Review
Post ScreenCurrent and future drugs targeting one class of innate immunity receptors: the Toll-like receptors
Post Screen
Introduction
The mammalian immune system protects against invading pathogens and cancer cells and can be divided into two major components: the innate immune response and the adaptive immune response. The former is composed of several types of cells, including dendritic cells (DCs), macrophages and monocytes, polynuclear cells (e.g. neutrophils and mast cells), natural killer (NK) cells, γδ T cells and natural killer T cells (NKT cells). The innate immune system detects large classes of pathogens or abnormal cells through a limited number of germline-encoded receptors such as Toll-like receptors (TLRs), and serves as a first line of defense against infectious agents, preventing rapidly dividing pathogens from overwhelming the infected organism.
The adaptive immune response is the basis of immunological memory, used by vaccines. It is mediated through T cells and B cells bearing clonal receptors (i.e. T-cell receptors and antibodies) generated randomly through somatic recombination. The T and B cells that express receptors with high affinity and specificity for molecular structures of pathogens or abnormal cells undergo clonal expansion, exert their effector function and are conserved as memory cells.
Interest in innate immunity cells and receptors has recently increased because their central role in triggering inflammatory signals that are necessary for a subsequent immune response cascade was demonstrated, and because it was found recently that innate immunity signals serve as gatekeepers for mounting an efficient adaptive immune response. Thus, coordinated actions of innate and adaptive immune cells will eventually lead to the complete removal of the pathogen and to the generation of memory, which will guarantee a more rapid and accurate response in case of re-infection (Table 1; Figure 1).
The structures recognized by innate immunity cells are a limited array of conserved molecules that represent the molecular signature of pathogens and transformed cells. These structures, usually called pathogen-associated molecular patterns (PAMPs), are highly conserved (e.g. bacterial cell wall components) and are often essential for pathogen survival.
Innate immunity receptors, referred to as pattern recognition receptors (PRRs), are a class of proteins capable of recognizing PAMPs. The recently discovered TLRs represent the best-characterized class of PRR. Ten different TLRs have been identified, each of them recognizing one, or several, PAMP. Signaling through PRRs is transmitted through evolutionary conserved inflammation pathways, for example via nuclear factor-κB (NF-κB) and activation of interferon regulatory factor (IRF), explaining the central role of PRRs in triggering inflammation processes that further enhance activation of innate immune effectors, and are necessary for the development of potent adaptive responses.
Genetic PRR defects lead to increased risks for different types of infections and cancer [1]. Agonists of PRRs are, therefore, attractive targets to stimulate both arms of the immune response in infectious diseases and cancer indications; conversely, antagonists can be important in controlling some chronic inflammation processes. The natural PRR ligands, or PAMPs, are often the basis for first generation agonist molecules that can be developed for proof-of-concept experiments in preclinical models or in early clinical trials. This strategy has been applied to several TLRs, and a few other innate immunity receptors such as receptors of γδ T cells 2, 3 and NK cells 4, 5. Because drugs targeting TLRs are much more advanced in clinical development, this review will focus on this family of receptors, describe the current understanding of TLR function and the scientific rationale for developing TLR agonists, as well as the current status of drugs that target these receptors in vaccines, infectious disease, allergy and cancer.
Section snippets
Toll-like receptors: key receptors for inflammatory processes
Only six years have passed since the discovery of the first TLR 6, 7, 8, and rarely has a research field exploded so rapidly. All the TLRs (i.e. ten human TLRs) have now been cloned, a lot of their ligands discovered and the main signaling pathways identified – following homology searches in the human genome, the list seems to be closed. Many excellent in-depth reviews have been published describing the natural ligands and molecular pathways of signal transduction 9, 10, 11 and they are briefly
Clinical trials involving Toll-like receptor agonists
The rationale for using TLR agonists that trigger inflammation will result in the production of cytokines, activation of innate immunity effector cells and, eventually, the adaptive immune response against cancer cells or infectious agents that could lead to long-term protection. Depending on the type of inflammatory signals they induce, different agonists targeting different receptors have been developed as vaccine adjuvants, anti-infectious agents, anticancer agents and in anti-allergy
Future challenges in the use of Toll-like receptor agonists
Although the clinical results mentioned here are encouraging in several indications, questions remain to be answered so that a clear rationale about how to use TLR agonists can be formed.
First, although most molecules in development are agonists, several preclinical data show the involvement of innate immunity receptors, such as TLR9 [42] and NKG2D [43], in some chronic inflammatory diseases [10]. Indeed, some self molecular structures are very similar or identical to TLR ligands and, if
Concluding remarks
From their mechanism of action, innate immunity receptor agonists have an obvious potential interest as vaccine-adjuvant or anti-infectious agents. TLR agonists have already demonstrated their value in these indications as vaccine adjuvants (e.g. MPL – a vaccine adjuvant for HBV) and stand-alone therapies (e.g. imiquimod – a cream for the treatment of genital warts). Encouraging results in early-phase clinical trials in HBV and HCV show that TLR agonists could be important in other therapeutic
Acknowledgements
I thank Y. Morel, C. Paturel and L. Voellmy for helpful discussions and critical reading of the article.
References (51)
- et al.
Sensing cell stress and transformation through Vγ9Vδ2 T cell-mediated recognition of the isoprenoid pathway metabolites
Microbes Infect.
(2005) Innate immunity against hematological malignancies
Cytotherapy
(2002)The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults
Cell
(1996)How Toll-like receptors signal: what we know and what we don’t know
Curr. Opin. Immunol.
(2006)Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial
Lancet
(2004)Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine
Vaccine
(2004)Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults
Vaccine
(2006)Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two Phase III, randomized, vehicle-controlled studies
J. Am. Acad. Dermatol.
(2004)Imiquimod for actinic keratosis: systematic review and meta-analysis
J. Invest. Dermatol.
(2006)Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-α/β-inducible gene expression, without significant toxicity
Blood
(2005)
NKG2D blockade prevents autoimmune diabetes in NOD mice
Immunity
The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion
J. Invest. Dermatol.
Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod
J. Invest. Dermatol.
Toll-like receptors in the pathogenesis of human disease
Nat. Immunol.
In vivo immunomanipulation of Vγ9Vδ2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model
J. Immunol.
Receptors for HLA class-I molecules in human natural killer cells
Annu. Rev. Immunol.
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Nature
Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene
Science
Toll-like receptor signalling
Nat. Rev. Immunol.
Inferences, questions and possibilities in Toll-like receptor signalling
Nature
Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity
J. Immunol.
Taking toll: lipid A mimetics as adjuvants and immunomodulators
Trends Microbiol.
Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents
Expert Opin. Biol. Ther.
Glycoprotein-D-adjuvant vaccine to prevent genital herpes
N. Engl. J. Med.
Synthetic oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODNs) and modified analogs as novel anticancer therapeutics
Curr. Pharm. Des.
Cited by (77)
Curdlan oligosaccharides having higher immunostimulatory activity than curdlan in mice treated with cyclophosphamide
2019, Carbohydrate PolymersCitation Excerpt :Macrophages express a broad range of plasma membrane receptors that mediate their interaction with natural and altered-self components of the host as well as a range of microorganisms (Taylor et al., 2005). β-Glucan from different resources including zymosan, laminarin, lichenin, cellulose and curdlan, has been reported to be the ligand for several receptors on the membrane of macrophages/monocytes including Dectin-1 (Brown & Gordon, 2001; Tsoni & Brown, 2008), CR3 (CD11b/CD18) (Ganesan et al., 2014; Thornton, Vĕtvicka, Pitman, Goldman, & Ross, 1996), TLR2 (Luther, Torosantucci, Brakhage, Heesemann, & Ebel, 2007; Sato et al., 2003) and TLR4 (Romagne, 2007). Recognized by those receptors, β-glucan can activate downstream immune-associated signal pathways, like MAPK and NF-κB and lead to the release of cytokines (Geijtenbeek & Gringhuis, 2009).
Immunostimulant effects and potential application of β-glucans derived from marine yeast Debaryomyces hansenii in goat peripheral blood leucocytes
2018, International Journal of Biological MacromoleculesCitation Excerpt :Dectin-1 is considered to be the major β -glucan receptor present on immune cells that can recognize β–glucans with β (1–3) linkages [64]. In addition, it has been widely known that LPS (lipopolysaccharide) of the Gram-negative bacteria, fungal cells and zymosan (consisting of many different molecular moieties) can bind TLR4 (mostly located on the cell surface of macrophages) facilitating MyD88 dependent intracellular signaling that induce cytokines favoring Th1 cell differentiation [65,66]. Zymosan is obtained from yeast cell walls and is composed of insoluble β-glucans and mannan [67].
Animal models of human disease: Inflammation
2014, Biochemical PharmacologyCitation Excerpt :Research using the already described animal models reflected these discoveries and confirmed that in rodents, principally mouse models, PRRs controlled the innate response to microbial infection and also played a role in how the adaptive immune response responded to produce an immunological memory of the infection and then worked in concert with the adaptive response in terms of re-infection [73]. This did not however, result in any clinical breakthroughs in sepsis treatments [74]. There are at least two explanations that will be discussed below.
Bis-N-norgliovictin, a small-molecule compound from marine fungus, inhibits LPS-induced inflammation in macrophages and improves survival in sepsis
2013, European Journal of Pharmacology