3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis.

3-Hydroxyanthranilic acid (HAA), a compound generated during tryptophan metabolism initiated by indoleamine 2,3-dioxygenase, is known to induce T cell death, but its molecular target is not known. Here we report that HAA inhibits NF-kappaB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-kappaB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-kappaB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-kappaB activation or induce cell death upon Toll-like receptor 4 stimulation in dendritic cells. Thus, HAA is a natural inhibitor that restrains T cell expansion and activation.

Induction of a homeostatic circuit in lung tissue by microbial compounds.

TGFbeta presented and activated by integrin alphavbeta6 expressed on alveolar epithelial cells (AEC) continuously inhibits the functionality of alveolar macrophages (AM). Despite this inhibition, AM retain their ability to respond to inhaled microorganisms. Herein we describe a homeostatic circuit through which the effects of microbial products on macrophages transiently circumvent this inhibition by repressing alphavbeta6 expression on AEC. Subsequent production of matrix metalloproteinases by activated AM activates latent TGFbeta, reinduces alphavbeta6 expression, and thereby reinstates tonic inhibition of AM function. Our results reveal how AM can be activated while minimizing their potential to inflict collateral damage to the adjacent lung tissue and indicate that tissue-specific microenvironmental factors shape organ-specific defense strategies against microbial invasion.

Inhibition of experimental asthma by indoleamine 2,3-dioxygenase.

Epidemiological evidence points to the inverse relationship between microbial exposure and the prevalence of allergic asthma and autoimmune diseases in Westernized countries. The molecular basis for this observation has not yet been completely delineated. Here we report that the administration of certain toll-like receptor (TLR) ligands, via the activation of innate immunity, induces high levels of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism in various organs. TLR9 ligand-induced pulmonary IDO activity inhibits Th2-driven experimental asthma. IDO activity expressed by resident lung cells rather than by pulmonary DCs suppressed lung inflammation and airway hyperreactivity. Our results provide a mechanistic insight into the various formulations of the hygiene hypothesis and underscore the notion that activation of innate immunity can inhibit adaptive Th cell responses.

Optimized conjugation ratios lead to allergen immunostimulatory oligodeoxynucleotide conjugates with retained immunogenicity and minimal anaphylactogenicity.

BACKGROUND: Immunotherapy has gradually fallen out of favor for the treatment of many allergic diseases because of the overall convenience, safety, and efficacy of medications. However, investigations suggest that allergen/immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) conjugates (AICs) might have improved safety and efficacy compared with allergen extracts. OBJECTIVE: We determined whether changes in the ISS-ODN conjugation ratio would effect the immunogenicity and allergenicity of AIC. METHODS: Immunogenicity was determined by means of AIC vaccination of mice, followed by analysis of antigen-specific antibody and cytokine responses. The allergenicity of AIC was determined in mast cell release studies and in murine models of anaphylaxis and the Arthus reaction. RESULTS: AIC induced a stronger immune response than allergen alone or allergen mixed with ISS-ODN, but higher-level ISS-ODN conjugation reduced its immunogenicity modestly. In mast cell degranulation studies AIC was approximately 100-fold less allergenic than native allergen, with stepwise increases in the ODN conjugation ratio leading to stepwise decreases in allergenicity. In anaphylaxis studies death rates were reduced from 100% with native allergen challenge to as low as 0% with high-ratio ISS-ODN AIC challenge. Similar results were obtained in an Arthus reaction model. CONCLUSION: These investigations establish that AIC is both significantly more immunogenic and less allergenic than native allergens and the techniques used might have further utility for the standardization and optimization of AIC formulations for use in allergic patients.

DNA-based vaccines for allergic disease.

Allergen-specific immunotherapy, although efficacious, is now less frequently used because of potential adverse reactions. Recently, two new types of allergen immunotherapy have been developed that appear to overcome this problem, namely allergen gene vaccination and vaccination with allergen-immunstimulatory DNA conjugates. In animal models of allergy, both have been shown to induce nonallergic T-helper cell type 1 immune responses to allergens and downregulate pre-existing T-helper cell type 2 responses. In initial clinical trials with allergic patients, allergen-immunostimulatory DNA conjugates were well-tolerated, induced immunoglobulin-G but not immunoglobulin-E antibodies and appeared to have great potential as a novel, safe and efficacious type of allergen specific immunotherapy.