Treatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System (original) (raw)
Related papers
Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases
Nature Communications, 2015
Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1 D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.
Modulating Toll-like Receptor 7 and 9 Responses as Therapy for Allergy and Autoimmunity
Current Allergy and Asthma Reports, 2011
Type I allergic diseases, such as allergic rhinitis and asthma, depend on allergen-induced T-helper type 2 (Th2) cells and IgE-secreting plasma cells. Fortunately, this harmful immune response can be modified by engaging Toll-like receptor (TLR)7 and TLR9, offering hopes to allergy sufferers. While clinical trials employing synthetic ligands for TLR7 or TLR9 are under way, one can wonder whether TLR7 or TLR9 engagements may trigger inadvertent autoreactivity and/or Th1-/Th17-mediated tissue pathology. To neutralize such danger, we have pioneered the development of potent TLR9 pathway antagonists, inhibitory oligonucleotides (INH-ODNs), which work in a sequence-specific manner. Interestingly, INH-ODNs also have TLR7-inhibitory properties; however, these effects appear to be sequence independent and phosphorothioate backbone dependent. In B cells, co-engagement of the Bcell receptor for antigen and TLR7 or TLR9 may influence how INH-ODNs impose their regulatory effects. INH-ODNs block TLR9 activation by competitively antagonizing ligand binding to proteolytically cleaved C-terminal TLR9 fragment. One may envision future use of INH-ODNs in systemic autoimmune diseases, DNA-mediated sepsis, or other situations in which chronic inflammation results from abnormal TLR7-and/or TLR9-mediated immune activation.
Synthesis and Immunological Characterization of Toll-Like Receptor 7 Agonistic Conjugates
Bioconjugate Chemistry, 2009
Activation of toll-like receptors (TLRs) on cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs, therefore, represent potential immune adjuvants. In this study, a potent TLR7 agonist was conjugated to phospholipids, poly(ethylene glycol) (PEG), or phospholipid-PEG via a versatile benzoic acid functional group. Compared to the unmodified TLR7 agonist, each conjugate displayed a distinctive immunological profile in vitro and in vivo. In mouse macrophages and human peripheral blood mononuclear cells, the phospholipid TLR7 agonist conjugate was at least 100-fold more potent than the free TLR7 ligands, while the potency of PEG-phospholipid conjugate was similar to that of the unmodified TLR7 agonist. When administered systemically in mice, the phospholipid and phospholipid-PEG TLR7 conjugates induced prolonged increases in the levels of proinflammatory cytokines in serum, compared to the unmodified TLR7 activator. When the conjugates were used as adjuvants during vaccination, only the phospholipid TLR7 agonist conjugates induced both Th1 and Th2 antigen-specific immune responses. These data show that the immunostimulatory activity of a TLR7 ligand can be amplified and focused by conjugation, thus broadening the potential therapeutic application of these agents.
Journal of Inflammation, 2010
Background: Dendritic cells (DC) are main gate-keepers of the immune system, bridging the innate and adaptive immune system. DCs are able to mature into inflammatory DCs at sites of inflammation in both autoimmune and allergic disease, thereby sustaining a continuous activation of the adaptive immune system at sites of inflammation. This function of DCs makes them attractive target cells for therapeutic intervention in inflammatory diseases. We have designed a DC-based screening model by which drug candidates can be evaluated for their ability to suppress DC maturation into an inflammatory and disease promoting phenotype. Methods: Human monocyte derived DCs were differentiated using IL-4 and GM-CSF to immature DCs (imDCs). The imDCs were treated with various combinations of TLR-agonists and pro-inflammatory cytokines to identify cocktails with ability to mature imDCs into inflammatory DCs. The effect of the cocktails on DC maturation was evaluated using ELISA and cytokine arrays to measure secreted cytokines and chemokines. FACS analysis was used to assess expression of maturation markers, and functional studies were carried out using naïve allogeneic T-cells to assay for a Th1-promoting DC phenotype. Results: Nine cocktails were designed with potent ability to induce secretion of the Th1-promoting cytokines IL-12p70 and TNFα from imDCs, and three were able to induce the Th17-promoting cytokine IL-23. The cocktails were further characterized using cytokine arrays, showing induction of inflammation related cytokines and chemokines like CXCL10, CCL2, CCL4, CCL8, CCL15, CCL20 and IL-8, of which some are present in a range of autoimmune pathologies. Prostaglandin E2 secretion was identified from DCs treated with TLR agonists poly I:C and peptidoglycan, but not LPS. The cocktails were able to induce DC maturation markers like HLA-DR, CD40, CD80, CD83 and CD86, except the TLR7/8 agonist R848. Functional end-points made by co-culture of allogeneic CD4 + T cells with the cocktail treated DCs, showed that five cocktails in particular could induce a classical Th1-phenotype with ability to secrete high amounts of the hallmark cytokine IFNγ. The model was validated using dexamethasone and two COX-inhibitors, which were able to suppress the cocktail driven pro-inflammatory DC maturation. Conclusions: The identification of novel Th1-promoting cocktails allows screening of anti-inflammatory drug candidates by assessing the ability to suppress the activation and differentiation of imDCs into inflammatory DCs with a specific Th1-promoting phenotype. The model thus provides a screening tool, which can identify potential anti-inflammatory effects on the natural regulator of the immune response, the dendritic cell.
Immunity, 2007
Nucleic acid-binding innate immune receptors such as Toll-like receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa, which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
F1000 - Post-publication peer review of the biomedical literature, 2007
Nucleic acid-binding innate immune receptors such as TLR7 and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa, which correlates with a duplication of TLR7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrate that duplication of the TLR7 gene is the sole requirement for this accelerated autoimmunity, as reduction of TLR7 gene dosage abolishes the Yaa phenotype. Further, we describe new transgenic lines that overexpress TLR7 alone, and find that at levels beyond a 2-fold increase, spontaneous autoimmunity develops. While a modest increase in TLR7 gene dosage promotes autoreactive lymphocytes with RNA specificities and myeloid cell expansion, a substantial increase in TLR7 expression causes fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
Toll-like receptors: promising therapeutic targets for inflammatory diseases
Archives of Pharmacal Research, 2016
The health of living organisms is constantly challenged by bacterial and viral threats. The recognition of pathogenic microorganisms by diverse receptors triggers a variety of host defense mechanisms, leading to their eradication. Toll-like receptors (TLRs), which are type I transmembrane proteins, recognize specific signatures of the invading microbes and activate a cascade of downstream signals inducing the secretion of inflammatory cytokines, chemokines, and type I interferons. The TLR response not only counteracts the pathogens but also initiates and shapes the adaptive immune response. Under normal conditions, inflammation is downregulated after the removal of the pathogen and cellular debris. However, a dysfunctional TLR-mediated response maintains a chronic inflammatory state and leads to local and systemic deleterious effects in host cells and tissues. Such inappropriate TLR response has been attributed to the development and progression of multiple diseases such as cancer, autoimmune, and inflammatory diseases. In this review, we discuss the emerging role of TLRs in the pathogenesis of inflammatory diseases and how targeting of TLRs offers a promising therapeutic strategy for the prevention and treatment of various inflammatory diseases. Additionally, we highlight a number of TLR-targeting agents that are in the developmental stage or in clinical trials.
The AAPS Journal, 2014
Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigenspecific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.