Dust mite-induced asthma in cynomolgus monkeys

Abstract

Animal models exhibiting high homology with humans at the genetic and pathophysiological levels will facilitate identification and validation of gene targets underlying asthma. In the present study, a nonhuman primate model of allergic asthma was developed by sensitizing cynomolgus monkeys to dust mite antigen. Sensitization elevated allergen-specific serum IgE and IgG levels, and peripheral blood mononuclear cells isolated from sensitized animals released IL-4, IL-5, and IL-10, but not IFN-gamma. Aerosolized allergen decreased dynamic compliance and induced airway inflammation and hyperresponsiveness to aerosolized histamine. Albuterol and dexamethasone inhibited the airway constriction and allergen-induced inflammation, respectively. Airway wall remodeling that included goblet cell hyperplasia, basement membrane thickening, and smooth muscle hypertrophy was particularly evident in neonatally sensitized animals. In contrast to animals sensitized as adults, neonatally sensitized animals exhibited increased sensitivity to adenosine and larger allergen-induced changes in airway resistance and dynamic compliance. These results demonstrate that sensitization of cynomolgus monkeys with dust mite induces asthmalike symptoms, some of which may be dependent on age at the time of sensitization.

Shortening of the Induction Period of Allergic Asthma in Cynomolgus Monkeys by Ascaris suum and House Dust Mite

“…In addition, natural sensitivity to dust mites had been documented in monkeys (24), increasing the relevance of the allergen. We added the subcutaneous injection in the sensitization by HDM because several studies showed that sensitization by subcutaneous injection with HDM could elicit allergen-specific IgE production (9) and allergic asthma symptoms (15,16). As we expected, the sensitization with HDM succeeded to induce asthmatic responses as well as DNP-As.…”

“…For these reasons, actively immunized monkeys should be used for the development of asthma models. Several groups published articles about such models (15,16). The methods reported required a long term such as a halfyear or a year.…”

“…Thus far, although wildcaught cynomolgus monkeys (10 -13) and squirrel monkeys (14) sensitive to inhaled Ascaris suum allergen had been used, these wild-caught monkeys are not currently available. Recently, several studies showed that sensitization of monkeys with allergens could elicit allergen-specific IgE production (9) and allergic asthma symptoms upon allergen provocation (15,16). However, a long period of time is required for the development of these models (15,16).…”

“…Recently, several studies showed that sensitization of monkeys with allergens could elicit allergen-specific IgE production (9) and allergic asthma symptoms upon allergen provocation (15,16). However, a long period of time is required for the development of these models (15,16). Development of a non-human primate model of asthma in a short period would be useful for target validation and evaluation of therapeutic candidates.…”

“…Although the majority of asthmatic patients is sensitized with mites, very few investigators used mites or mite extracts as immunizing agents (9,15,16). Therefore, we sensitized cynomolgus monkeys by house dust mite extracts (HDM) under the similar protocol.…”