Blomia tropicalis–Specific TCR Transgenic Th2 Cells Induce Inducible BALT and Severe Asthma in Mice by an IL-4/IL-13–Dependent Mechanism

Abstract

Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes. Transfer of highly polarized transgenic CD4 effector Th2 cells, termed BT-II, followed by repeated inhalation of Blo t 5 expands these cells in the lung >100-fold, and subsequent Blo t 5 challenge induced decreased body temperature, reduction in movement, and a fall in specific lung compliance unseen in conventional mouse asthma models following a physiological allergen challenge. These mice exhibit lung eosinophilia; smooth muscle cell, collagen, and goblet cell hyperplasia; hyper IgE syndrome; mucus plugging; and extensive inducible BALT. In addition, there is a fall in total lung volume and forced expiratory volume at 100 ms. These pathophysiological changes were substantially reduced and, in some cases, completely abolished by administration of neutralizing mAbs specific for IL-4 and IL-13 on weeks 1, 2, and 3. This IL-4/IL-13-dependent inducible BALT model will be useful for investigating the pathophysiological mechanisms that underlie asthma and the development of more effective drugs for treating severe asthma.

Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

“…In a recent report, transfer of T H 2 cells and lung stimulation with Blomia mite protein allergen caused severe lung inflammation, through increased type-2 inflammation (IL-4 and IL-13). 48 In this model, increased mucus hypersecretion, tissue remodelling and severe inflammation were observed. 48 Most models use repeated chronic allergen challenges to induce tissue remodelling, which are characterized by allergen-specific T H 2 responses.…”

“…48 In this model, increased mucus hypersecretion, tissue remodelling and severe inflammation were observed. 48 Most models use repeated chronic allergen challenges to induce tissue remodelling, which are characterized by allergen-specific T H 2 responses. Chronic asthma models typically consist of an initial allergic sensitization step, followed by repeated low-level allergen exposure/challenge over an extended period of time (up to 12 weeks) to induce chronic allergic inflammation.…”

New variants in NLRP3 inflammasome genes increase risk for asthma and Blomia tropicalis-induced allergy in a Brazilian population

“…Recent studies have shown that IL-33 cytokine is the key element that links early events after lung epithelial cells contact with the allergen and Th2 response, resulting on asthma [9] , [44] . An experimental mice model receiving CD4+ effector Th2 cells, exposed to Bt antigens have developed lung eosinophilia, hyperplasia of smooth muscle cells and goblet cell, as well as overproduction of IgE and mucus production through IL-13 [6] .…”

“…Asthma is a disease that affect the life of people, being more prevalent in childhood [1] . Blomia tropicalis (Bt) mite rapidly settles in homes of climates countries such as Brazil [2] , being the main asthma-induced allergen in the tropics [3] , [4] , [5] , [6] . Atopic asthma is characterized by inflammation of airways, with predominance of Th2-type cytokines, as IL-13, and eosinophilic inflammation [7] .…”

ML-7 attenuates airway inflammation and remodeling via inhibiting the secretion of Th2 cytokines in mice model of asthma

“…In asthma, the imbalance of the proportion of T-helper type 1 (Th1) to Th2 cells activates the CD4 + Th2 cell immune response and the release of interleukin (IL)-13, −25, −5, −4 and −33, prompting the transformation of B cells into immunoglobulin (Ig)E-secreting cells ( 23 , 24 ). Among these ILs, IL-25 and −33 are known as vital pro-inflammatory mediators that induce the release of Th2-associated cytokines, including IL-5, IL-4 and IL-13, which elevate serum IgE, as well as airway hyperresponsiveness, remodeling and mucus hypersecretion ( 25 – 28 ).…”