scholarly journals Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice

2018 ◽  
Vol 115 (37) ◽  
pp. E8698-E8706 ◽  
Author(s):  
Ying Wang ◽  
Lijing Su ◽  
Matthew D. Morin ◽  
Brian T. Jones ◽  
Yuto Mifune ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Innate Immune ◽  
The Novel ◽  
Adjuvant Effect ◽  
Tlr2 Agonist ◽  
Primary Mouse ◽  
Mouse Peritoneal Macrophages ◽  
Human And Mouse ◽  
Dc Maturation

Successful cancer immunotherapy entails activation of innate immune receptors to promote dendritic cell (DC) maturation, antigen presentation, up-regulation of costimulatory molecules, and cytokine secretion, leading to activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 compounds for innate immune activators using TNF production by THP-1 cells as a readout. We identified and optimized a potent human and mouse Toll-like receptor (TLR)1/TLR2 agonist, Diprovocim, which exhibited an EC50 of 110 pM in human THP-1 cells and 1.3 nM in primary mouse peritoneal macrophages. In mice, Diprovocim-adjuvanted ovalbumin immunization promoted antigen-specific humoral and CTL responses and synergized with anti–PD-L1 treatment to inhibit tumor growth, generating long-term antitumor memory, curing or prolonging survival of mice engrafted with the murine melanoma B16-OVA. Diprovocim induced greater frequencies of tumor-infiltrating leukocytes than alum, of which CD8 T cells were necessary for the antitumor effect of immunization plus anti–PD-L1 treatment.

Hypoxia enhances lysosomal TNF-α degradation in mouse peritoneal macrophages

2008 ◽  
Vol 295 (1) ◽  
pp. C2-C12 ◽  
Author(s):  
Nitza Lahat ◽  
Michal A. Rahat ◽  
Amalia Kinarty ◽  
Lea Weiss-Cerem ◽  
Sigalit Pinchevski ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Tnf Α ◽  
Primary Mouse ◽  
Factor Α ◽  
Secretory Lysosomes ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

Infection, simulated by lipopolysaccharide (LPS), is a potent stimulator of tumor necrosis factor-α (TNF-α) production, and hypoxia often synergizes with LPS to induce higher levels of the secreted cytokine. However, we show that in primary mouse peritoneal macrophages and in three mouse peritoneal macrophage cell lines (RAW 264.7, J774A.1, and PMJ-2R), hypoxia (O2 < 0.3%) reduces the secretion of LPS-induced TNF-α ( P < 0.01). In RAW 264.7 cells this reduction was not regulated transcriptionally as TNF-α mRNA levels remained unchanged. Rather, hypoxia and LPS reduced the intracellular levels of TNF-α by twofold ( P < 0.01) by enhancing its degradation in the lysosomes and inhibiting its secretion via secretory lysosomes, as shown by confocal microscopy and verified by the use of the lysosome inhibitor Bafilomycin A1. In addition, although hypoxia did not change the accumulation of the soluble receptor TNF-RII, it increased its binding to the secreted TNF-α by twofold ( P < 0.05). We suggest that these two posttranslational regulatory checkpoints coexist in hypoxia and may partially explain the reduced secretion and diminished biological activity of TNF-α in hypoxic peritoneal macrophages.

scholarly journals Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Brendon Y. Chua ◽  
Chinn Yi Wong ◽  
Edin J. Mifsud ◽  
Kathryn M. Edenborough ◽  
Toshiki Sekiya ◽  
...  
Keyword(s):  
Immune System ◽  
Influenza Vaccine ◽  
Innate Immune System ◽  
Virus Transmission ◽  
Innate Immune ◽  
Influenza Vaccines ◽  
Tlr2 Agonist ◽  
Adaptive Immune ◽  
Heterologous Virus

ABSTRACTThe continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8+T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8+T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity.IMPORTANCEThe innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.

scholarly journals Extracellular vesicles secreted by Giardia duodenalis regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways

2021 ◽  
Vol 15 (4) ◽  
pp. e0009304
Author(s):  
Panpan Zhao ◽  
Lili Cao ◽  
Xiaocen Wang ◽  
Jingquan Dong ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Host Cell ◽  
Signaling Pathways ◽  
Extracellular Vesicles ◽  
Nlrp3 Inflammasome ◽  
Diarrheal Disease ◽  
Giardia Duodenalis ◽  
Peritoneal Macrophages ◽  
Primary Mouse ◽  
Mouse Peritoneal Macrophages

Giardia duodenalis, also known as G. intestinalis or G. lamblia, is the major cause of giardiasis leading to diarrheal disease with 280 million people infections annually worldwide. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism participating in cells communications. The aim of this study is to explore the roles of G. duodenalis EVs (GEVs) in host-pathogen interactions using primary mouse peritoneal macrophages as a model. Multiple methods of electron microscopy, nanoparticle tracking analysis, proteomic assays, flow cytometry, immunofluorescence, qPCR, western blot, ELISA, inhibition assays, were used to characterize GEVs, and explore its effects on the host cell innate immunity as well as the underlying mechanism using primary mouse peritoneal macrophages. Results showed that GEVs displayed typical cup-shaped structure with 150 nm in diameter. GEVs could be captured by macrophages and triggered immune response by increasing the production of inflammatory cytokines Il1β, Il6, Il10, Il12, Il17, Ifng, Tnf, Il18, Ccl20 and Cxcl2. Furthermore, activation of TLR2 and NLRP3 inflammasome signaling pathways involved in this process. In addition, CA-074 methyl ester (an inhibitor of cathepsin B) or zVAD-fmk (an inhibitor of pan-caspase) pretreatment entirely diminished these effects triggered by GEVs exposure. Taken together, these findings demonstrated that GEVs could be internalized into mouse peritoneal macrophages and regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.

Concussion in sports in children and adolescents – to play or not to play?

2017 ◽  
Vol 65 (3) ◽  
Keyword(s):  
Gender Differences ◽  
Children And Adolescents ◽  
Return To Sport ◽  
Consensus Conference ◽  
Return To School ◽  
The Novel ◽  
International Consensus ◽  
Persistent Symptoms ◽  
New Findings

A lot has been published on the topic concussion in sports during the last years, conscience was sharpened, much was structured and defined more precisely, help tools were developed and rules changed. This article summarizes the fifth edition of the recently published guidelines of the “International Consensus Conference on Concussion in Sport”. In addition, new findings regarding gender differences and recovery will be presented, as well as the modified “return-to-sport” and the novel “return-to-school” protocols. Despite increased knowledge many questions remain such as the therapy of persistent symptoms or long-term sequelae of recurrent concussions.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals Waning antibody responses in COVID-19: what can we learn from the analysis of other coronaviruses?

Infection ◽  
2021 ◽  
Author(s):  
Ali Hamady ◽  
JinJu Lee ◽  
Zuzanna A. Loboda
Keyword(s):  
Cross Reactivity ◽  
Antibody Responses ◽  
The Novel ◽  
Incidence And Mortality ◽  
Antibody Titres ◽  
Human Coronaviruses ◽  
Public Health Strategies ◽  
Antibody Dynamics

Abstract Objectives The coronavirus disease 2019 (COVID-19), caused by the novel betacoronavirus severe acute respiratory syndrome 2 (SARS-CoV-2), was declared a pandemic in March 2020. Due to the continuing surge in incidence and mortality globally, determining whether protective, long-term immunity develops after initial infection or vaccination has become critical. Methods/Results In this narrative review, we evaluate the latest understanding of antibody-mediated immunity to SARS-CoV-2 and to other coronaviruses (SARS-CoV, Middle East respiratory syndrome coronavirus and the four endemic human coronaviruses) in order to predict the consequences of antibody waning on long-term immunity against SARS-CoV-2. We summarise their antibody dynamics, including the potential effects of cross-reactivity and antibody waning on vaccination and other public health strategies. At present, based on our comparison with other coronaviruses we estimate that natural antibody-mediated protection for SARS-CoV-2 is likely to last for 1–2 years and therefore, if vaccine-induced antibodies follow a similar course, booster doses may be required. However, other factors such as memory B- and T-cells and new viral strains will also affect the duration of both natural and vaccine-mediated immunity. Conclusion Overall, antibody titres required for protection are yet to be established and inaccuracies of serological methods may be affecting this. We expect that with standardisation of serological testing and studies with longer follow-up, the implications of antibody waning will become clearer.

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