN-gamma and IL-12 were elaborated by acid anhydride-activated LNC, with the exception of PA-stimulated LNC that displayed increased amounts of IL-12 in comparison with other acid anhydrides. Thus, prolonged topical exposure of mice to five different acid anhydrides in each case resulted in the development of a predominantly Th2-type cytokine secretion phenotype, consistent with the ability of these materials to provoke asthma and respiratory allergy through a type 2 (possibly IgE-mediated) mechanism. Taken together with the results of previous investigations with a wider range of chemical allergens, these data suggest that induced cytokine secretion patterns or 'fingerprints' allow discrimination between contact and respiratory allergens and consequently represent a suitable approach to prospective evaluation of respiratory sensitization hazard.
职业接触某些酸酐，包括偏苯三酸酐（TMA）、马来酸酐（MA）、邻苯二甲酸酐（PA）、六氢邻苯二甲酸酐（HHPA）和甲基四氢邻苯二甲酸酐（MTHPA），与呼吸道过敏或哮喘的发生有关。关于这些化学物质可能导致呼吸道致敏的机制存在相当大的争议，特别是关于特异性IgE抗体的普遍要求。尽管对于IgE的强制性作用存在争议，但越来越多的共识是，化学性呼吸道超敏反应与具有2型（Th2）表型的T淋巴细胞的选择性发育有关。在当前的研究中，我们已经在小鼠中表征了长期局部接触五种酸酐所引发的免疫反应的性质。在实现相似总体免疫原性的应用条件下，我们将PA、MA、HHPA和MTHPA诱导的细胞因子反应与同时接触TMA或参考接触性变应原2,4-二硝基氯苯（DNCB）所引发的反应进行了比较。引流局部接触DNCB部位的淋巴结细胞（LNC）总是高表达1型细胞因子干扰素-γ（IFN-γ）和白细胞介素-12（IL-12），但仅低表达2型细胞因子白细胞介素-4（IL-4）和白细胞介素-10（IL-10）。在每个实验中，TMA激活的LNC表现出相反的2型细胞因子产生表型。在每种情况下，其他酸酐都引发了2型细胞因子分泌谱，与接触参考呼吸道变应原TMA后观察到的情况相比，IL-10表达相当，但IL-4产生稍弱。在每个实验中，酸酐激活的LNC产生的IFN-γ和IL-12水平相对较低，但PA刺激的LNC除外，与其他酸酐相比，其IL-12含量增加。因此，小鼠长期局部接触五种不同的酸酐，在每种情况下都会导致主要为Th2型细胞因子分泌表型的出现，这与这些物质通过2型（可能是IgE介导的）机制引发哮喘和呼吸道过敏的能力一致。结合先前对更广泛化学变应原的研究结果，这些数据表明，诱导的细胞因子分泌模式或“指纹”能够区分接触性变应原和呼吸道变应原，因此代表了一种前瞻性评估呼吸道致敏危害的合适方法。
