Hopkins Josephine E, Naisbitt Dean J, Kitteringham Neil R, Dearman Rebecca J, Kimber Ian, Park B Kevin
Department of Pharmacology and Therapeutics, The University of Liverpool, P. O. Box 147, Liverpool L69 3GE, England.
Chem Res Toxicol. 2005 Feb;18(2):375-81. doi: 10.1021/tx049688+.
Sensitizing chemicals can cause different forms of allergy, allergic contact dermatitis, or sensitization of the respiratory tract. These discrete types of chemicals induce in mice qualitatively divergent immune responses; contact allergens provoke preferential type 1 responses, whereas respiratory allergens stimulate selective type 2 responses. We have questioned whether the ability of chemicals to initiate polarized immune responses is in part a function of the nature of their association with protein. Cytokine secretion profiles provoked following topical exposure of BALB/c mice to dinitrochlorobenzene (DNCB), dinitrofluorobenzene (DNFB), fluorescein isothiocyanate (FITC), trimellitic anhydride (TMA), and dinitrobenzenesulfonyl chloride (DNBSCl) were compared with the distribution of covalent binding to U937 cells and/or to serum proteins in vitro. DNCB and DNFB each provoked a type 1 cytokine secretion profile, with high levels of IFN-gamma, but relatively low levels of type 2 cytokines IL-4, -5, and -10. The converse selective type 2 phenotype was seen following equivalent exposure to TMA, FITC, or DNBSCl. Each chemical bound covalently to U937 cells and to serum proteins, when incubated with cells or serum alone. When incubated with cells and serum together, DNCB and DNFB bound selectively to cellular protein, whereas TMA, FITC, and DNBSCl bound selectively to serum. These investigations show that the distribution of antigen formation of chemical allergens in an in vitro model system segregates with the type of cytokines secreted from activated lymph node cells in an in vivo mouse model. Chemical allergens that stimulate type 1 cytokine secretion profiles bind selectively to cellular proteins, whereas others that provoke type 2 cytokine profiles bind preferentially to serum proteins.
致敏化学物质可引发不同形式的过敏、过敏性接触性皮炎或呼吸道致敏。这些不同类型的化学物质在小鼠中诱导出性质不同的免疫反应；接触性变应原引发优先的1型反应，而呼吸道变应原刺激选择性的2型反应。我们曾质疑化学物质引发极化免疫反应的能力是否部分取决于它们与蛋白质结合的性质。将BALB/c小鼠局部暴露于二硝基氯苯（DNCB）、二硝基氟苯（DNFB）、异硫氰酸荧光素（FITC）、偏苯三酸酐（TMA）和二硝基苯磺酰氯（DNBSCl）后引发的细胞因子分泌谱，与体外与U937细胞和/或血清蛋白的共价结合分布进行了比较。DNCB和DNFB各自引发1型细胞因子分泌谱，IFN-γ水平高，但2型细胞因子IL-4、-5和-10水平相对较低。在同等暴露于TMA、FITC或DNBSCl后观察到相反的选择性2型表型。每种化学物质单独与细胞或血清孵育时，均与U937细胞和血清蛋白共价结合。当与细胞和血清一起孵育时，DNCB和DNFB选择性地与细胞蛋白结合，而TMA、FITC和DNBSCl选择性地与血清结合。这些研究表明，体外模型系统中化学变应原的抗原形成分布与体内小鼠模型中活化淋巴结细胞分泌的细胞因子类型相关。刺激1型细胞因子分泌谱的化学变应原选择性地与细胞蛋白结合，而引发2型细胞因子谱的其他变应原则优先与血清蛋白结合。
