NIAID Plan for Research on Immune Tolerance
Part 3: Detailed Research Plan
C: Asthma and Allergic Diseases
Asthma and allergic diseases are attractive models for development of new approaches to alter the human immune response. These diseases are increasing in prevalence and account for high medical and social costs. Despite the availability of proven therapies and many new agents in development, even the most effective pharmacotherapies have serious limitations. Some data suggest that either reduced allergen exposure, or conventional allergen immunotherapy, can block the development of asthma and/or exacerbations of asthma. However, there are obstacles to translating these findings into clinical practice, perhaps because present approaches to environmental control do not sufficiently reduce allergen levels, and because conventional immunotherapy causes only weak modulation of the human immune response. The most promising approach is to develop new methods of inhibiting allergic immune responses and/or inducing tolerance to allergens.
The development of new approaches would be enhanced by the many widely available, well standardized and clinically validated tests, including blood studies, skin tests, and pulmonary function tests, that can be used to characterize allergic responses from the immunological and physiological perspectives. Moreover, it may soon be possible to enhance the identification and stratification of at-risk individuals based on the discovery of genes that predispose to asthma and atopy.
Allergen immunotherapy was developed empirically ~80 years ago and relatively little effort has been made to develop more robust and long-lasting allergen immunotherapies, based on fundamental principles of immunology. However, concerns about the efficacy of conventional immunotherapy have stimulated research into new approaches to tolerize to allergen. A variety of avenues are being explored and build on the fact that many clinically important allergens have been identified, purified, cloned, epitope-mapped, produced as biologically active recombinant proteins, and administered safely by mucosal and cutaneous routes. With these reagents, the timing, dose, route, and molecular form for the allergen can be tightly controlled. Approaches that combine non-antigen specific methods (e.g., second signal blockade and cytokine modulation) and antigen-specific tolerance appear very promising in animal models and are close to entering Phase I and/or Phase II clinical studies in man. Among these are: 1) "DNA vaccines" comprised of plasmid DNA encoding recombinant allergens, which induce long-lasting allergen-specific tolerance in mice; 2) immunostimulatory oligonucleotides, small sequences of bacterial DNA that drive the Th1 immune responses when co-administered with protein allergens; 3) T cell co-stimulatory blockade in conjunction with allergen challenge; 4) peptide vaccines representing T cell epitopes of allergen; 5) immunization with Mycobacterium vaccae, which non-specifically drives Th1 immune responses; 6) monoclonal antibodies to IgE, which deplete plasma IgE and down-regulate mast cells and basophil receptors for IgE; and 7) co-administration of allergen and cytokines.
Asthma and Allergic Diseases: Specific Initiatives
Asthma and Allergic Diseases: Detailed Research Plan
NIAID Cooperative Clinical Trial in Allergen Immunotherapy
The establishment of a Cooperative Clinical Trial in Allergen Immunotherapy will provide the infrastructure to capitalize on current opportunities to evaluate tolerogenic approaches for the treatment of human allergic diseases. With such a program, standardized clinical trials at all phases would be carried out by clinical investigators in cooperation with basic immunologists to assess safety, efficacy, mechanisms of action, and therapeutic effect of multiple approaches, including second signal blockade, DNA, oligonucleotide and microbial adjuvants, and co-administration of cytokines. The Cooperative Clinical Trial in Allergen Immunotherapy would be linked to the Human Immunology Cooperative Study Groups to support basic and mechanistic studies of new allergen immunotherapies.
Multidisciplinary Research Centers in Asthma and Allergic Diseases
To facilitate future discovery, a network of Research Centers will be important for the development and testing of new reagents and approaches for tolerizing human allergic responses. The basic and translational research conducted by these Centers would span many disciplines (e.g., T and B cell immunology; antigen [allergen] processing and presentation; biology and function of mast cells, eosinophils, and basophils; high-resolution structural studies of allergens; and vaccinology) with the ultimate aim of discovering new tolerizing approaches. Shared resource cores (e.g., for the purification of allergens or for production and modification of recombinant allergens; for structural characterization of allergens; for production of DNA vaccines and other DNA-based therapies; and for testing experimental therapies in appropriate animal models) would serve all Research Centers in the network.
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