As described in our recent DiscoveryDossier “Asthma Therapeutics: New treatment options and emerging drug discovery targets” co-produced with Professor Peter Barnes, the incidence of asthma has dramatically increased over recent years. This represents a profound public health problem, each year responsible for 9 million visits to health care providers, over 1.8 million emergency room visits, and over 460,000 hospitalizations in the US alone. As well as placing a considerable burden in terms of direct medical costs, asthma is one of the leading causes of work or school absenteeism. Paralleling the dramatic growth in its incidence, asthma is driving one of the most rapidly growing global therapeutic markets. The impact that increased incidence is having on therapeutic market values is further increased by a considerable degree of under-treatment of asthma. Global revenue for 2001 from asthma therapies has been reported by some to be as high as $11.7 billion and up until recently annual growth rates of 10-15% have been reported. Most sources however predict that this level of growth is not sustainable. The anti-asthmatic market is well served by existing therapies, such as the beta2-agonists and corticosteroids that can treat 95% of asthma patients. Competition within the anti-asthmatic market will therefore grow increasingly intense. Future asthma therapies will focus on the treatment of patients whose condition is not satisfactorily controlled by currently used approaches and on the improvement of patient compliance that is currently very poor, especially with respect to inhaled treatment.

NK cells, components of the innate immune system, have been associated with immune surveillance of tumor cells and defense mechanisms against various pathogens. The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. Since NK cells are normally present in considerable numbers in human lung interstitium, these cells may also play a role in the response of the asthmatic airway to allergen. Indeed patients with asthma show increased numbers of NK cells and stronger NK activity in peripheral blood than normal healthy blood donors.

In 1999 Korsgren et al reported that depletion of NK1.1+ cells inhibits pulmonary eosinophil and CD3+ T cell infiltration as well as increased levels of IgE, IL-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. More recently, researchers at Stanford University reported that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of a specific type of T cell with NK function, V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to a general inability of these mice to produce Th2 responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR appears to be related to changes in pathways governing the antigen-stimulated levels of IL-4 and IL-13, two cytokines, which as described in our recent dossier are key to the asthma process, and which, at least with respect to IL-13, represent very promising targets for asthma therapeutics. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may therefore be clinically effective in limiting the development of AHR and asthma.

Entry date Monday, May 19, 2003

Adapted from Akbari et al, Nat Med 2003 May;9(5):582-8 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk