Corry D B, Grünig G, Hadeiba H, Kurup V P, Warnock M L, Sheppard D, Rennick D M, Locksley R M
Department of Medicine, University of California San Francisco, USA.
Mol Med. 1998 May;4(5):344-55.
The pathogenesis of asthma is believed to reflect antigen-induced airway inflammation leading to the recruitment of eosinophils and activation of mast cells through cell-associated IgE. Controversies persist however, regarding the relative importance of different pathogenic cells and effector molecules.
A variety of gene-targeted mice were examined for the induction of cholinergic airway hyperresponsiveness (AH), allergic airway inflammation, mucus production, and serum IgE reactivity following intratracheal challenge with a potent allergen. AH was determined using whole-body plethysmography following acetylcholine challenge. Where possible, results were confirmed using neutralizing antibodies and cell-specific reconstitution of immune deficient mice.
T and B cell-deficient, recombinase-activating-gene-deficient mice (RAG -/-) failed to develop significant allergic inflammation and AH following allergen challenge. Reconstitution of RAG -/- mice with CD4+ T cells alone was sufficient to restore allergen-induced AH, allergic inflammation, and goblet cell hyperplasia, but not IgE reactivity. Sensitized B cell-deficient mice also developed airway hyperreactivity and lung inflammation comparable to that of wild-type animals, confirming that antibodies were dispensable. Treatment with neutralizing anti-IL-4 antibody or sensitization of IL-4-deficient mice resulted in loss of airway hyperreactivity, whereas treatment with anti-IL-5 antibody or sensitization of IL-5-deficient mice had no effect.
In mice, CD4+ T cells are alone sufficient to mediate many of the pathognomonic changes that occur in human asthma by a mechanism dependent upon IL-4, but independent of IL-5, IgE, or both. Clarification of the role played by CD4+ T cells is likely to stimulate important therapeutic advances in treatment of asthma.
哮喘的发病机制被认为反映了抗原诱导的气道炎症，通过细胞相关的IgE导致嗜酸性粒细胞的募集和肥大细胞的激活。然而，关于不同致病细胞和效应分子的相对重要性仍存在争议。
在用强效变应原进行气管内激发后，检查了多种基因靶向小鼠的胆碱能气道高反应性（AH）、过敏性气道炎症、黏液产生和血清IgE反应性的诱导情况。使用乙酰胆碱激发后的全身体积描记法测定AH。在可能的情况下，使用中和抗体和免疫缺陷小鼠的细胞特异性重建来确认结果。
T细胞和B细胞缺陷、重组酶激活基因缺陷小鼠（RAG -/-）在变应原激发后未能出现明显的过敏性炎症和AH。仅用CD4 + T细胞重建RAG -/-小鼠足以恢复变应原诱导的AH、过敏性炎症和杯状细胞增生，但不能恢复IgE反应性。致敏的B细胞缺陷小鼠也出现了与野生型动物相当的气道高反应性和肺部炎症，证实抗体并非必需。用中和抗IL-4抗体治疗或IL-4缺陷小鼠致敏导致气道高反应性丧失，而用抗IL-5抗体治疗或IL-5缺陷小鼠致敏则无影响。
在小鼠中，CD4 + T细胞单独足以通过依赖IL-4但独立于IL-5、IgE或两者的机制介导人类哮喘中发生的许多特征性变化。阐明CD4 + T细胞所起的作用可能会推动哮喘治疗的重要治疗进展。
