Vaccines Incorporating Toll-Like Receptor Ligands - Attaching the HA antigen to a TLR can produce a strong immunogenic response and can be produced quickly and easily in E. coli. - BioPharm

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Vaccines Incorporating Toll-Like Receptor Ligands
Attaching the HA antigen to a TLR can produce a strong immunogenic response and can be produced quickly and easily in E. coli.


BioPharm International Supplements


The Advent of Toll-like Receptors

In the mid-1980s, the Toll protein of the fruit fly, Drosophila melanogaster, was first described.2 In Drosophila, Toll controls, among other things, the release of peptides that are active against infectious agents, a major line of defense.3 In subsequent years, a related set of Toll-like receptors (TLRs) were found on or in mammalian APCs, including dendritic cells, macrophages, endothelial cells, and some plasmacytoid cells.4 Together with neutrophils, eosinophils, basophils, and mast cells, these constitute the "innate immune system." These cells mount the first attack against incoming pathogens, resulting in an inflammatory response that is the necessary predecessor of the T-cell and B-cell "adaptive immune response."


Figure 1. The known Toll-like receptors (TLRs) and their ligands. Pathogen-associated molecules are recognized by TLRs.
In 1997, Medzhitov, Janeway, and others demonstrated that TLRs are the mediators of the innate immune response.5 TLRs collectively recognize families of structures that are unique to pathogens and not part of mammalian biology. These structures are collectively termed pathogen-associated molecular patterns (PAMPs), and they provide the primary signal to the mammalian host that a pathogenic insult has occurred.5 Figure 1 illustrates the known TLRs and their ligands, or PAMPs.6 Each TLR binds a specific class of pathogen-related molecules. For example, TLR4 binds to lipopolysaccharides (LPS) found on the surface of bacteria but not in the mammalian host.1 TLR3 binds to double-stranded RNA (dsRNA), a non-mammalian nucleic acid conformation that is the genome structure or replication intermediate of many viruses.1 TLR5 binds to flagellin, a protein that polymerizes to form the bacterial flagella.1 Mammalian TLRs are expressed either on the surface or in an internal compartment inside of an APC. In general, cell surface TLRs tend to recognize bacterial components (e.g., lipoproteins, lipopolysaccharides, flagellin) whereas internal TLRs tend to recognize nucleic acids and analogs (e.g., dsRNA, CpG oligonucleotides, or nucleotide derivatives).

PAMP and TLR Binding


Figure 2. Toll-like receptors' mechanism of action: the stimulation of Toll-like receptors activates pathways that 1) promote antigen processing and presentation and 2) provide the second signal to T cells, informing them that the antigens are proper subjects for vigorous immune response.
Binding of a PAMP to a TLR results in a cascade of events inside an APC (Figure 2, unpublished data). First, the PAMP-pathogen complex binds to a TLR and is internalized to an endocytic vesicle. The vesicle now contains an activated TLR that sends a series of signals to the nucleus. These signals drive the fusion of the vesicle with a lysosome where the contents are degraded into peptides for presentation in the groove of the MHC class I or class II complex.5 TLR signaling triggers expression of genes for cytokines, which stimulate neighboring T cells as well as the expression of co-stimulatory molecules (CD80/86) that bind to the T cell and promote its activation.1 This triad of peptide processing and presentation, cytokine secretion, and T-cell co-stimulation satisfies the criteria for activating a T cell and initiating a productive immune response.


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