Mouse models of asthma: not only proteins, but also chemicals can act as allergens
07/07/2009 - VHIR Seminar
Dr. Jeroen Vanoirbeek, PhD."K.U. Leuven Fac. Medicine
Dep. Of Public Healh Occupational,
Enviromental & Insurance Medicine"
Date: 07/07/2009 Hour: 15:30 Location: Hall, ground floor, general area HUVH
Summary of Paper
Not only high molecular weight (HWM) agents, but also low molecular weight (LMW) agents used on the work floor can act as asthmogens and result in occupational asthma (OA)(Figure 1.). OA is probably the result of multiple genetic, environmental, and behavioural influences (Figure 2.). The identification of host factors, polymorphisms, and candidate genes associated with OA can improve our understanding of the mechanisms involved in asthma. Traditionally, HMW agents are considered to induce an IgE-mediated response, similar to atopic asthma . This is also the case for a part of the LMW compounds. Nevertheless, for several LMW agents, no specific-IgE antibodies can be detected, suggesting other immune mechanisms play a role in this type of OA, despite the fact that the clinical, functional, and pathologic features of OA induced by LMW asthmogens are very similar to atopic asthma. Recent advances have been made in humane research as well as animal experiments to unravel the mechanisms of the immune responses induced by LMW asthmogens. An important issue addressed in animal models is that primary sensitization, preceding asthma, does not only develop after exposure of the sensitizers to the respiratory mucus, but also after dermal contact with the sensitizers. In this context, a mouse model chemical-induced asthma was developed, in which dermal applications of a sensitizing chemical are followed by a single airway challenge, leading to an asthma-like phenotype resembling OA induced by chemicals. More specifically, after dermal treatment on both ears (days 1 and 8) and an intranasal challenge on day 15 with toluene diisocyanate (TDI), a known occupational respiratory allergen, the mice show pronounced signs of airway obstruction immediately after intranasal instillation and signs of increased bronchial hyperreactivity to methacholine 22 hours later (Figure 3.). The non-specific airway reactivity is accompanied by an influx of granulocytes (mainly neutrophils) in the broncho-alveolar lavage (BAL) fluid, and a limited infiltration of eosinophils around the blood vessels of the lung. In the serum of TDI-treated mice, an increase in total serum IgE and IgG1 was found. Lymphocytes obtained from the retro-auricular and superficial cervical lymph nodes, which drain the ears and nose, respectively, show an increase in the T and B cells and a secretion profile (after in vitro stimulation with concanavalin A) of both Th1 and Th2 lymphocytes, i.e. an increase of both IFN-? and IL-4. We confirmed the importance of lymphocytes in our model using SCID (severe combined immunodeficient) mice. The SCID mice have no T and B lymphocytes and they did not show an asthmatic response in our model when treated with TDI (Figure 4.). Subsequently, we validated the model using trimellitic anhydride (TMA), a known respiratory sensitizer, which yielded an asthmatic response and compared it to dinitrochlorobenzene (DNCB), a known dermal sensitizer, which was not positive in this mouse model. To further characterize the “asthmatic” response, we determined other relevant physiological endpoints. In a maximal endurance (swim) test we showed that TDI-treated mice have a reduced exercise capacity 1 hour after intranasal challenge and this reduction in exercise capacity is still present 22 hours after the intranasal exposure. This type of functional response has never been shown in mice models of asthma before. Recently, we introduced persulfate salts, used in bleaching product and the main cause of OA hairdressers, in our model. We showed for the first time the dermal and respiratory sensitizing properties of ammonium persulfate in mice (Figure 5.). In conclusion, the increasing publication in the field of OA give the possibility to combine all knowledge on in vivo, in vitro, epidemiologic and case-control studies, leading to the revealing of the immunologic mechanisms of action of chemical-induced asthma (Figure 6.). Nevertheless, we are aware that there is still much to do.