MD Biosciences Blog

Suitable Preclinical Models Needed For Novel Asthma Treatments

Posted by MD Biosciences

on Apr 6, 2011 11:08:00 AM

There is a major unmet need in the treatment of asthma which is growing in incidence and prevalence in industrialized countries. The prevalence of asthma has doubled in the Western world over the previous 20 years. In addition to the estimated 180,000 asthma related deaths per year, there is a substantial economic burden due to lost school/work days and increased medical costs.

Allergic asthma is typically triggered by allergens in the air such as pollen, mold, dust mites etc and is commonly characterized by reversible airway destruction, elevated levels of IgE causing mast cell activation, chronic airway inflammation and airway hyper-responsiveness (AHR). The immunological processes involved are characterized by proliferation and activation of Th2 lymphocytes, setting off an allergic cascade. Treatments currently available act by dampening inflammation or relaxing airways but do not alter underlying pathology and disease exacerbations still occur. These facts highlight the need for novel treatments, which in turn require suitable efficacy models.

Ovalbumin-induced Asthma Model
The immune response during asthma is well preserved between mice and humans. In human asthma, eosinophils and lymphocytes are found to infiltrate the bronchial mucosa. Increased mucus secretion and production of Th2 associated cytokines such as IL-4, IL-5 and IL-13 are also found. IL-4 induces differentiation of CD4 T cells into Th2 cells, induces the proliferation of activated B cells and is the major cytokine involved in B cell class switching to IgE (the antibody isotype most associated with human asthma). IL-5 is involved in eosinophil activation and also facilitates B cell growth and antibody production. The activities of IL-13 and IL-4 show a high level of overlap, although it is thought that IL-4 acts primarily in the initial sensitisation, with IL-13 more important during secondary exposure to the allergen. In addition to inducing IgE production, IL-13 can induce AHR, goblet cell metaplasia and airway glycoprotein hypersecretion, which all contribute to airway obstruction. Mast cells are also central to the development of asthma due to their ability to release an array of preformed and newly synthesized inflammatory mediators such as cytokines, leukotrienes and prostaglandins. Mast cells are also thought to be involved in the tissue remodelling that occurs later in asthma.

While we know many factors and events that play an important role in the initiation, progression and persistence of allergic asthma, there is still a lot to be understood about the immunoregulatory mechanisms. The murine OVA-induced asthma model is a widely used model that results in the characteristic features of asthma allowing the study and assessment of novel treatments.

OVA-induced asthma preclinical efficacy, pre-clinical contract research

 

 

 

The study of lung function
In recent years there has been much discussion as to whether methods of studying lung function in pre-clinical models of allergic lung inflammation are worthwhile. Some researchers maintain that the physiological differences in rodent lung function versus human lungs mean that lung function studies in rodents are meaningless. Despite this, the most consistent diagnostic feature of asthma is airway hyperresponsiveness (AHR) in response to chemicals such as Methacholine or Adenosine. For this reason, many researchers feel that in order for an asthma therapeutic to be efficacious, it must be shown to affect AHR.

Although much research on this topic has been carried out, we still do not fully understand why the AHR response occurs. Airway inflammation involving cytokines such as IL-4, IL-5 and IL-13 and cells such as mast cells and eosinophils as well as neurogenic abnormalities are believed to contribute to AHR.

Analysis of BALF fluid for cell composition and cytokine excretion
In a BALF sample from a normal lung, macrophages make up greater than 90 percent of the cells present. In a normal lung the lymphocytes represent 10% of the cells, however in the OVA preclinical model, there is an increase in number of lymphocytes even if the % remains static. Cytokines excretion is also elevated in the BALF of an asthmatic mouse.

Conclusion
Preclinical asthma models remain an important tool for the industry as they are well-characterized and offer well-established readouts such as pulmonary cell influx and antibody levels, which have good correlation with human disease. The wide range of readouts allows the design of experiments with the greatest potential to identify any anti-asthmatic activities possessed by test compounds.

Topics: Inflammation