Severe asthma, airway re-modelling and induced bronchial associated lymphoid tissue produced using novel dust mite specific CD4 T cell receptor transgenic mice (HYP2P.327)

Abstract

Patients with severe asthma are very difficult to manage are present a major medical challenge. Development of clinical asthma requires many years of patient exposure to allergens. Mouse asthma models require weeks and are normally transitory and do not lead to allergen-induced dyspnea. We have followed an alternative approach to conventional immunization through the transfer highly polarized CD4 T cell receptor transgenic T cells specific for the dust mite allergen Blo t 5 followed by thrice weekly intranasal recombinant challenge with recombinant allergen to induce persistent high levels of eosinophilia (4 million/mouse lavage) and serum IgE (40,000 ng/ml) and specific IgG1 (30,000 ng/ml). Intranasal challenge of these mice with 25ug of allergen is well tolerated, but a fourfold increase to 100ug induces respiratory symptoms within 15 minutes. These mice show evidence of mucus plugging, increased collagen deposition, mucus hypersecretion and the formation of bronchial associated lymphoid structures (iBALT). Neutralization of IL-4 or IL-13 with monoclonal antibody reduced the response and a combination of these two was most effective. Many drugs reduce respiratory inflammation in mice yet fail to benefit asthmatic patients. We hope that the model described here may help identify new/better drugs for the treatment of patients with severe asthma.