Lucinda Beck

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.

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-κB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-κB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-κB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-κB 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.

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.

Protein-Immunostimulatory DNA-Conjugate

The original finding made by Tokunaga and colleagues (1,2) demonstrated that DNA from Mycobacterium bovis Bacillus Calmette Guerin has antitumor activities and induces natural killer (NK) cells to secrete interferon-γ (IFN-γ). Over the last 10 yr, this finding has stimulated much research on the immunostimulatory properties of bacterial DNA. It was shown that bacterial immunostimulatory DNA sequences (ISS) consist of palindromic sequences of the motif purine-purine-CpG-pyrimidine-pyrimidine (3,4). This motif occurs about 20 times more often in bacterial DNA than in mammalian DNA (5). Furthermore, the cytosine of the crucial CpG sequence in ISS is usually methylated in mammalian DNA and methylated CpG motifs do not show the immuno-stimulatory properties of ISS (6). ISS not only activate NK cells to secrete IFN-γ, but also activate both murine and human antigen presenting cells (APC) to secrete type 1 cytokines such as, IFN-a, β, IL-6, IL-12, and IL-18 (4,7,8), which direct the immune response toward a Th 1 immune response. ISS also induce costimulatory molecules on APC (9) and cause human B-cell proliferation and IgM secretion (10). Another property of ISS is the ability to induce “cross-priming,” the phenomenon of priming CD8+ cytotoxic lymphocytes (CTL) against foreign protein antigens (11,12).

Protective Immunity of Immunostimulatory Sequences Against Mycobacterial Infection

M. avium infection is a common opportunistic infection in patients infected with human immunodeficiency virus (AIDS; Acquired Immunodeficiency disease syndrome) (1,2), and can also cause disease in immunocompetent individuals. In AIDS, disseminated M. avium infection is a major cause of morbidity and mortality, and is extremely difficult to treat in these patients because it responds poorly to available antimycobacterial therapies (3).