Generation of Th1-Polarizing Dendritic Cells Using the TLR7/8 Agonist CL075

Spranger, Stefani; Javorovic, Miran; Bürdek, Maja; Wilde, Susanne; Mosetter, Barbara; Tippmer, Stefanie; Bigalke, Iris; Geiger, Christiane; Schendel, Dolores J.; Frankenberger, Bernhard

doi:10.4049/jimmunol.1000060

Cited by 72 publications

(74 citation statements)

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“…4,31,32 Our results reveal significantly lower in vivo and in vitro amounts of pro-inflammatory cytokines in the Lt.shTLR7-injected joints and Lt.shTLR7-transduced CIASFs, respectively. Furthermore, i.a.…”

Section: Discussionmentioning

confidence: 75%

“…1 -3 Notably, the Th1-and Th17-mediated immune responses can be initiated or augmented through the ligation of TLRs with their ligands. 4,5 However, strong TLR-induced responses might contribute to the induction of autoimmunity and lead to lethal systemic inflammation. 6 Animal experiments have documented the ability of TLR ligands in triggering the onset of arthritis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of Toll-like receptor 7 short hairpin RNA gene

Chen¹,

Shiau²,

Li³

et al. 2011

Gene Ther

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Knockdown of Toll-like receptors (TLRs) is a novel therapeutic strategy in treating patients with rheumatoid arthritis (RA). We examined the effects of lentiviral vector-mediated delivery of TLR7 short hairpin RNA gene (Lt.shTLR7) on collagen-induced arthritis (CIA). After being immunized on days 0 and 7, Sprague -Dawley rats received intra-articular (i.a.) injection of Lt.shTLR7 or scramble control vector on days 7 and 10. The therapeutic effects were evaluated by measuring ankle circumferences, articular index, and radiographic and histological scores on killing on day 16. Microvessel densities, vascular endothelial growth factor (VEGF) levels, pro-inflammatory cytokine concentrations and T-cell numbers within the synovial tissues were measured. Moreover, VEGF and pro-inflammatory cytokine concentrations in culture supernatants from TLR7-transfected synovial fibroblasts (SFs) stimulated with imiquimod or endogenous ligands were examined. There were significant reduction in ankle circumferences, articular indexes, and radiographic and histological scores. Microvessel densities, VEGF concentrations, interleukin (IL)-1b and IL-6 levels and T-cell densities within synovial tissues were significantly lower. Induction of VEGF, IL-1b and IL-6 production from stimulated SFs was significantly suppressed. Taken together, these data demonstrate the effects of i.a. lentiviral vector-mediated delivery of shTLR7 RNA gene on inhibition of CIA, and implicate the manipulation of TLR7 as a potential therapeutic strategy in RA patients.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of Toll-like receptor 7 short hairpin RNA gene

Chen¹,

Shiau²,

Li³

et al. 2011

Gene Ther

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“…[50][51][52][53][54] We currently test the clinical use of DCs generated with a 3D protocol, based on a collaboration with Prof. Schendel and collegues. 55 This protocol includes a TLR seven out of eight agonist that enhance the IL-12 secretion of the DCs and their ability to generate Th1-like responses in vitro and in mouse models. 56 Of note, it remains to be seen if this or other modifications yield the desired effect in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

et al. 2016

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The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n D 22) received the vaccine without any adjuvant; the next cohort (n D 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumorspecific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p D 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators.

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“…Therefore, DC vaccines are an alternative approach for cell-based immunotherapy (1)(2)(3)(4)(5). DCs generally have been derived from peripheral mononuclear cells of human blood or spleen or bone marrow in animal models (6)(7)(8), and different methods can be used for loading them. Despite a large number of DC vaccine studies, only one study was approved by the Food and Drug Administration (FDA), which consists of not only DCs but also other antigen presenting cells (9).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of dendritic cells with vaccine and vaccine–antibody complex and effect on immune response

Hatipoğlu¹,

Söğüt²,

Ercan³

et al. 2013

Turk J Biol

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Dendritic cell (DC) vaccines are a promising and potent therapeutic tool for chronic diseases, autoimmune diseases, and cancer because of the unique ability of DCs to stimulate T cells. The challenge of DC vaccines is to find an effective form for antigen presentation. Although pure antigens, antigen complexes, plasmids, and mRNA have been used in different studies, no proper application to overcome this problem has been found yet. In this study, we investigated the eligibility of a commercial hepatitis B virus (HBV) vaccine or a vaccine-monoclonal antibody complex for antigen loading of DCs for a therapeutic purpose. DCs were derived from the bone marrow of transgenic hepatitis B (HBV-tg) mice using a granulocyte macrophage-colony stimulating factor and interleukin-4, and then loaded with a commercial HBV vaccine (containing hepatitis B virus surface antigens and aluminum hydroxide adjuvant) or a vaccine-antibody complex. HBV-tg mice were immunized with the vaccine and vaccine-antibody loaded DCs. Optimum HBV vaccine concentration and loading time were determined by 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) methods. Therapeutic effects of vaccine-antibody loaded DCs were determined by the evaluation of antibody response and hepatitis B surface expression levels in HBV-tg mice. Our results showed that commercial HBV vaccine loaded DCs induced humoral response in HBV-tg mice but had no effect on cellular immunity.

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Generation of Th1-Polarizing Dendritic Cells Using the TLR7/8 Agonist CL075

Abstract: Material

Cited by 72 publications

References 50 publications

Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of Toll-like receptor 7 short hairpin RNA gene

Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of Toll-like receptor 7 short hairpin RNA gene

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

Stimulation of dendritic cells with vaccine and vaccine–antibody complex and effect on immune response

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