Arylalkenyl and aryalkynyl substituted imidazoquinoline compounds, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral, and neoplastic, are disclosed.

Pubmed 19729616 Authors: Amit I,Garber M,Chevrier N,Leite AP,Donner Y,Eisenhaure T,Guttman M,Grenier JK,Li W,Zuk O,Schubert LA,Birditt B,Shay T,Goren A,Zhang X,Smith Z,Deering R,McDonald RC,Cabili M,Bernstein BE,Rinn JL,Meissner A,Root DE,Hacohen N,Regev A ...

An amount of a compound or salt effective to induce or inhibit cytokme biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or mots cytokmes such as, for example, IFN-a, TNF-ot, IL-1, IL-6, IL-10 and IL-12 mat is increased (induced) or decreased (inhibited) over a background level of such cytokmes. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ngJkg to about 50 mgJkg, preferably about 10 ugJkg to about 5 mgJkg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral ...

In chronic diseases, such as HIV infection, plasmacytoid dendritic cells (pDCs) are rendered dysfunctional, as measured by their decreased capacity to produce IFN-α. In this study, we identified elevated levels of T cell Ig and mucin-domain containing molecule-3 (Tim-3)-expressing pDCs in the blood of HIV-infected donors. The frequency of Tim-3-expressing pDCs correlated inversely with CD4 T cell counts and positively with HIV viral loads. A lower frequency of pDCs expressing Tim-3 produced IFN-α or TNF-α in response to the TLR7 agonists imiquimod and Sendai virus and to the TLR9 agonist CpG. Thus, Tim-3 may serve as a biomarker of pDC dysfunction in HIV infection. The source and function of Tim-3 was investigated on enriched pDC populations from donors not infected with HIV. Tim-3 induction was achieved in response to viral and artificial stimuli, as well as exogenous IFN-α, and was PI3K dependent. Potent pDC-activating stimuli, such as CpG, imiquimod, and Sendai virus, induced the most ...

Like a tourist without a map, tumor-fighting T cells have a hard time finding their destination without directions. According to Clark et al. (page 2221), dismantling these directions helps skin cancer cells hide from killer T cells.. To enter the skin, T cells must grab on to the adhesive molecule E-selectin, which is expressed on the endothelial cells lining blood vessels in the skin. The authors now find that many of the vessels in skin cancer lesions lack E-selectin, causing beneficial T cells to pass by unaware. The tumors were instead populated by suppressive regulatory (T reg) cells, perhaps coaxed in by the tumor to safeguard against killer cells that somehow gain access. Both tactics have also been seen in other types of human cancer.. Reversing the suppressive effect of T reg cells is one of the beneficial effects of topical immune-stimulating drugs like the TLR agonist imiquimod, which is effective in treating certain types of skin cancer. Indeed, Clark et al. found that imiquimod ...

The conventional dendritic cell (cDC) II (CD8- 33D1+) subset is more efficient in processing antigens for presentation by MHC II than the cDC I (CD8+CD205+) subset ...

When using imiquimod, the dosing instructions will depend on the condition being treated and other factors. This eMedTV resource presents a brief description of how your treatment plan will be determined. This page also links to more detailed information.

The Plasmacytoid Dendritic Cell Isolation Kit II allows the isolation of untouched human plasmacytoid dendritic cells (PDCs) from PBMCs. Having evolved from the first-generation kit (# 130-092-207), it now offers even better cell purity and yield in a faster procedure. - Belgique

CD303 (BDCA-2) antibodies have been used, for example, to identify, characterize, and enumerate plasmacytoid dendritic cells in whole blood of healthy and HIV-infected individuals, and for analyzing the role of DC-SIGN in HIV infection and transmission. Furthermore, CD303 (BDCA-2) antibodies have been used to identify and enumerate plasmacytoid dendritic cells in blood and bone marrow samples before and after hematopoietic stem cell mobilization or transplantation. CD303 (BDCA-2) antibodies have also been used for immunohistochemical staining, for example, to identify plasmacytoid dendritic cells in tissue sections from patients with different inflammatory skin diseases. Clone REA693 recognizes the CD303 (BDCA-2) antigen which is expressed on human plasmacytoid dendritic cells in blood, lymphoid (e.g. tonsils and bone marrow), and non-lymphoid tissue. Specific expression allows direct identification of plasmacytoid dendritic cells using just one marker. CD303 (BDCA-2)+ plasmacytoid dendritic cells in

Our findings clearly indicate that Spi-B is specifically required for development of human pDCs. These data add to observations that mice deficient for ICSBP/IRF-8 lack pDCs and CD8α+ DCs (13). Thus, both the ETS factor Spi-B and the IRF factor ICSBP/IRF-8 appear to be essential for pDC development. Interestingly, the ETS and IRF factors can cooperatively assemble on composite ETS-IRF DNA (EICE) elements, which were initially discovered in the immunoglobulin light chain enhancers but have later been found in promoters and enhancers of B lymphoid and myeloid genes (27). Similar to PU.1 and IRF-4, Spi-B and ICSBP/IRF-8 assemble in an ETS-IRF ternary complex of which the crystal structure was resolved recently (27). Given that both ICSBP/IRF-8 and Spi-B are required for pDC development, the structural data of Escalante et al. (27) make it very likely that Spi-B and ICSBP/IRF-8 cooperate in controlling pDC development.. Recent data have made clear that pDCs can develop both from Flt3+ lymphoid as ...

Elif Colak, Alasdair Leslie, Kieran Zausmer, Elham Khatamzas, Andriy V. Kubarenko, Tica Pichulik, Sascha N. Klimosch, Alice Mayer, Owen Siggs, Andreas Hector, Roman Fischer, Benedikt Klesser, Anna Rautanen, Martin Frank, Adrian V S Hill, Bélnéldicte Manoury, Bruce Beutler, Dominik Hartl, Alison Simmons, Alexander N R Weber ...

Plasmacytoid dendritic cell precursors (pDCs) play a key role at the interface of innate and acquired immunity in anti-viral responses by sensing viral infectio...

Sigma-Aldrich offers abstracts and full-text articles by [Jordan Ari Schwartz, Kiera L Clayton, Shariq Mujib, Hongliang Zhang, A K M Nur-Ur Rahman, Jun Liu, Feng Yun Yue, Erika Benko, Colin Kovacs, Mario A Ostrowski].

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抗原ペプチドが同定されていない腫瘍に対する細胞傷害性T細胞(CTL)を誘導するために，当研究室で樹立した白血病性形質細胞様樹状細胞株(leukemic plasmacytoid dendritic cell line; PMDC05)の直接

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The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of ...

Differential expression of Toll-like receptor (TLR) by conventional dendritic cells (cDCs) and plasmacytoid DC (pDCs) has been suggested to influence the type o

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Pattern recognition receptors, including the Toll-like receptors (TLRs), are important in the induction and activation of two critical arms of the host defence to pathogens and microorganisms; the rapid innate immune response (as characterised by the production of Th1 promoting cytokines and type 1 interferons) and the adaptive immune response. Through this activation, ligands and agonists of TLRs can enhance immunotherapeutic efficacy. Resiquimod is a small (water-soluble) agonist of the endosome-located Toll-like receptors 7 and 8 (TLR7/8). However due to its molecular attributes it rapidly distributes throughout the body after injection. To circumvent this, these TLR agonists can be incorporated within delivery systems, such as liposomes, to promote the co-delivery of both antigen and agonists to antigen presenting cells. In this present study, resiquimod has been chemically conjugated to a lipid to form a lipid-TLR7/8 agonist conjugate which can be incorporated within immunogenic cationic ...

PubMed Central Canada (PMC Canada) provides free access to a stable and permanent online digital archive of full-text, peer-reviewed health and life sciences research publications. It builds on PubMed Central (PMC), the U.S. National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature and is a member of the broader PMC International (PMCI) network of e-repositories.

Immunohistochemical staining revealed a typical blastic plasmacytoid dendritic cell neoplasm (BPDCN) phenotype; the nodules stained positively for CD4, CD56, and CD123, and negatively for CD3, CD8, MPO, TdT, and Epstein-Barr virus. The patient was treated with six cycles of CHOP, and achieved complete remission. Five months later, he presented with a headache and left ptosis. Examination of the cerebrospinal fluid (CSF) showed numerous medium-sized monomorphic cells, either in loose clusters or dispersed singly. The nuclei were round or irregular, showing fine chromatin and prominent nucleoli, and the cytoplasm was scant and grey-blue, with intracytoplasmic microvacuoles and pseudopodia ...

TY - JOUR. T1 - Identification of plasmacytoid pre-dendritic cells by one-color flow cytometry for phenotype screening. AU - Magyarics, Zoltan. AU - Csillag, Aniko. AU - Pazmandi, Kitti. AU - Rajnavolgyi, Eva. AU - Bacsi, Attila. PY - 2008/3/1. Y1 - 2008/3/1. N2 - Plasmacytoid pre-dendritic cells (pDCs) are able to prime and polarize naive T-cells, while also having an important effector function in antiviral immunity through the rapid and robust production of interferon-α. The main setback of pDCs investigation is the rarity and ex vivo fragility of these cells. Relative simple, reliable, and accurate methods for phenotypic analysis and functional studies of pDCs without isolation would be a great deal of interest. Fresh whole blood samples were analyzed by two-color and one-color flow cytometric pDC-identification assays. The changes in the surface expression of CD62L and HLA-DQ on pDCs in whole blood samples after 24-h treatment with imiquimod, a toll-like receptor 7 agonist, were analyzed. ...

K. 34, each imiquimod cost canada element was modulated between stimulus A Imiquimгd consecutive dark frames followed by eight consecutive light frames) and stimulus B (16 consecutive dark frames) according to a binary m-sequence. Second, the symptoms resolved after dialysis.

摘 要：Toll样受体4(TLR4)是固有免疫系统中能够识别病原相关分子模式的受体家族成员，可识别革兰氏阴性菌的脂多糖(LPS)而在细菌感染性疾病的发生中起重要作用。近年来越来越多的研究发现，TLR4还广泛参与病毒感染性疾病的发生和病毒的免疫逃逸，由于其信号转导通路的独特性和细胞定位的可变性，再次引起人们极大的研究兴趣。该文将介绍TLR4的生物学特性、信号转导通路及TLR4与病毒感染的最新研究进展 ...

Link to Pubmed [PMID] - 28181493. Nat Commun 2017 02;8:14253. Plasmacytoid dendritic cells (pDC) are specialized in secretion of type I interferon in response to pathogens. Here we show that natural monoamines and synthetic amines inhibit pDC activation by RNA viruses. Furthermore, a synthetic analogue of histamine reduces type I interferon production in a mouse model of influenza infection. We identify CXC chemokine receptor 4 (CXCR4) as a receptor used by amines to inhibit pDC. Our study establishes a functional link between natural amines and the innate immune system and identifies CXCR4 as a potential on-off switch of pDC activity with therapeutic potential.. https://www.ncbi.nlm.nih.gov/pubmed/28181493 ...

The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 μM).

The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor

On December 21, 2018, the Food and Drug Administration approved tagraxofusp-erzs (ELZONRIS™, Stemline Therapeutics), a CD123-directed cytotoxin, for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older

These findings are consistent with the idea that plasmacytoid DCs are mediators of muscle inflammation in juvenile DM. The abundance of CD83+ plasmacytoid DCs in perivascular areas and the overexpression of CCL19 and CCL21 in perivascular cellular foci suggest that in situ activation and maturation …

This webpage describes Toll-Like Receptors present in mice and humans and their corresponding ligands, adapter proteins, and accessory molecules. The website also provides a comprehensive distribution list of TLRs expression in both mouse and human cells. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.

This webpage describes Toll-Like Receptors present in mice and humans and their corresponding ligands, adapter proteins, and accessory molecules. The website also provides a comprehensive distribution list of TLRs expression in both mouse and human cells. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.

Design:. Prospective, randomized controlled clinical trial. This will be a pilot study. All subjects will undergo baseline anal Pap, HRA with biopsies as indicated, and anal HPV testing. If AIN 2 or 3 is discovered on histopathologic examination, subject will be offered observation only or treatment. If he chooses treatment, he will be randomized to: 1) imiquimod anal suppositories three times weekly for 3 months, or 2) appropriate ablative therapy as determined by colorectal surgeon. During imiquimod treatment (not applicable to ablative group as their treatment will be completed in one visit) subjects will be followed for 2 weeks, 4 weeks, 8 weeks, and 12 weeks with anal Pap, HRA with biopsies as indicated, and anal HPV testing. After therapy completed in each treatment group, subjects will be followed for 1 month, 3 months, 6 months, 9 months, and 12 months post-therapy with anal Pap, HRA with biopsies as indicated, and anal HPV testing. Observation only subjects will be evaluated every 3 ...

TY - JOUR. T1 - Blastic plasmacytoid dendritic cell neoplasm. T2 - Evolving insights in an aggressive hematopoietic malignancy with a predilection of skin involvement. AU - Gera, Shweta. AU - Dekmezian, Mhair S.. AU - Duvic, Madeleine. AU - Tschen, Jaime A.. AU - Vega, Francisco. AU - Cho-Vega, Jeong Hee. PY - 2014/1/1. Y1 - 2014/1/1. N2 - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) derived from precursors of plasmacytoid dendritic cells is a very rare, unique, and highly aggressive immature hematopoietic malignancy, more frequently occurring among healthy elderly adults. BPDCN can be characterized by a striking predilection for cutaneous involvement, which is often detected incidentally by dermatologists and is difficult to clinically distinguish it from other primary skin lesions and histologically from leukemia/lymphoma cutis. Thus, histological diagnosis of cutaneous biopsies is crucial to correctly classify this entity. Most patients eventually progress to acute myeloid leukemia ...

The recent discovery of an ancient family of toll-like receptors (TLRs) in the immune system has substantially enhanced the potential for a variety of therapies, for both failing immune systems, which leaves the body open to infection or over-active ones, which can lead to chronic inflammation. Signaling by Toll-Like Receptors provides a comprehensive review of important techniques in molecular biology, cell biology, biochemistry, genetics, and immunology and their critical application to the study of toll-like receptor structure, biological function, and the intracellular signaling triggered by these receptors, as well as the high promise for uncovering effective pharmaceutica ...

Delphine Fougeron, Laurye van Maele, Pascal Songhet, Delphine Cayet, David Hot, et al.. Indirect Toll-like receptor 5-mediated activation of conventional dendritic cells promotes the mucosal adjuvant activity of flagellin in the respiratory tract. Vaccine, Elsevier, 2015, 33 (29), pp.11. ⟨10.1016/j.vaccine.2015.05.022⟩. ⟨inserm-01182907⟩ ...

Toll-like receptors are pattern-recognition receptors that have key roles in detecting microbes and initiating inflammatory responses. Recently, a host of new microbial products that activate specific Toll-like receptors have been defined, and additional components that mediate intracellular signali …

The development and implementation of a scalable process for the manufacture of the Toll-like receptor (TLR7) agonist PF-4171455 (1) is described. Initial routes used to synthesise 1 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the transfer between Medicinal Chemistry and Research-API, collaboration provided a fit for purpose route for the kilo-scale synthesis of 1. Key aspects of the synthesis included (i) a safe and practical synthesis of a key nitropyridone intermediate 7 over four steps, (ii) a sequential regioselective chlorination to selectively functionalise 7 and (iii) use of a carbamate as a tethered carbonyl group, allowing an efficient regiospecific synthesis of 1.. ...

TY - JOUR. T1 - Signatures of balancing selection in toll-like receptor (TLRs) genes - novel insights from a free-living rodent. AU - Kloch, Agnieszka. AU - Wenzel, Marius A.. AU - Laetsch, Dominik R.. AU - Michalski, Olek. AU - Bajer, Anna AU - Behnke, Jerzy M.. AU - Welc-Falȩciak, Renata. AU - Piertney, Stuart B.. N1 - Correction to: Scientific Reports https://doi.org/10.1038/s41598-018-26672-2, published online 30 May 2018 The work was supported by grant no. DEC-2012/07/B/NZ8/00058 from the Polish National Science Centre to A.K. Field studies were funded by grant MNiI 2P04C09827 „Badania naturalnych źródeł zarażenia mikropasożytów patogennych dla człowieka to AB. We are thankful to Dr. hab W. Babik who provided access to an Illumina MiSeq platform, and to K. Dudek who prepared the Nextera library. Special thanks to A. Biedrzycka for her valuable comments on the final version of the manuscript. We also would like to thank two anonymous reviewers for their valuable comments that ...

The IUPHAR/BPS Guide to Pharmacology. TLR2 - Toll-like receptor family. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.

Toll-like receptor 9 (TLR9), a naturally existing immune regulatory site, not only takes part in enhancing anti-tumor immunity but also promoting the ..

BOMFIM, G. F.... Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats. Life Sciences 122 n. p. 1-7 FEB 1 2015. Artigo Científico.

Ation was dependent on TLR7. Thus, despite the fact that TLR8 is expressed on MedChemExpress Crenolanib murine microglia and astrocytes, it appears to only

Endogenous mechanisms of ischemic preconditioning-tolerance have reviled the brains ability to reprogram (precondition) its response to acute ischemia from tha...

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As part of the innate immune system the Toll-like receptor (TLR) signaling pathway contributes to the first line of defense against microbial pathogens. The...

Plasmacytoid Dendritic Cells in the Duodenum of Individuals Diagnosed with Myalgic Encephalomyelitis Are Uniquely Immunoreactive to Antibodies to...

I recently (12 Nov 2008) learned that a friend of mine, C.A.M. Wagner, was diagnosed with a rare and aggressive form of bone cancer called plasmacytoid dendritic cell neoplasm. Perhaps only 100 people have received this diagnosis.. C.A.M. and I, along with about 10 others, worked for our fraternity headquarters right out of school. Though we traveled independently to more than 200 universities a semester, we each grew rather close and still keep in touch.. C.A.M., I hope the talented team of doctors and scientist do all they can to make you better.. ...