Chapoval S P, Marietta E V, Smart M K, David C S
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
J Allergy Clin Immunol. 2001 Nov;108(5):764-71. doi: 10.1067/mai.2001.118794.
Airway inflammation is central to the pathogenesis of allergic asthma, and molecules that mediate this process obviously represent targets for therapy.
To study the role of CD4(+) T cells and/or HLA-DQ molecules in allergic asthma, we have generated and characterized models of short ragweed allergen (SRW)-induced inflammation using transgenic mice with HLA-DQ (DQ6 or DQ8), human CD4 (hCD4), or both on a genetic background that lacks mouse MHC II and CD4 (Abeta(0)/mCD4(0)).
Mice were actively sensitized and later challenged intranasally with SRW allergenic extract. Bronchoalveolar lavage fluid composition, airway inflammation and hyperresponsiveness, blood eosinophil levels, and cell proliferation were examined.
In response to SRW treatment, both DQ6 and DQ8 transgenic mice expressing hCD4 developed pulmonary eosinophilia and associated lung tissue damage with increase in eosinophil peroxidase and T(H)2 cytokines in bronchoalveolar lavage fluid, strong airway hyperreactivity, and persistent blood eosinophilia. The response was independent of mast cells/histamine pathway and was mediated by DQ-restricted hCD4(+) T cells. Interestingly, lungs of CD4-deficient DQ6 transgenic mice showed an eosinophilic inflammation without local increase in cytokines and eosinophil peroxidase. The allergic reaction was absent in double-knockout mice and mice expressing either DQ8 or hCD4 alone.
DQ6 molecules are critical to SRW-induced allergy and can operate in the presence or absence of CD4. However, both DQ antigens and CD4 molecules are critical for full manifestation of allergen-induced asthma in transgenic mice.
气道炎症是过敏性哮喘发病机制的核心，介导这一过程的分子显然是治疗的靶点。
为研究CD4(+) T细胞和/或HLA-DQ分子在过敏性哮喘中的作用，我们构建并鉴定了短豚草过敏原（SRW）诱导的炎症模型，该模型采用了在缺乏小鼠MHC II和CD4（Abeta(0)/mCD4(0)）基因背景下的携带HLA-DQ（DQ6或DQ8）、人CD4（hCD4）或两者皆有的转基因小鼠。
小鼠经主动致敏，随后经鼻给予SRW变应原提取物进行激发。检测支气管肺泡灌洗液成分、气道炎症和高反应性、血液嗜酸性粒细胞水平以及细胞增殖情况。
对SRW处理的反应中，表达hCD4的DQ6和DQ8转基因小鼠均出现肺部嗜酸性粒细胞增多以及相关的肺组织损伤，支气管肺泡灌洗液中嗜酸性粒细胞过氧化物酶和T(H)2细胞因子增加，气道高反应性增强，血液嗜酸性粒细胞持续增多。该反应独立于肥大细胞/组胺途径，由DQ限制的hCD4(+) T细胞介导。有趣的是，CD4缺陷的DQ6转基因小鼠的肺表现出嗜酸性粒细胞炎症，但细胞因子和嗜酸性粒细胞过氧化物酶无局部增加。双敲除小鼠以及单独表达DQ8或hCD4的小鼠未出现过敏反应。
DQ6分子对SRW诱导的过敏反应至关重要，在有或没有CD4的情况下均可发挥作用。然而，对于转基因小鼠中变应原诱导的哮喘的充分表现，DQ抗原和CD4分子均至关重要。
