Food allergy is thought to be the result of dysregulated IgE/Th2 responses and defective oral tolerance, but the mechanisms by which susceptible individuals fail to develop tolerance to otherwise harmless Ags are yet to be determined. Analyses of dendritic cells (DCs) have defined a class of molecular targets involving a set of C-type lectin receptors (CLRs) with specificity to carbohydrate moieties, critical in generating either immunity or tolerance. We have recently obtained preliminary evidence that Lewis-x and complex mannose structures differentially modulate DCs leading to the induction of Th2 response and tolerance, respectively. We hypothesize that depending on the ligand structure and the CLRs, targeting the DCs with engineered glycoconjugates that mimic the natural ligands for CLRs will lead to immunity or tolerance. We further hypothesize that allergens containing complex glycan structures are able to interact with CLRs and modulate DC functions. In this exploratory R21 project, we intend to test these hypotheses, and pursue a two-step protocol to identify functional glycoconjugates targeting DCs for tolerance induction. Moreover, in vitro binding and functional assays will be performed to investigate the ability of food allergens to target CLRs and modulate DC functions. This proposal is designed to ultimately identify the molecular mechanisms and efficacious tolerance- inducing strategies for food allergy. The DC-specific CLRs, with their diverse roles in DC-T cell interactions and, in some cases, DC-induced T-cell tolerance, stand out as attractive molecular targets. The striking examples of CLR-oligosaccharide promoted tolerance present a very strong case for their potential to target and induce tolerogenic DCs. A successful, tolerance-inducing strategy based on oligosaccharide-CLR interactions would be significant in and of itself. The exploration of the CLR-ligand axis thus presents an exciting opportunity for the design and evaluation of glycoconjugates as potential prophylactic/therapeutic agents, and for the analysis of their respective CLRs as likely determinants for food allergy. Food allergy is quite common and, in severe cases, can be fatal; thus far, strict avoidance of allergen sources is the only option for alleviating this potentially life-threatening condition. This highlights the need for developing effective strategies to correct this dysregulated immune response, which in turn depends upon a better understanding of the underlying mechanisms. Food allergy is thought to be the result of defective oral tolerance to food antigens, but the mechanisms by which susceptible individuals fail to develop tolerance to otherwise harmless antigens are yet to be determined. Recent advance in analysis of a critical immune cell population, dendritic cells (DCs), has defined a class of molecular targets involving a set of C-type lectin receptors (CLRs) with specificity to carbohydrate moieties on antigens, critical in generating either immunity or tolerance. Our overall objective is, therefore, to evaluate glycoconjugates as potential prophylactic/therapeutic agents, and to investigate their respective CLRs as likely determinants for food allergy. In this exploratory R21 project, we intend to pursue a two-step protocol to identify functional glycoconjugates targeting DCs for tolerance induction. Moreover, binding and functional assays will be performed to investigate the ability of food allergens to target CLRs and modulate DC functions. ? ? ?
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