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Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands.

Toussi DN, Massari P - Vaccines (Basel) (2014)

Bottom Line: Although the detailed molecular mechanism of action of many adjuvants is still elusive, the discovery of Toll-like receptors (TLRs) has provided new critical information on immunostimulatory effect of numerous bacterial components that engage TLRs.The potential of such TLR adjuvants in improving the design and the outcomes of several vaccines is continuously evolving, as new agonists are discovered and tested in experimental and clinical models of vaccination.In this review, a summary of the recent progress in development of TLR adjuvants is presented.

View Article: PubMed Central - PubMed

Affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Deana.Toussi@bmc.org.

ABSTRACT
Vaccine efficacy is optimized by addition of immune adjuvants. However, although adjuvants have been used for over a century, to date, only few adjuvants are approved for human use, mostly aimed at improving vaccine efficacy and antigen-specific protective antibody production. The mechanism of action of immune adjuvants is diverse, depending on their chemical and molecular nature, ranging from non-specific effects (i.e., antigen depot at the immunization site) to specific activation of immune cells leading to improved host innate and adaptive responses. Although the detailed molecular mechanism of action of many adjuvants is still elusive, the discovery of Toll-like receptors (TLRs) has provided new critical information on immunostimulatory effect of numerous bacterial components that engage TLRs. These ligands have been shown to improve both the quality and the quantity of host adaptive immune responses when used in vaccine formulations targeted to infectious diseases and cancer that require both humoral and cell-mediated immunity. The potential of such TLR adjuvants in improving the design and the outcomes of several vaccines is continuously evolving, as new agonists are discovered and tested in experimental and clinical models of vaccination. In this review, a summary of the recent progress in development of TLR adjuvants is presented.

No MeSH data available.


Related in: MedlinePlus

Schematic cartoon of Toll-like receptor (TLR) signaling [17,24,27,28,29,30]. Extracellular TLR homodimers (TLR4 and TLR5) are represented in black; heterodimers of TLR2 and TLR1, TLR6 or TLR10 are indicated in black/green. Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray.
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vaccines-02-00323-f001: Schematic cartoon of Toll-like receptor (TLR) signaling [17,24,27,28,29,30]. Extracellular TLR homodimers (TLR4 and TLR5) are represented in black; heterodimers of TLR2 and TLR1, TLR6 or TLR10 are indicated in black/green. Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray.

Mentions: The structure of TLRs is that of horse-shoe shaped proteins composed of three domains: an extracellular or cytoplasmic leucine-rich repeat (LRR) domain which mediates ligand recognition, a single trans-membrane domain, and an intra-cytoplasmic domain, the TIR domain, homologous to the corresponding intracellular domain of the IL-1 receptor (IL-1R) Toll/IL-1R [17]. In humans, 10 TLRs have been identified so far. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are surface-expressed and recognize extracellular ligands and microorganisms, while TLR3, TLR7, TLR8 and TLR9 are situated on endosomal membranes within the cell and are engaged by intracellular ligands and microrganisms [17]. Ligand binding and TLR homo- or heterodimerization brings the TIR domains of adjacent TLRs together, providing a conformational change necessary to trigger signaling. Binding of additional adaptor proteins is also essential for intracellular cascades. Adaptor proteins include the myeloid differentiation factor 88 (MyD88) [27], the MyD88 adaptor-like protein (Mal/TIRAP), the TIR domain-containing adaptor protein inducing interferon-β (TRIF/TICAM) and the TRIF-related adaptor molecule (TRAM) [28,29] (Figure 1). Negative regulators of TLR function have also been identified and include the Toll-interacting protein (Tollip), IRAK-M, the α- and HEAT-Armadillo-motif-containing protein (SARM) and the B cell adaptor for PI3K (BCAP) [30].


Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands.

Toussi DN, Massari P - Vaccines (Basel) (2014)

Schematic cartoon of Toll-like receptor (TLR) signaling [17,24,27,28,29,30]. Extracellular TLR homodimers (TLR4 and TLR5) are represented in black; heterodimers of TLR2 and TLR1, TLR6 or TLR10 are indicated in black/green. Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4494261&req=5

vaccines-02-00323-f001: Schematic cartoon of Toll-like receptor (TLR) signaling [17,24,27,28,29,30]. Extracellular TLR homodimers (TLR4 and TLR5) are represented in black; heterodimers of TLR2 and TLR1, TLR6 or TLR10 are indicated in black/green. Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray.
Mentions: The structure of TLRs is that of horse-shoe shaped proteins composed of three domains: an extracellular or cytoplasmic leucine-rich repeat (LRR) domain which mediates ligand recognition, a single trans-membrane domain, and an intra-cytoplasmic domain, the TIR domain, homologous to the corresponding intracellular domain of the IL-1 receptor (IL-1R) Toll/IL-1R [17]. In humans, 10 TLRs have been identified so far. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are surface-expressed and recognize extracellular ligands and microorganisms, while TLR3, TLR7, TLR8 and TLR9 are situated on endosomal membranes within the cell and are engaged by intracellular ligands and microrganisms [17]. Ligand binding and TLR homo- or heterodimerization brings the TIR domains of adjacent TLRs together, providing a conformational change necessary to trigger signaling. Binding of additional adaptor proteins is also essential for intracellular cascades. Adaptor proteins include the myeloid differentiation factor 88 (MyD88) [27], the MyD88 adaptor-like protein (Mal/TIRAP), the TIR domain-containing adaptor protein inducing interferon-β (TRIF/TICAM) and the TRIF-related adaptor molecule (TRAM) [28,29] (Figure 1). Negative regulators of TLR function have also been identified and include the Toll-interacting protein (Tollip), IRAK-M, the α- and HEAT-Armadillo-motif-containing protein (SARM) and the B cell adaptor for PI3K (BCAP) [30].

Bottom Line: Although the detailed molecular mechanism of action of many adjuvants is still elusive, the discovery of Toll-like receptors (TLRs) has provided new critical information on immunostimulatory effect of numerous bacterial components that engage TLRs.The potential of such TLR adjuvants in improving the design and the outcomes of several vaccines is continuously evolving, as new agonists are discovered and tested in experimental and clinical models of vaccination.In this review, a summary of the recent progress in development of TLR adjuvants is presented.

View Article: PubMed Central - PubMed

Affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Deana.Toussi@bmc.org.

ABSTRACT
Vaccine efficacy is optimized by addition of immune adjuvants. However, although adjuvants have been used for over a century, to date, only few adjuvants are approved for human use, mostly aimed at improving vaccine efficacy and antigen-specific protective antibody production. The mechanism of action of immune adjuvants is diverse, depending on their chemical and molecular nature, ranging from non-specific effects (i.e., antigen depot at the immunization site) to specific activation of immune cells leading to improved host innate and adaptive responses. Although the detailed molecular mechanism of action of many adjuvants is still elusive, the discovery of Toll-like receptors (TLRs) has provided new critical information on immunostimulatory effect of numerous bacterial components that engage TLRs. These ligands have been shown to improve both the quality and the quantity of host adaptive immune responses when used in vaccine formulations targeted to infectious diseases and cancer that require both humoral and cell-mediated immunity. The potential of such TLR adjuvants in improving the design and the outcomes of several vaccines is continuously evolving, as new agonists are discovered and tested in experimental and clinical models of vaccination. In this review, a summary of the recent progress in development of TLR adjuvants is presented.

No MeSH data available.


Related in: MedlinePlus