ABSTRACT
BACKGROUND: Immunomodulatory interventions play a key role in the treatment of infections and cancer as well as allergic diseases. Adjuvants such as micro- and nanoparticles are often added to immunomodulatory therapies to enhance the triggered immune response. Here, we report the immunological assessment of novel and economically manufactured microparticle adjuvants, namely strontium-doped hydroxyapatite porous spheres (SHAS), which we suggest for the use as adjuvant and carrier in allergen-specific immunotherapy (ASIT). METHODS AND RESULTS: Scanning electron microscopy revealed that the synthesis procedure developed for the production of SHAS results in a highly homogeneous population of spheres. Strontium-doped hydroxyapatite porous spheres bound and released proteins such as ovalbumin (OVA) or the major cat allergen Fel d 1. SHAS-OVA were taken up by human monocyte-derived dendritic cells (mdDCs) and murine DCs and did not have any necrotic or apoptotic effects even at high densities. In a murine model of ASIT for allergic asthmatic inflammation, we found that OVA released from subcutaneously injected SHAS-OVA led to a sustained stimulation of both CD4+ and CD8+ T cells. Allergen-specific immunotherapy with SHAS-OVA as compared to soluble OVA resulted in similar humoral responses but in a higher efficacy as assessed by symptom scoring. CONCLUSION: We conclude that SHAS may constitute a suitable carrier and adjuvant for ASIT with great potential due to its unique protein-binding properties.
Subject(s)
Adjuvants, Immunologic , Allergens/immunology , Desensitization, Immunologic , Hydroxyapatites , Hypersensitivity/immunology , Phosphatidylethanolamines , Strontium , Allergens/administration & dosage , Animals , Dendritic Cells/immunology , Dendritic Cells/metabolism , Desensitization, Immunologic/methods , Disease Models, Animal , Female , Hydroxyapatites/chemistry , Hypersensitivity/therapy , Immunization , Immunoglobulin E/immunology , Immunoglobulin G/immunology , Lymphocyte Activation/immunology , Mice , Ovalbumin/immunology , Phosphatidylethanolamines/chemistry , Strontium/chemistry , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Treatment OutcomeABSTRACT
Allergic diseases are considered the epidemics of the twentieth century estimated to affect more than 30% of the population in industrialized countries with a still increasing incidence. During the past two decades, the application of molecular biology allowed cloning, production and characterization of hundreds of recombinant allergens. In turn, knowledge about molecular, chemical and biologically relevant allergens contributed to increase our understanding of the mechanisms underlying IgE-mediated type I hypersensitivity reactions. It has been largely demonstrated that fungi are potent sources of allergenic molecules covering a vast variety of molecular structures including enzymes, toxins, cell wall components and phylogenetically highly conserved cross-reactive proteins. Despite the large knowledge accumulated and the compelling evidence for an involvement of fungal allergens in the pathophysiology of allergic diseases, fungi as a prominent source of allergens are still largely neglected in basic research as well as in clinical practice. This review aims to highlight the impact of fungal allergens with focus on asthma and atopic dermatitis.
Subject(s)
Fungi/immunology , Hypersensitivity/microbiology , Antigens, Fungal/immunology , Humans , Molecular Sequence DataABSTRACT
Fruiting body lectins are ubiquitous in higher fungi and characterized by being synthesized in the cytoplasm and up-regulated during sexual development. The function of these lectins is unclear. A lack of phenotype in sexual development upon inactivation of the respective genes argues against a function in this process. We tested a series of characterized fruiting body lectins from different fungi for toxicity towards the nematode Caenorhabditis elegans, the mosquito Aedes aegypti and the amoeba Acanthamoeba castellanii. Most of the fungal lectins were found to be toxic towards at least one of the three target organisms. By altering either the fungal lectin or the glycans of the target organisms, or by including soluble carbohydrate ligands as competitors, we demonstrate that the observed toxicity is dependent on the interaction between the fungal lectins and specific glycans in the target organisms. The toxicity was found to be dose-dependent such that low levels of lectin were no longer toxic but still led to food avoidance by C. elegans. Finally, we show, in an ecologically more relevant scenario, that challenging the vegetative mycelium of Coprinopsis cinerea with the fungal-feeding nematode Aphelenchus avenae induces the expression of the nematotoxic fruiting body lectins CGL1 and CGL2. Based on these findings, we propose that filamentous fungi possess an inducible resistance against predators and parasites mediated by lectins that are specific for glycans of these antagonists.
