Soup Kettle Topics: Immunotherapy

Background: Immunotherapy (IT) has undergone rigorous trials to evaluate its therapeutic benefit in the treatment of allergic respiratory disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of IT on the underlying inflammatory component of allergic respiratory disease.

Results: The clinical relevance of these observations belies our understanding of allergic inflammation as the subsoil for the development of abnormal airway physiology, heightened bronchial reactivity, and the development of chronic asthmatic symptomatology.

Conclusions: IT provides the potential to downregulate this inflammatory cascade, reduce IgE antibody production, and attenuate symptoms. Conceptually, early intervention of allergic disease holds the most promise as a therapeutic intervention capable of arresting the progression of the disease, altering the severity of the disease, and/or preventing the development of the respiratory disease process.

New vaccine development for potential use in human medicine is buoyant. New science (genomics and proteomics) is presenting major new opportunities. New approaches (DNA vaccines, new combination vaccines, new formulations, novel delivery routes, new adjuvants) are being vigorously explored. New needs (defence vaccines) are being identified. One common element in all these varied areas is that pre-clinical evaluation of a candidate new vaccine is a pre-requisite before initiation of clinical trials in humans. Laboratory evaluation also usually continues during the clinical phase of vaccine development. Pre-clinical and laboratory evaluations often involve animals. Data from these studies are used to support an application for marketing authorisation. Regulatory Authorities use precedent to help assess these applications. Where no precedent exists the Regulatory Authorities apply risk-benefit analyses based on the perceived risks of a new product or process. These perceived risks are constantly reviewed as experience is gained. The World Health Organisation facilitates the development of scientific consensus on issues that have an impact on the quality and safety of biological medicines, including vaccines. New vaccine technologies often present new challenges for the safety and efficacy evaluation of candidate preparations. Animal models are usually very important in this process. The number of new vaccine candidates seems set to increase in the short-term.

Over the last 30 years several approaches to modify immunotherapy have been tested, including allergoids, alum precipitation, and most recently peptides. However, none of these have replaced the traditional regimens. Over the same period our scientific understanding of allergic disease has been transformed. Today it is possible to identify and monitor changes occurring during treatment and to target many different aspects of the immune system. Recombinant technology provides a powerful technique both for sequencing proteins and producing allergens in commercial quantities. The recombinant proteins can be modified by site-directed mutagenesis so as to decrease their reactivity with IgE antibodies while maintaining reactivity with T cells. Knowledge of the tertiary structure of allergens will make it simpler to identify and change surface epitopes. A completely different approach is to use plasmids to introduce the genes for an allergen. The strength of this technique is that the plasmid can be designed to control expression and also to influence the cytokine profile of the response or the isotype of antibodies produced. Finally, different adjuvants can be used with proteins to alter the response. These include IL-12, immunostimulatory sequences of DNA, and bacterial proteins such as those used in HibVax. It is now possible to identify the cells that control the immune response to allergens and to design treatments that will either downregulate or change the response of T cells. The challenge is to transform this information into an effective treatment for allergic disease.