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https://www.readbyqxmd.com/read/29444493/modulators-of-innate-immunity-as-novel-therapeutics-for-treatment-of-chronic-hepatitis-b
#1
REVIEW
Aleksei Suslov, Stefan Wieland, Stephan Menne
The first line defense mechanisms against viral infection are mediated by the innate immune system. Viral components are detected by infected cells and/or innate immune cells that express different sensory receptors. They in turn mediate induction of direct antiviral mechanisms and further modulation of innate and adaptive immune responses. For evading the innate system, most viruses have evolved efficient mechanisms to block sensing and/or antiviral functions of the innate response. Interestingly, hepatitis B virus (HBV) seems to act like a stealth virus that escapes cell intrinsic antiviral mechanisms through avoiding recognition by the innate system rather than blocking its effector functions...
February 11, 2018: Current Opinion in Virology
https://www.readbyqxmd.com/read/29437897/tlr9-toll-like-receptor-9-agonist-suppresses-angiogenesis-by-differentially-regulating-vegfa-vascular-endothelial-growth-factor-a-and-sflt1-soluble-vascular-endothelial-growth-factor-receptor-1-in-preeclampsia
#2
Biwei He, Xingyu Yang, Yamei Li, Ding Huang, Xin Xu, Wenjun Yang, Yan Dai, Huijuan Zhang, Zhengjun Chen, Weiwei Cheng
Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women...
February 5, 2018: Hypertension
https://www.readbyqxmd.com/read/29436396/rapid-activation-of-tumor-associated-macrophages-boosts-preexisting-tumor-immunity
#3
Sabine Hoves, Chia-Huey Ooi, Carsten Wolter, Hadassah Sade, Stefan Bissinger, Martina Schmittnaegel, Oliver Ast, Anna M Giusti, Katharina Wartha, Valeria Runza, Wei Xu, Yvonne Kienast, Michael A Cannarile, Hyam Levitsky, Solange Romagnoli, Michele De Palma, Dominik Rüttinger, Carola H Ries
Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29436395/myeloid-targeted-immunotherapies-act-in-synergy-to-induce-inflammation-and-antitumor-immunity
#4
Curtis J Perry, Andrés R Muñoz-Rojas, Katrina M Meeth, Laura N Kellman, Robert A Amezquita, Durga Thakral, Victor Y Du, Jake Xiao Wang, William Damsky, Alexandra L Kuhlmann, Joel W Sher, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech
Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29433938/b-cell-lymphoma-immunotherapy-using-tlr9-targeted-oligonucleotide-stat3-inhibitors
#5
Xingli Zhao, Zhuoran Zhang, Dayson Moreira, Yu-Lin Su, Haejung Won, Tomasz Adamus, Zhenyuan Dong, Yong Liang, Hongwei H Yin, Piotr Swiderski, Raju K Pillai, Larry Kwak, Stephen Forman, Marcin Kortylewski
Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells...
January 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29433450/pathogen-recognition-by-nk-cells-amplifies-the-pro-inflammatory-cytokine-production-of-monocyte-derived-dc-via-ifn-%C3%AE
#6
Tammy Oth, Thomas H P M Habets, Wilfred T V Germeraad, Marijke I Zonneveld, Gerard M J Bos, Joris Vanderlocht
BACKGROUND: Besides their prominent role in the elimination of infected or malignantly transformed cells, natural killer (NK) cells serve as modulators of adaptive immune responses. Enhancing bidirectional crosstalk between NK cells and dendritic cells (DC) is considered a promising tool to potentiate cancer vaccines. We investigated to what extent direct sensing of viral and bacterial motifs by NK cells contributes to the response of inflammatory DC against the same pathogenic stimulus...
February 13, 2018: BMC Immunology
https://www.readbyqxmd.com/read/29427663/intracellular-formyl-peptide-receptor-regulates-na%C3%A3-ve-cd4-t-cell-migration
#7
Ha Young Lee, Yu Sun Jeong, Mingyu Lee, Hee-Seok Kweon, Yang Hoon Huh, Joon Seong Park, Ji Eun Hwang, Kyuseok Kim, Yoe-Sik Bae
We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or the nucleus of naïve CD4 T cell. Activation of naïve CD4 T cells with synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via pertussis toxin-sensitive manner. Knockdown of FPR1, but not knockdown of FPR3, blocked dTAT-WKYMVm-induced naïve CD4 T cell migration. Stimulation of naïve CD4 T cells with dTAT-WKYMVm elicited the activation of ERK, p38 MAPK, and Akt...
February 7, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29425920/sting-signaling-promotes-inflammation-in-experimental-acute-pancreatitis
#8
Qinglan Zhao, Yi Wei, Stephen J Pandol, Lingyin Li, Aida Habtezion
BACKGROUND & AIMS: Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a pattern recognition receptor on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation mice with AP. METHODS: We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet...
February 6, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29422905/immunomodulatory-properties-of-carvone-inhalation-and-its-effects-on-contextual-fear-memory-in-mice
#9
Aritz Lasarte-Cia, Teresa Lozano, Marta Pérez-González, Marta Gorraiz, Kristina Iribarren, Sandra Hervás-Stubbs, Pablo Sarobe, Obdulia Rabal, Mar Cuadrado-Tejedor, Ana García-Osta, Noelia Casares, Juan José Lasarte
A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29422777/imiquimod-inhibits-growth-and-induces-differentiation-of-myeloid-leukemia-cell-lines
#10
Eva Villamón, Javier González-Fernández, Esperanza Such, José Vicente Cervera, Daniel Gozalbo, M Luisa Gil
Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML. Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL)...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29421216/the-preparation-and-physico-chemical-characterization-of-aluminum-hydroxide-tlr7a-a-novel-vaccine-adjuvant-comprising-a-small-molecule-adsorbed-to-aluminum-hydroxide
#11
Padma Malyala, Donatello Laera, Simona Cianetti, Simone Bufali, Marianna Aggravi, Elvira Ianni, Casey Judge, Gillis Otten, Manmohan Singh, Derek T O' Hagan
Adjuvants are necessary to enable vaccine development against a significant number of challenging pathogens for which effective vaccines are not available [1]. We engineered a novel small-molecule immune potentiator (SMIP), a benzonaphthyridine agonist targeting toll-like receptor 7 (TLR7), as a vaccine adjuvant. TLR7 agonist (TLR7a) was engineered to be adsorbed onto aluminum hydroxide (AlOH), and the resulting AlOH/TLR7a was evaluated as a vaccine adjuvant [2-6]. AlOH/TLR7a exploits the flexibility of AlOH formulations, has an application in many vaccine candidates, and induced good efficacy and safety profiles against all tested antigens (bacterial- and viral-derived protein antigens, toxoids, glycoconjugates, etc...
February 5, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29420901/enhancing-efficacy-and-stability-of-an-anti-heroin-vaccine-examination-of-antinociception-opioid-binding-profile-and-lethality
#12
Candy S Hwang, Paul T Bremer, Cody J Wenthur, Sam On Ho, SuMing Chiang, Beverly Ellis, Bin Zhou, Gary Fujii, Kim D Janda
In recent years, drug conjugate vaccines have shown promise as therapeutics for substance use disorder. As a means to improve the efficacy of a heroin conjugate vaccine, we systematically explored twenty vaccine formulations with varying combinations of carrier proteins and adjuvants. In regard to adjuvants, we explored a Toll-like receptor 9 (TLR9) agonist and a TLR3 agonist in the presence of alum. The TLR9 agonist was cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826), while the TLR3 agonist was virus-derived genomic doubled-stranded RNA (dsRNA)...
February 8, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29415982/combination-therapy-with-proteasome-inhibitors-and-tlr-agonists-enhances-tumour-cell-death-and-il-1%C3%AE-production
#13
Anthony C Tang, Seyed M Rahavi, Shan-Yu Fung, Henry Y Lu, Hong Yang, Chinten J Lim, Gregor S Reid, Stuart E Turvey
Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-κB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1β maturation and secretion after TLR stimulation...
February 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29415945/validating-a-selective-s1p1-receptor-modulator-syl930-for-psoriasis-treatment
#14
Ming Ji, Nina Xue, Fangfang Lai, Xiaoying Zhang, Sen Zhang, Yuchen Wang, Jing Jin, Xiaoguang Chen
Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment...
February 7, 2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29414647/methamphetamine-modulates-the-production-of-interleukin-6-and-tumor-necrosis-factor-alpha-via-the-camp-pka-creb-signaling-pathway-in-lipopolysaccharide-activated-microglia
#15
Biao Wang, Teng Chen, Jing Wang, Yuwei Jia, Huixun Ren, Feng Wu, Mei Hu, Yanjiong Chen
Methamphetamine (METH) elicits neuroinflammatory effects that may implicate its regulatory role on the microglial immune response. However, the mechanism underlying this remains unclear. In the present study, the effects of METH on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) productions were tested in BV-2 cells and primary microglial cells. Additionally, western blot analysis was used to examine the phosphorylation of mitogenactivated protein kinases (MAPKs)...
January 29, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29412659/retinoic-acid-receptor-related-orphan-receptor-gamma-t-ror%C3%AE-t-agonists-as-potential-small-molecule-therapeutics-for-cancer-immunotherapy
#16
Ruomeng Qiu, Yonghui Wang
The recent success of PD-1/PD-L1 antibodies for advanced cancer treatment has led to the conclusion that activating the immune system can be employed to fight cancer. These results also encourage the development of small molecule immuno-modulators for cancer immunotherapy. RORγt is a key transcription factor mediating Th17 cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. Since RORγt agonists have been shown to increase basal activity of RORγt and promote Th17 cell differentiation, development of RORγt agonists could provide a unique approach to cancer immunotherapy...
February 7, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29411777/lymphoid-tissue-resident-alcaligenes-lps-induces-iga-production-without-excessive-inflammatory-responses-via-weak-tlr4-agonist-activity
#17
Naoko Shibata, Jun Kunisawa, Koji Hosomi, Yukari Fujimoto, Keisuke Mizote, Naohiro Kitayama, Atsushi Shimoyama, Hitomi Mimuro, Shintaro Sato, Natsuko Kishishita, Ken J Ishii, Koichi Fukase, Hiroshi Kiyono
Alcaligenes are opportunistic commensal bacteria that reside in gut-associated lymphoid tissues such as Peyer's patches (PPs); however, how they create and maintain their homeostatic environment, without inducing an excessive inflammatory response remained unclear. We show here that Alcaligenes-derived lipopolysaccharide (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 and promotes IL-6 production from dendritic cells, which consequently enhances IgA production. The inflammatory activity of Alcaligenes LPS was weaker than that of Escherichia coli-derived LPS and therefore no excessive inflammation was induced by Alcaligenes LPS in vitro or in vivo...
February 7, 2018: Mucosal Immunology
https://www.readbyqxmd.com/read/29410064/icam-1-upregulation-is-not-required-for-retinoic-acid-induced-human-eosinophil-survival
#18
Shigeharu Ueki, Junko Nishikawa, Mineyo Fukuchi, Yasunori Konno, Masahide Takeda, Yuki Moritoki, Junichi Chihara, Ayumi Omokawa, Tomoo Saga, Makoto Hirokawa
Active metabolites of vitamin A, retinoic acids (RAs), are known to play critical roles in mucosal immune responses and dramatically inhibit human eosinophil apoptosis, but the detailed mechanisms have not been elucidated. We previously screened for ICAM-1 (CD54) upregulation in RA-stimulated human eosinophils by gene microarray analysis. As ICAM-1 induction and activation were observed to have a role in maintenance of eosinophil survival, we tested the hypothesis that RAs prolong eosinophil survival through ICAM-1 outside-in signaling...
January 31, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29409680/routing-dependent-immune-responses-after-experimental-r848-adjuvated-vaccination
#19
Susan van Aalst, Manon A A Jansen, Irene S Ludwig, Ruurd van der Zee, Willem van Eden, Femke Broere
Most traditional vaccines are administered via the intramuscular route. Other routes of administration however, can induce equal or improved protective memory responses and might provide practical advantages such as needle-free immunization, dose sparing and induction of tissue-specific (mucosal) immunity. Here we explored the differences in immunological outcome after immunization with model antigens via two promising immunization routes (intradermal and intranasal) with or without the experimental adjuvant and TLR7/8-agonist R848...
February 3, 2018: Vaccine
https://www.readbyqxmd.com/read/29405962/progesterone-attenuates-hypertension-and-autoantibody-levels-to-the-angiotensin-ii-type-1-receptor-in-response-to-elevated-cadmium-during-pregnancy
#20
Qiong Zhang, Yinping Huang, Keke Zhang, Yan Yan, Jie Wu, Fan Wang, Yuan Zhao, Huifang Xu, Wei Jiang, Danyang Yu, Yongtao Chen, Duyun Ye
INTRODUCTION: Preeclampsia is associated with the presence of pathogenic angiotensin-receptor-activating autoantibodies. Cadmium is an increasingly prevalent environmental pollutant that can mimic oestrogens, which may enhance immunoglobulin production. Progesterone exerts opposite effects to oestrogen. METHODS: We measured the levels of cadmium and progesterone in preeclamptic patients and controls. Pregnant rats exposed to cadmium (0.125 mg/kg body weight) from gestational day 9-12 were treated with/without progesterone (3 mg/kg) beginning from gestational day 9 to delivery...
February 2018: Placenta
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