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Sample records for enhanced hiv-specific immunity

  1. Engineering HIV-Specific Immunity with Chimeric Antigen Receptors.

    Science.gov (United States)

    Kitchen, Scott G; Zack, Jerome A

    2016-12-01

    HIV remains a highly important public health and clinical issue despite many recent advances in attempting to develop a cure, which has remained elusive for most people infected with HIV. HIV disease can be controlled with pharmacologic therapies; however, these treatments are expensive, may have severe side effects, and are not curative. Consequently, an improved means to control or eliminate HIV replication is needed. Cytotoxic T lymphocytes (CTLs) play a critical role in controlling viral replication and are an important part in the ability of the immune response to eradicate most viral infections. There are considerable efforts to enhance CTL responses in HIV-infected individuals in hopes of providing the immune response with armaments to more effectively control viral replication. In this review, we discuss some of these efforts and focus on the development of a gene therapy-based approach to engineer hematopoietic stem cells with an HIV-1-specific chimeric antigen receptor, which seeks to provide an inexhaustible source of HIV-1-specific immune cells that are MHC unrestricted and superior to natural antiviral T cell responses. These efforts provide the basis for further development of T cell functional enhancement to target and treat chronic HIV infection in hopes of eradicating the virus from the body.

  2. Decreased HIV-specific T-regulatory responses are associated with effective DC-vaccine induced immunity.

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    Vedran Brezar

    2015-03-01

    Full Text Available The role of regulatory T cells (Tregs in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC loaded with HIV-lipopeptides (LIPO-5-DC vaccine in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs. Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3 before vaccination (week -4 to 2.1% (IQR 1.1-3.9 at week 16 following 4 immunizations (p=0.001 and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001. Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5-DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16 and inversely correlated with HIV-specific IFN-γ-producing cells (r=-0.64, p=0.002. We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI.

  3. Dissecting the HIV-specific immune response: a systems biology approach.

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    Peretz, Yoav; Cameron, Cheryl; Sékaly, Rafick-Pierre

    2012-01-01

    Several unique HIV-infected or HIV-resistant cohorts have been studied over the years to try and delineate the correlates of protection. Although several mechanisms have been put forward, studies aiming to integrate the different mechanisms into a comprehensive model are still lacking. Current systems biology approaches emphasize the importance of unifying independent datasets, provide tools that facilitate hypothesis formulation and testing, and direct us toward uncovering novel therapeutic targets by defining molecular networks perturbed during disease. This review will focus on the current findings that utilized systems biology techniques in order to identify correlates of protection from HIV disease progression and resistance to infection in unique cohorts of individuals as well as in nonhuman primate models of SIV infection. Using systems biology technologies and data analysis tools, the studies described herein have found that pathways implicated in survival, cell cycling, inflammation, and oxidative stress work in unison to limit pathology caused by chronic immune activation. This situation favors the survival of effector lymphocytes and limits the dissemination of viral particles in HIV elite controllers, exposed-uninfected individuals, and natural hosts of SIV infection. Systems and computational biology tools have clearly expanded our understanding of HIV pathogenesis by unifying independent observations and by giving us novel molecular targets to pursue. These molecular signatures have the potential to uncover correlates of protection in HIV disease and, in the era of personalized medicine, to determine predictive signatures of treatment efficacy and/or failure.

  4. Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

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    Tsai, Angela; Irrinki, Alivelu; Kaur, Jasmine; Cihlar, Tomas; Kukolj, George; Sloan, Derek D; Murry, Jeffrey P

    2017-04-15

    Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently

  5. Adaptive HIV-specific B cell-derived humoral immune defenses of the intestinal mucosa in children exposed to HIV via breast-feeding.

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    Sandrine Moussa

    Full Text Available BACKGROUND: We evaluated whether B cell-derived immune defenses of the gastro-intestinal tract are activated to produce HIV-specific antibodies in children continuously exposed to HIV via breast-feeding. METHODS: Couples of HIV-1-infected mothers (n = 14 and their breastfed non HIV-infected (n = 8 and HIV-infected (n = 6 babies, and healthy HIV-negative mothers and breastfed babies (n = 10 as controls, were prospectively included at the Complexe Pédiatrique of Bangui, Central African Republic. Immunoglobulins (IgA, IgG and IgM and anti-gp160 antibodies from mother's milk and stools of breastfed children were quantified by ELISA. Immunoaffinity purified anti-gp160 antibodies were characterized functionally regarding their capacity to reduce attachment and/or infection of R5- and X4- tropic HIV-1 strains on human colorectal epithelial HT29 cells line or monocyte-derived-macrophages (MDM. RESULTS: The levels of total IgA and IgG were increased in milk of HIV-infected mothers and stools of HIV-exposed children, indicating the activation of B cell-derived mucosal immunity. Breast milk samples as well as stool samples from HIV-negative and HIV-infected babies exposed to HIV by breast-feeding, contained high levels of HIV-specific antibodies, mainly IgG antibodies, less frequently IgA antibodies, and rarely IgM antibodies. Relative ratios of excretion by reference to lactoferrin calculated for HIV-specific IgA, IgG and IgM in stools of HIV-exposed children were largely superior to 1, indicating active production of HIV-specific antibodies by the intestinal mucosa. Antibodies to gp160 purified from pooled stools of HIV-exposed breastfed children inhibited the attachment of HIV-1NDK on HT29 cells by 63% and on MDM by 77%, and the attachment of HIV-1JRCSF on MDM by 40%; and the infection of MDM by HIV-1JRCSF by 93%. CONCLUSIONS: The intestinal mucosa of children exposed to HIV by breast-feeding produces HIV-specific antibodies harbouring

  6. A comparative analysis of HIV-specific mucosal/systemic T cell immunity and avidity following rDNA/rFPV and poxvirus-poxvirus prime boost immunisations.

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    Ranasinghe, Charani; Eyers, Fiona; Stambas, John; Boyle, David B; Ramshaw, Ian A; Ramsay, Alistair J

    2011-04-05

    In this study we have firstly compared a range of recombinant DNA poxvirus prime-boost immunisation strategies and shown that combined intramuscular (i.m.) 2× DNA-HIV/intranasal (i.n.) 2× FPV-HIV prime-boost immunisation can generate high-level of HIV-specific systemic (spleen) and mucosal (genito-rectal nodes, vaginal tissues and lung tissues) T cell responses and HIV-1 p24 Gag-specific serum IgG1, IgG2a and mucosal IgG, SIgA responses in vaginal secretions in BALB/c mice. Data indicate that following rDNA priming, two rFPV booster immunisations were necessary to generate good antibody and mucosal T cell immunity. This data also revealed that mucosal uptake of recombinant fowl pox (rFPV) was far superior to plasmid DNA. To further evaluate CD8+ T cell immunity, i.m. 2× DNA-HIV/i.n. 1× FPV-HIV immunisation strategy was directly compared with single shot poxvirus/poxvirus, i.n. FPV-HIV/i.m. VV-HIV immunisation. Results indicate that the latter strategy was able to generate strong sustained HIV-specific CD8+ T cells with higher avidity, broader cytokine/chemokine profiles and better protection following influenza-K(d)Gag(197-205) challenge compared to rDNA poxvirus prime-boost strategy. Our findings further substantiate the importance of vector selection/combination, order and route of delivery when designing effective vaccines for HIV-1. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. DNA-MVA-protein vaccination of rhesus macaques induces HIV-specific immunity in mucosal-associated lymph nodes and functional antibodies.

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    Chege, Gerald K; Burgers, Wendy A; Müller, Tracey L; Gray, Clive M; Shephard, Enid G; Barnett, Susan W; Ferrari, Guido; Montefiori, David; Williamson, Carolyn; Williamson, Anna-Lise

    2017-02-07

    Successful future HIV vaccines are expected to generate an effective cellular and humoral response against the virus in both the peripheral blood and mucosal compartments. We previously reported the development of DNA-C and MVA-C vaccines based on HIV-1 subtype C and demonstrated their immunogenicity when given in a DNA prime-MVA boost combination in a nonhuman primate model. In the current study, rhesus macaques previously vaccinated with a DNA-C and MVA-C vaccine regimen were re-vaccinated 3.5years later with MVA-C followed by a protein vaccine based on HIV-1 subtype C envelope formulated with MF59 adjuvant (gp140Env/MF59), and finally a concurrent boost with both vaccines. A single MVA-C re-vaccination elicited T cell responses in all animals similar to previous peak responses, with 4/7 demonstrating responses >1000 SFU/10 6 PBMC. In contrast to an Env/MF59-only vaccine, concurrent boosting with MVA-C and Env/MF59 induced HIV-specific cellular responses in multiple mucosal associated lymph nodes in 6/7 animals, with high magnitude responses in some animals. Both vaccine regimens induced high titer Env-specific antibodies with ADCC activity, as well as neutralization of Tier 1 viruses and modest Tier 2 neutralization. These data demonstrate the feasibility of inducing HIV-specific immunity in the blood and mucosal sites of viral entry by means of DNA and poxvirus-vectored vaccines, in combination with a HIV envelope-based protein vaccine. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

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    Christian Prebensen

    Full Text Available Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

  9. Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen.

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    Paul F McKay

    Full Text Available Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNA-poxvirus-protein strategy in mice and rabbits, administering MVA and protein immunizations either sequentially or simultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef with HIV CN54gp140 protein (+/-GLA-AF adjuvant and either co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. The DNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to the boost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccine components. Moreover, a high proportion of the total mucosal IgG (20 - 50% present in the vaginal vault of these vaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccine modality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIV CN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene product expressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA and GLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequential vaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit of the condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced, an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.

  10. HIV-specific CD8+ T cells: serial killers condemned to die?

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    Petrovas, Constantinos; Mueller, Yvonne M; Katsikis, Peter D

    2004-04-01

    An increasing body of evidence supports a key role for cytotoxic CD8+ T cells (CTL) in controlling HIV infection. Although a vigorous HIV-specific CD8+ T cell response is raised during the primary infection, these cells ultimately fail to control virus and prevent disease progression. The failure of CTL to control HIV infection has been attributed to a number of strategies HIV employs to evade the immune system. Recently, intrinsic defects in the CTL themselves have been proposed to contribute to the failure of CTL to control HIV. HIV-specific CD8+ T cells differ in their effector/memory phenotype from other virus-specific CD8+ T cells indicating that their differentiation status differs. This altered differentiation may affect effector functions as well as homing properties of these cells. Other studies have indicated that activation of HIV-specific CTL may be impaired and this contributes to their dysfunction. The effector function of these CTL may also be affected. There are conflicting reports about their ability to kill, whereas IFNgamma production does not appear to be impaired in these cells. In this review we focus on recent work indicating that apoptosis may be an important mechanism through which HIV evades the CTL response. In particular, HIV-specific CD8+ T cells are highly susceptible to CD95/Fas-induced apoptosis. This leads to the hypothesis that virus-specific cytotoxic T cells can be eliminated upon binding CD95L/FasL on HIV-infected cells. Understanding the intrinsic defects of CTL in HIV infection could lead to new therapeutic strategies and optimized vaccination protocols that enhance the HIV-specific cytotoxic response.

  11. Sculpting humoral immunity through dengue vaccination to enhance protective immunity

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    Wayne eCrill

    2012-11-01

    Full Text Available Dengue viruses (DENV are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF. Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1 DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT with this cross-reactivity reduced (CRR vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naïve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine induced immune

  12. Trained immunity: A smart way to enhance innate immune defence.

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    van der Meer, Jos W M; Joosten, Leo A B; Riksen, Niels; Netea, Mihai G

    2015-11-01

    The innate arm of the immune system is generally viewed as primitive and non-specific and - in contrast to the adaptive immune arm - not to possess memory. However in plants and invertebrate animals that lack adaptive immunity, innate immunity will exhibit a prolonged enhanced functional state after adequate priming. A similar enhancement of function of the innate immunity has occasionally been described in vertebrates, including humans. Over the past few years we have studied this phenomenon in greater detail and we have coined the term 'Trained (innate) immunity' (TI). TI can be induced by a variety of stimuli, of which we have studied BCG and β-glucan in greater detail. The non-specific protective effects of BCG that have been observed in vaccination studies in the literature are probably due to TI. Monocytes and macrophages are among the main cells of the innate immune arm that can be trained. We have discovered that both BCG (via NOD2 signalling) and β-glucan (via dectin-1) induce epigenetic reprogramming, in particular stable changes in histone trimethylation at H3K4. These epigenetic changes lead to cellular activation, enhanced cytokine production and a change in the metabolic state of the cell with a shift from oxidative phosphorylation to aerobic glycolysis. TI is not only important for host defence and vaccine responses, but most probably also for diseases like atherosclerosis. Modulation of TI is a promising area for new treatments. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Maternal immunity enhances systemic recall immune responses upon oral immunization of piglets with F4 fimbriae.

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    Nguyen, Ut V; Melkebeek, Vesna; Devriendt, Bert; Goetstouwers, Tiphanie; Van Poucke, Mario; Peelman, Luc; Goddeeris, Bruno M; Cox, Eric

    2015-06-23

    F4 enterotoxigenic Escherichia coli (ETEC) cause diarrhoea and mortality in piglets leading to severe economic losses. Oral immunization of piglets with F4 fimbriae induces a protective intestinal immune response evidenced by an F4-specific serum and intestinal IgA response. However, successful oral immunization of pigs with F4 fimbriae in the presence of maternal immunity has not been demonstrated yet. In the present study we aimed to evaluate the effect of maternal immunity on the induction of a systemic immune response upon oral immunization of piglets. Whereas F4-specific IgG and IgA could be induced by oral immunization of pigs without maternal antibodies and by intramuscular immunization of pigs with maternal antibodies, no such response was seen in the orally immunized animals with maternal antibodies. Since maternal antibodies can mask an antibody response, we also looked by ELIspot assays for circulating F4-specific antibody secreting cells (ASCs). Enumerating the F4-specific ASCs within the circulating peripheral blood mononuclear cells, and the number of F4-specific IgA ASCs within the circulating IgA(+) B-cells revealed an F4-specific immune response in the orally immunized animals with maternal antibodies. Interestingly, results suggest a more robust IgA booster response by oral immunization of pigs with than without maternal antibodies. These results demonstrate that oral immunization of piglets with F4-specific maternal antibodies is feasible and that these maternal antibodies seem to enhance the secondary systemic immune response. Furthermore, our ELIspot assay on enriched IgA(+) B-cells could be used as a screening procedure to optimize mucosal immunization protocols in pigs with maternal immunity.

  14. The immune enhancer, thymoquinone, and the hope of utilizing the ...

    African Journals Online (AJOL)

    The immune enhancer, thymoquinone, and the hope of utilizing the immune system of Aedes caspius against disease agents. ... immunity-reproduction conflict, it was concluded that the impact of immune stimulation and/or enhancement on the vector reproduction constitutes a limiting factor to the utilization of thymoquinone ...

  15. Increased sequence diversity coverage improves detection of HIV-Specific T cell responses

    DEFF Research Database (Denmark)

    Frahm, N.; Kaufmann, D.E.; Yusim, K.

    2007-01-01

    The accurate identification of HIV-specific T cell responses is important for determining the relationship between immune response, viral control, and disease progression. HIV-specific immune responses are usually measured using peptide sets based on consensus sequences, which frequently miss...... assay, these "toggled" peptides detected HIV-specific CD4(+) and CD8(+) T cell responses of significantly higher breadth and magnitude than matched consensus peptides. The observed increases were explained by a closer match of the toggled peptides to the autologous viral sequence. Toggled peptides...... responses to regions where test set and infecting virus differ. In this study, we report the design of a peptide test set with significantly increased coverage of HIV sequence diversity by including alternative amino acids at variable positions during the peptide synthesis step. In an IFN-gamma ELISpot...

  16. Activation of NK cells by HIV-specific ADCC antibodies: role for granulocytes in expressing HIV-1 peptide epitopes.

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    Madhavi, Vijaya; Navis, Marjon; Chung, Amy W; Isitman, Gamze; Wren, Leia H; De Rose, Robert; Kent, Stephen J; Stratov, Ivan

    2013-05-01

    HIV-specific ADCC antibodies could play a role in providing protective immunity. We have developed a whole blood ADCC assay that measures NK cell activation in response to HIV peptide epitopes. These HIV peptide-specific ADCC responses are associated with escape from immune recognition and slower progression of HIV infection and represent interesting HIV vaccine antigens. However, the mechanism by which these epitopes are expressed and whether or not they induce NK-mediated killing of cells expressing such peptide-antigens is not understood. Herein, we show that fluorescent-tagged ADCC peptide epitopes associate with blood granulocytes. The peptide-associated granulocytes become a specific target for antibody-mediated killing, as shown by enhanced expression of apoptosis marker Annexin and reduction in cell numbers. When HIV Envelope gp140 protein is utilized in the ADCC assay, we detected binding to its ligand, CD4. During the incubation, cells co-expressing gp140 and CD4 reduce in number. We also detected increasing Annexin expression in these cells. These data indicate that blood cells expressing HIV-specific ADCC epitopes are targeted for killing by NK cells in the presence of ADCC antibodies in HIV+ plasma and provide a clearer framework to evaluate these antigens as vaccine candidates.

  17. Enhancing Immune Checkpoint Inhibitor Therapy In Kidney Cancer

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0141 TITLE: Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer PRINCIPAL INVESTIGATOR: Hans-Joerg Hammers...Immune Checkpoint Inhibitor therapy in Kidney Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH- 15-1-0141 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...to develop strategies to enhance immune checkpoint inhibition in kidney cancer . The work is designed to test different strategies to induce or

  18. Characterization of HIV-Specific CD4+T Cell Responses against Peptides Selected with Broad Population and Pathogen Coverage

    DEFF Research Database (Denmark)

    Buggert, Marcus; Norstrom, Melissa M.; Czarnecki, Chris

    2012-01-01

    CD4+ T cells orchestrate immunity against viral infections, but their importance in HIV infection remains controversial. Nevertheless, comprehensive studies have associated increase in breadth and functional characteristics of HIV-specific CD4+ T cells with decreased viral load. A major challenge...... for the identification of HIV-specific CD4+ T cells targeting broadly reactive epitopes in populations with diverse ethnic background stems from the vast genomic variation of HIV and the diversity of the host cellular immune system. Here, we describe a novel epitope selection strategy, PopCover, that aims to resolve......% of the predicted peptides were found to induce HIV-specific CD4+ T cell responses. The Gag and Nef peptides induced most responses. The vast majority of the peptides (93%) had predicted restriction to the patient's HLA alleles. Interestingly, the viral load in viremic patients was inversely correlated...

  19. Pyriproxyfen enhances the immunoglobulin G immune response in mice.

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    Sharmin, Tanjina; Satho, Tomomitsu; Irie, Keiichi; Watanabe, Mineo; Hosokawa, Masato; Hiramatsu, Yukihiro; Talukder, Parimal; Okuno, Takahiro; Tsuruda, Shodai; Uyeda, Saori; Fukmits, Yuki; Tamura, Yukie; Nakashima, Yukihiko; Imoto, Masumi; Toda, Akihisa; Kashige, Nobuhiro; Miake, Fumio

    2013-04-01

    Pyriproxyfen is a juvenile hormone mimic of vital importance for insect development with little risk to humans. This study was performed to investigate whether large doses of pyriproxyfen affect the immune response in mammals. Mice were immunized thrice with ovalbumin in 5% ethanol, with or without pyriproxyfen or alum. Large doses of pyriproxyfen (9 or 15 mM) significantly enhanced specific total IgG immune response. This enhancement was no longer present 24 hr after treatment with pyriproxyfen. These results suggest that pyriproxyfen is a safe chemical. Moreover, pyriproxyfen induced higher titers of IgG2a and enhanced tumor necrosis factor-alpha and gamma-interferon responses whereas alum induced IgG1 with enhanced interleukin-4 and -10. These observations indicate that the mechanism of immune enhancement by pyriproxyfen may differ from that of alum. © 2013 The Societies and Wiley Publishing Asia Pty Ltd.

  20. Longitudinal dynamics of the HIV-specific B cell response during intermittent treatment of primary HIV infection.

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    Godelieve J de Bree

    Full Text Available Neutralizing antibodies develop in natural HIV-1 infection. Their development often takes several years and may rely on chronic virus exposure. At the same time recent studies show that treatment early in infection may provide opportunities for immune preservation. However, it is unknown how intermittent treatment in early infection affects development of the humoral immune response over time. We investigate the effect of cART in early HIV infection on the properties of the memory B cell compartment following 6 months of cART or in the absence of treatment. The patients included participated in the Primo-SHM trial where patients with an early HIV-1 infection were randomized to no treatment or treatment for 24 or 60 weeks.Primo-SHM trial patients selected for the present study were untreated (n = 23 or treated for 24 weeks (n = 24. Here we investigate memory B cell properties at viral set-point and at a late time point (respectively median 54 and 73 weeks before (re-initiation of treatment.At viral set-point, the memory B cell compartment in treated patients demonstrated significantly lower fractions of antigen-primed, activated, memory B cells (p = 0.006. In contrast to untreated patients, in treated patients the humoral HIV-specific response reached a set point over time. At a transcriptional level, sets of genes that showed enhanced expression in memory B cells at viral setpoint in untreated patients, conversely showed rapid increase of expression of the same genes in treated patients at the late time point.These data suggest that, although the memory B cell compartment is phenotypically preserved until viral setpoint after treatment interruption, the development of the HIV-specific antibody response may benefit from exposure to HIV. The effect of viral exposure on B cell properties is also reflected by longitudinal changes in transcriptional profile in memory B cells over time in early treated patients.

  1. Immune Depletion to Enhance Immunotoxin Therapy

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    Patients with advanced mesothelioma who have not benefited from previous chemotherapy will receive pentostatin and cyclophosphamide to prevent an anti-immunotoxin immune response prior to and in conjunction with SS1P immunotoxin therapy.

  2. Targeting the tumor microenvironment to enhance antitumor immune responses

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    Van der Jeught, Kevin; Bialkowski, Lukasz; Daszkiewicz, Lidia; Broos, Katrijn; Goyvaerts, Cleo; Renmans, Dries; Van Lint, Sandra; Heirman, Carlo; Thielemans, Kris; Breckpot, Karine

    2015-01-01

    The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients. PMID:25682197

  3. Abundance of early functional HIV-specific CD8+ T cells does not predict AIDS-free survival time

    NARCIS (Netherlands)

    Schellens, Ingrid M. M.; Borghans, José A. M.; Jansen, Christine A.; de Cuyper, Iris M.; Geskus, Ronald B.; van Baarle, Debbie; Miedema, Frank

    2008-01-01

    BACKGROUND: T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8(+) and CD4(+) T cells producing IFNgamma and IL-2 have been associated with control of viremia and are therefore

  4. Immunomodulator-based enhancement of anti smallpox immune responses.

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    Martínez, Osmarie; Miranda, Eric; Ramírez, Maite; Santos, Saritza; Rivera, Carlos; Vázquez, Luis; Sánchez, Tomás; Tremblay, Raymond L; Ríos-Olivares, Eddy; Otero, Miguel

    2015-01-01

    The current live vaccinia virus vaccine used in the prevention of smallpox is contraindicated for millions of immune-compromised individuals. Although vaccination with the current smallpox vaccine produces protective immunity, it might result in mild to serious health complications for some vaccinees. Thus, there is a critical need for the production of a safe virus-free vaccine against smallpox that is available to everyone. For that reason, we investigated the impact of imiquimod and resiquimod (Toll-like receptors agonists), and the codon-usage optimization of the vaccinia virus A27L gene in the enhancement of the immune response, with intent of producing a safe, virus-free DNA vaccine coding for the A27 vaccinia virus protein. We analyzed the cellular-immune response by measuring the IFN-γ production of splenocytes by ELISPOT, the humoral-immune responses measuring total IgG and IgG2a/IgG1 ratios by ELISA, and the TH1 and TH2 cytokine profiles by ELISA, in mice immunized with our vaccine formulation. The proposed vaccine formulation enhanced the A27L vaccine-mediated production of IFN-γ on mouse spleens, and increased the humoral immunity with a TH1-biased response. Also, our vaccine induced a TH1 cytokine milieu, which is important against viral infections. These results support the efforts to find a new mechanism to enhance an immune response against smallpox, through the implementation of a safe, virus-free DNA vaccination platform.

  5. Natural killer cells enhance the immune surveillance of cancer

    Directory of Open Access Journals (Sweden)

    Faisal Nouroz

    2016-04-01

    Full Text Available Immune system (IS is comprised of molecules, cells, tissues and organs involved in host defense mechanism from infectious agents or tumor cells. On crossing the cell barriers by these infectious agents, the defense mechanism is alerted by the immune system to respond against these invading microbes. Innate immune response (IIR and acquired immune response (AIR are working in parallel to control these invading microbes. IIR is composed of various types of phagocytes and lymphocytes, while AIR is comprised of T and B lymphocytes. All the cells of the immune system cooperatively work against infectious agents and cancerous cells but Natural killer (NK cells are playing an important role to respond to tumor by enhancing the expression of complementary domain (CD86 on dendritic cells (DCs and production of IL-12. NK cells demolished tumor through perforin and granzyme, which are important for immune surveillance and death of tumor cells induced by cytokines such as tumor necrosis factor (TNF, Fas ligand (CD178, interferon-γ (IFN-γ and IL-10. These cytokines have inhibited proliferation of tumor by inducing anti-angiogenic factors and maintaining cross talk with other immune cells. Natural products like transfer factor plus, immune modulator mix, ascorbic acid, Ganoderma lucidum, Agaricus blazei teas, nitrogenated soy extract, Andrographis paniculata and several phytochemicals enhanced the efficiency of NK cells in controlling cancers. Further studies will unravel the impact of NK cells in cancer control and how NK efficiency can be further enhanced.

  6. Newborn Mice Vaccination with BCG.HIVA222 + MVA.HIVA Enhances HIV-1-Specific Immune Responses: Influence of Age and Immunization Routes

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    Narcís Saubi

    2011-01-01

    Full Text Available We have evaluated the influence of age and immunization routes for induction of HIV-1- and M. tuberculosis-specific immune responses after neonatal (7 days old and adult (7 weeks old BALB/c mice immunization with BCG.HIVA222 prime and MVA.HIVA boost. The specific HIV-1 cellular immune responses were analyzed in spleen cells. The body weight of the newborn mice was weekly recorded. The frequencies of HIV-specific CD8+ T cells producing IFN-γ were higher in adult mice vaccinated intradermally and lower in adult and newborn mice vaccinated subcutaneously. In all cases the IFN-γ production was significantly higher when mice were primed with BCG.HIVA222 compared with BCGwt. When the HIV-specific CTL activity was assessed, the frequencies of specific killing were higher in newborn mice than in adults. The prime-boost vaccination regimen which includes BCG.HIVA222 and MVA.HIVA was safe when inoculated to newborn mice. The administration of BCG.HIVA222 to newborn mice is safe and immunogenic and increased the HIV-specific responses induced by MVA.HIVA vaccine. It might be a good model for infant HIV and Tuberculosis bivalent vaccine.

  7. Enhancing crop innate immunity: new promising trends

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    Pin-Yao eHuang

    2014-11-01

    Full Text Available Plants are constantly exposed to potentially pathogenic microbes present in their surrounding environment. Due to the activation of the pattern-triggered immunity (PTI response that largely relies on accurate detection of pathogen- or microbe-associated molecular patterns by pattern-recognition receptors (PRRs, plants are resistant to the majority of potential pathogens. However, adapted pathogens may avoid recognition or repress plant PTI and resulting diseases significantly affect crop yield worldwide. PTI provides protection against a wide range of pathogens. Reinforcement of PTI through genetic engineering may thus generate crops with broad-spectrum field resistance. In this review, new approaches based on fundamental discoveries in PTI to improve crop immunity are discussed. Notably, we highlight recent studies describing the interfamily transfer of PRRs or key regulators of PTI signalling.

  8. Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity

    Science.gov (United States)

    Belyakov, Igor M.; Moss, Bernard; Strober, Warren; Berzofsky, Jay A.

    1999-04-01

    Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.

  9. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control.

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    Adam R Hersperger

    2010-05-01

    Full Text Available Many immune correlates of CD8(+ T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8(+ T-cells to rapidly upregulate perforin--an essential molecule for cell-mediated cytotoxicity--following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35, viremic controllers (n = 29, chronic progressors (n = 27, and viremic nonprogressors (n = 6. Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8(+ T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8(+ T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8(+ T-cells to rapidly express perforin defines a novel correlate of control in HIV infection.

  10. Immunomodulator-based enhancement of anti smallpox immune responses.

    Directory of Open Access Journals (Sweden)

    Osmarie Martínez

    Full Text Available The current live vaccinia virus vaccine used in the prevention of smallpox is contraindicated for millions of immune-compromised individuals. Although vaccination with the current smallpox vaccine produces protective immunity, it might result in mild to serious health complications for some vaccinees. Thus, there is a critical need for the production of a safe virus-free vaccine against smallpox that is available to everyone. For that reason, we investigated the impact of imiquimod and resiquimod (Toll-like receptors agonists, and the codon-usage optimization of the vaccinia virus A27L gene in the enhancement of the immune response, with intent of producing a safe, virus-free DNA vaccine coding for the A27 vaccinia virus protein.We analyzed the cellular-immune response by measuring the IFN-γ production of splenocytes by ELISPOT, the humoral-immune responses measuring total IgG and IgG2a/IgG1 ratios by ELISA, and the TH1 and TH2 cytokine profiles by ELISA, in mice immunized with our vaccine formulation.The proposed vaccine formulation enhanced the A27L vaccine-mediated production of IFN-γ on mouse spleens, and increased the humoral immunity with a TH1-biased response. Also, our vaccine induced a TH1 cytokine milieu, which is important against viral infections.These results support the efforts to find a new mechanism to enhance an immune response against smallpox, through the implementation of a safe, virus-free DNA vaccination platform.

  11. Novel mucosal DNA-MVA HIV vaccination in which DNA-IL-12 plus cholera toxin B subunit (CTB) cooperates to enhance cellular systemic and mucosal genital tract immunity.

    Science.gov (United States)

    Maeto, Cynthia; Rodríguez, Ana María; Holgado, María Pía; Falivene, Juliana; Gherardi, María Magdalena

    2014-01-01

    Induction of local antiviral immune responses at the mucosal portal surfaces where HIV-1 and other viral pathogens are usually first encountered remains a primary goal for most vaccines against mucosally acquired viral infections. Exploring mucosal immunization regimes in order to find optimal vector combinations and also appropriate mucosal adjuvants in the HIV vaccine development is decisive. In this study we analyzed the interaction of DNA-IL-12 and cholera toxin B subunit (CTB) after their mucosal administration in DNA prime/MVA boost intranasal regimes, defining the cooperation of both adjuvants to enhance immune responses against the HIV-1 Env antigen. Our results demonstrated that nasal mucosal DNA/MVA immunization schemes can be effectively improved by the co-delivery of DNA-IL-12 plus CTB inducing elevated HIV-specific CD8 responses in spleen and more importantly in genital tract and genito-rectal draining lymph nodes. Remarkably, these CTL responses were of superior quality showing higher avidity, polyfunctionality and a broader cytokine profile. After IL-12+CTB co-delivery, the cellular responses induced showed an enhanced breadth recognizing with higher efficiency Env peptides from different subtypes. Even more, an in vivo CTL cytolytic assay demonstrated the higher specific CD8 T-cell performance after the IL-12+CTB immunization showing in an indirect manner its potential protective capacity. Improvements observed were maintained during the memory phase where we found higher proportions of specific central memory and T memory stem-like cells T-cell subpopulations. Together, our data show that DNA-IL-12 plus CTB can be effectively employed acting as mucosal adjuvants during DNA prime/MVA boost intranasal vaccinations, enhancing magnitude and quality of HIV-specific systemic and mucosal immune responses.

  12. Osteopathic lymphatic pump techniques to enhance immunity and treat pneumonia

    Science.gov (United States)

    Hodge, Lisa M.

    2012-01-01

    Pneumonia is a common cause of morbidity and mortality worldwide. While antibiotics are generally effective for the treatment of infection, the emergence of resistant strains of bacteria threatens their success. The osteopathic medical profession has designed a set of manipulative techniques called lymphatic pump techniques (LPT), to enhance the flow of lymph through the lymphatic system. Clinically, LPT is used to treat infection and oedemaand might be an effective adjuvant therapy in patients with pneumonia.The immune system uses the lymphatic and blood systems to survey to rid the body of pathogens; however, only recently have the effects of LPT on the lymphatic and immune systems been investigated. This short review highlightsclinical and basic science research studies that support the use of LPT to enhance the lymphatic and immune systems and treat pneumonia, and discusses the potential mechanisms by which LPT benefits patients with pneumonia. PMID:22977459

  13. Transgenerational effects enhance specific immune response in a wild passerine

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    Juli Broggi

    2016-03-01

    Full Text Available Vertebrate mothers transfer diverse compounds to developing embryos that can affect their development and final phenotype (i.e., maternal effects. However, the way such effects modulate offspring phenotype, in particular their immunity, remains unclear. To test the impact of maternal effects on offspring development, we treated wild breeding house sparrows (Passer domesticus in Sevilla, SE Spain with Newcastle disease virus (NDV vaccine. Female parents were vaccinated when caring for first broods, eliciting a specific immune response to NDV. The immune response to the same vaccine, and to the PHA inflammatory test were measured in 11-day-old chicks from their following brood. Vaccinated chicks from vaccinated mothers developed a stronger specific response that was related to maternal NDV antibody concentration while rearing their chicks. The chicks’ carotenoid concentration and total antioxidant capacity in blood were negatively related to NDV antibody concentration, whereas no relation with PHA response was found. Specific NDV antibodies could not be detected in 11-day-old control chicks from vaccinated mothers, implying that maternally transmitted antibodies are not directly involved but may promote offspring specific immunity through a priming effect, while other immunity components remain unaffected. Maternally transmitted antibodies in the house sparrow are short-lived, depend on maternal circulation levels and enhance pre-fledging chick specific immunity when exposed to the same pathogens as the mothers.

  14. Super-enhancers: Asset management in immune cell genomes.

    Science.gov (United States)

    Witte, Steven; O'Shea, John J; Vahedi, Golnaz

    2015-09-01

    Super-enhancers (SEs) are regions of the genome consisting of clusters of regulatory elements bound with very high amounts of transcription factors, and this architecture appears to be the hallmark of genes and noncoding RNAs linked with cell identity. Recent studies have identified SEs in CD4(+) T cells and have further linked these regions to single nucleotide polymorphisms (SNPs) associated with immune-mediated disorders, pointing to an important role for these structures in the T cell differentiation and function. Here we review the features that define SEs, and discuss their function within the broader understanding of the mechanisms that define immune cell identity and function. We propose that SEs present crucial regulatory hubs, coordinating intrinsic and extrinsic differentiation signals, and argue that delineating these regions will provide important insight into the factors and mechanisms that define immune cell identity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases.

    Science.gov (United States)

    Qiao, Guilin; Qin, Jianzhong; Kunda, Nicholas; Calata, Jed F; Mahmud, Dolores L; Gann, Peter; Fu, Yang-Xin; Rosenberg, Steven A; Prabhakar, Bellur S; Maker, Ajay V

    2017-04-15

    The majority of patients with colon cancer will develop advanced disease, with the liver being the most common site of metastatic disease. Patients with increased numbers of tumor-infiltrating lymphocytes in primary colon tumors and liver metastases have improved outcomes. However, the molecular factors that could empower antitumor immune responses in this setting remain to be elucidated. We reported that the immunostimulatory cytokine LIGHT (TNFSF14) in the microenvironment of colon cancer metastases associates with improved patient survival, and here we demonstrate in an immunocompetent murine model that colon tumors expressing LIGHT stimulate lymphocyte proliferation and tumor cell-specific antitumor immune responses. In this model, increasing LIGHT expression in the microenvironment of either primary tumors or liver metastases triggered regression of established tumors and slowed the growth of liver metastases, driven by cytotoxic T-lymphocyte-mediated antitumor immunity. These responses corresponded with significant increases in tumor-infiltrating lymphocytes and increased expression of lymphocyte-homing signals in the metastatic tumors. Furthermore, we demonstrated evidence of durable tumor-specific antitumor immunity. In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy. Cancer Res; 77(8); 1880-91. ©2017 AACR. ©2017 American Association for Cancer Research.

  16. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-01-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID:28854172

  17. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K.; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-09-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

  18. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    Science.gov (United States)

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  19. Combinatorial contextualization of peptidic epitopes for enhanced cellular immunity.

    Directory of Open Access Journals (Sweden)

    Masaki Ito

    Full Text Available Invocation of cellular immunity by epitopic peptides remains largely dependent on empirically developed protocols, such as interfusion of aluminum salts or emulsification using terpenoids and surfactants. To explore novel vaccine formulation, epitopic peptide motifs were co-programmed with structural motifs to produce artificial antigens using our "motif-programming" approach. As a proof of concept, we used an ovalbumin (OVA system and prepared an artificial protein library by combinatorially polymerizing MHC class I and II sequences from OVA along with a sequence that tends to form secondary structures. The purified endotoxin-free proteins were then examined for their ability to activate OVA-specific T-cell hybridoma cells after being processed within dendritic cells. One clone, F37A (containing three MHC I and two MHC II OVA epitopes, possessed a greater ability to evoke cellular immunity than the native OVA or the other artificial antigens. The sensitivity profiles of drugs that interfered with the F37A uptake differed from those of the other artificial proteins and OVA, suggesting that alteration of the cross-presentation pathway is responsible for the enhanced immunogenicity. Moreover, F37A, but not an epitopic peptide, invoked cellular immunity when injected together with monophosphoryl lipid A (MPL, and retarded tumor growth in mice. Thus, an artificially synthesized protein antigen induced cellular immunity in vivo in the absence of incomplete Freund's adjuvant or aluminum salts. The method described here could be potentially used for developing vaccines for such intractable ailments as AIDS, malaria and cancer, ailments in which cellular immunity likely play a crucial role in prevention and treatment.

  20. Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity

    OpenAIRE

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don

    2016-01-01

    ABSTRACT ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17...

  1. Elevated environmental temperature enhances immunity in experimental Chagas' disease.

    Science.gov (United States)

    Anderson, K J; Kuhn, R E

    1989-01-01

    C3H mice are highly susceptible to the Brazil strain of Trypanosoma cruzi. These mice usually die during the acute phase of infection and develop a profound immunosuppression to heterologous and parasite antigen. In this study, we confirmed earlier reports that infected mice maintained at elevated environmental temperature (36 degrees C) are significantly more resistant to T. cruzi than are mice kept at 20 to 24 degrees C. To determine whether the benefits of increased environmental temperature were due to alterations in the host immune system, the production of antibody to heterologous antigen and the development of parasite-specific T-helper cells were examined in noninfected and T. cruzi-infected mice. Mice were immunized with either sheep erythrocytes (SRBC) or trinitrophenyl groups (TNP) conjugated to fixed culture forms of T. cruzi, and the splenic direct plaque-forming cell (DPFC) responses to SRBC and to TNP-conjugated SRBC were determined. The DPFC response to SRBC from infected mice maintained at elevated environmental temperature was much higher than the suppressed response of infected mice held at room temperature and slightly higher than the response of age-matched noninfected control mice. Likewise, maintaining infected mice at 36 degrees C significantly enhanced the parasite-specific responses of T-helper cells, as reflected by anti-TNP DPFC responses of mice immunized with TNP-conjugated TC.

  2. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity.

    Science.gov (United States)

    Herrada, Andrés A; Contreras, Francisco J; Marini, Natacha P; Amador, Cristian A; González, Pablo A; Cortés, Claudia M; Riedel, Claudia A; Carvajal, Cristián A; Figueroa, Fernando; Michea, Luis F; Fardella, Carlos E; Kalergis, Alexis M

    2010-01-01

    Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8(+) T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-beta in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4(+) T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8(+) T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.

  3. Exercise-induced enhancement of immune function in the rat.

    Science.gov (United States)

    Kaufman, J C; Harris, T J; Higgins, J; Maisel, A S

    1994-07-01

    There have been many anecdotal reports that regular, moderate exercise confers some protective immunity against infection. There has been little scientific evidence to support this. It is also unclear whether training alters lymphocyte trafficking from the spleen to the periphery after a bout of exhaustive exercise. To determine the effect of moderate training on in vivo antibody production, using rats as an animal model, we gradually trained 18 rats using a swimming protocol for a 4-week period after injection and booster with Keyhole limpet hemocyanin antigen. There were 9 age-matched controls. At the conclusion of training, both groups underwent a short-term exhaustive swim. The trained group showed marked enhancement of IgM and IgG production. After short-term exercise, both groups had acute lymphocytosis, mainly T(suppressor)/cytolytic and natural killer cells with decreases in T(helper) (trained), B cells, and the Th-to-Ts ratio. The changes in the splenocyte subsets were the opposite of the changes in the peripheral blood. With respect to function, after exhaustive exercise, there was a slight increase in mitogenesis and interleukin-2 receptor expression to concanavalin A (untrained more than trained) compared with controls. Regular, moderate training enhances antibody production to specific de novo antigen both early and late. In addition, short-term exercise leads to selective release of immune cells from the spleen and results in slightly enhanced function of splenocytes. Direct stimulation by the sympathetic nervous system and catecholamines is the proposed mechanism for the changes seen after short-term exercise and possibly antibody production during training.

  4. Modulation of innate immune mechanisms to enhance vaccine induced immunity: Role of co-inhibitory molecules

    Directory of Open Access Journals (Sweden)

    Sreenivas eGannavaram

    2016-05-01

    Full Text Available No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several anti-leishmanial vaccine formulations have been tested in various animal models including genetically modified live attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells i.e., dendritic cells (DC and macrophages (M. Further, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs, and to condition the infected M towards anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of anti-microbial reactive oxygen, nitrogen molecules and pro-inflammatory cytokines such as IFN-, IL-12 and TNF-α. These early events limit the activation of TH1 effector cells and set the stage for pathogenesis. Further, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4+ and CD8+ T cells, and TH2 biased immunity that results in production of anti-inflammatory cytokines such as TGF-, and IL-10. More recent studies have also documented the induction of co-inhibitory ligands such as CTLA-4, PD-L1, CD200 and Tim-3 that induce exhaustion and/or non-proliferation in antigen experienced T cells. Most of these studies focus on viral infections in chronic phase thus limiting the direct application of these results from these studies to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine induced protective immunity can be modulated using strategies that enhance the co-stimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules such as PD-L1 and CD200. In this

  5. Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules.

    Science.gov (United States)

    Gannavaram, Sreenivas; Bhattacharya, Parna; Ismail, Nevien; Kaul, Amit; Singh, Rakesh; Nakhasi, Hira L

    2016-01-01

    No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4(+) and CD8(+) T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on

  6. Enhancement of anamnestic immunospecific antibody response in orally immunized chickens

    DEFF Research Database (Denmark)

    Mayo, Susan; Carlsson, Hans-Erik; Zagon, Andrea

    2008-01-01

    Production of immunospecific egg yolk antibodies (IgY antibodies) in egg laying hens through oral immunization is an attractive alternative to conventional antibody production in mammals for economic reasons as well as for animal welfare reasons. Oral immunization results in a systemic humoral...... of the immunization in week 18, demonstrating the presence of memory cells following the two initial oral immunizations. Considering that oral immunization results in approximately ten times lower concentrations of immunospecific antibodies in the egg yolk, compared to traditional subcutaneous immunization schemes...... response, but oral booster immunizations lack efficiency. The aim of the present study was to develop immunization schemes in which the concentration of immunospecific IgY would increase following oral booster immunizations. Two groups of egg laying hens (5 in each group) were immunized orally (each...

  7. Noise Immune Cavity Enhanced Optical Heterodyne Velocity Modulation Spectroscopy

    Science.gov (United States)

    Siller, Brian; Mills, Andrew; Porambo, Michael; McCall, Benjamin

    2011-06-01

    The technique of Cavity Enhanced Velocity Modulation Spectroscopy (CEVMS) has recently been developed. By demodulating the detector signal at twice the plasma modulation frequency (2f), the velocity-modulated ionic absorption signal can be extracted. Although the concentration-modulated excited neutral molecules are also observed at 2f, the ion and neutral signals can be distinguished and separated with phase-sensitive demodulation. The optical cavity provides two major benefits. It increases both the optical path length and the intracavity laser power by a factor of 2×Finesse/π. The multipass advantage allows for much longer path length than was previously possible with unidirectional multipass White cells. The power enhancement combined with perfectly overlapped counterpropagating beams within the cavity allows for sub-Doppler spectroscopy. Although CEVMS showed much potential, its sensitivity was ultimately limited by electronic noise from the plasma interfering with the cavity-locking electronics. We have further improved upon CEVMS by combining it with Noise Immune Cavity Enhanced Optical Heterodyne Molecular Spectroscopy (NICE-OHMS). The laser is frequency modulated at precisely an integer multiple of the free spectral range of the optical cavity; this allows the heterodyne sidebands to be coupled into the optical cavity. Heterodyne detection of the cavity leak-out is immune to noise in the laser-cavity lock, and 2f demodulation further decreases electronic noise in the system and retains ion-neutral discrimination. The additional level of modulation beyond ordinary CEVMS has the added advantage of enabling the observation of both absorption and dispersion signals simultaneously by using two RF mixers, each driving its own lock-in amplifier. In a single scan, four distinct signals can be obtained: absorption and dispersion for ions and excited neutrals. The technique has been demonstrated in the near-IR for N_2^+. B. M. Siller, A. A. Mills and B. J. Mc

  8. Natural killer cells enhance the immune surveillance of cancer

    OpenAIRE

    NOUROZ, FAISAL; Bibi, Farzana; Noreen, Shumaila; Masood, Nosheen

    2016-01-01

    Immune system (IS) is comprised of molecules, cells, tissues and organs involved in host defense mechanism from infectious agents or tumor cells. On crossing the cell barriers by these infectious agents, the defense mechanism is alerted by the immune system to respond against these invading microbes. Innate immune response (IIR) and acquired immune response (AIR) are working in parallel to control these invading microbes. IIR is composed of various types of phagocytes and lymphocytes, while A...

  9. Natural material adsorbed onto a polymer to enhance immune function

    Directory of Open Access Journals (Sweden)

    Reinaque AP

    2012-08-01

    Full Text Available Ana Paula Barcelos Reinaque,1 Eduardo Luzía França,2 Edson Fredulin Scherer,3 Mayra Aparecida Côrtes,1 Francisco José Dutra Souto,4 Adenilda Cristina Honorio-França51Post Graduate Program in Material Science, 2Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, 3Post Graduate Program in Material Science, Institute of Biological and Health Science, Federal University of Mato Grosso, Pontal do Araguaia, 4Faculty of Medical Sciences, Federal University of Mato Grosso, Cuiabá, 5Institute of Biological and Health Science, Federal University of Mato Grosso, Pontal do Araguaia, MT, BrazilBackground: In this study, we produced poly(ethylene glycol (PEG microspheres of different sizes and adsorbing a medicinal plant mixture, and verified their effect in vitro on the viability, superoxide production, and bactericidal activity of phagocytes in the blood.Methods: The medicinal plant mixture was adsorbed onto PEG microspheres and its effects were evaluated by flow cytometry and fluorescence microscopy.Results: Adsorption of the herbal mixture onto the PEG microspheres was achieved and the particles were internalized by phagocytes. PEG microspheres bearing the adsorbed herbal mixture stimulated superoxide release, and activated scavenging and microbicidal activity in phagocytes. No differences in functional activity were observed when the phagocytes were not incubated with PEG microspheres bearing the adsorbed herbal mixture.Conclusion: This system may be useful for the delivery of a variety of medicinal plants and can confer additional protection against infection. The data reported here suggest that a polymer adsorbed with a natural product is a treatment alternative for enhancing immune function.Keywords: natural product, polymer, adsorption, immune function, phagocytes

  10. Review: Natural killer cells enhance the immune surveillance of ...

    African Journals Online (AJOL)

    Immune system (IS) is comprised of molecules, cells, tissues and organs involved in host defense mechanism from infectious agents or tumor cells. On crossing the cell barriers by these infectious agents, the defense mechanism is alerted by the immune system to respond against these invading microbes. Innate immune ...

  11. Barriers to Immunizations and Strategies to Enhance Immunization Rates in Adults with Autoimmune Inflammatory Diseases.

    Science.gov (United States)

    Kirchner, Elizabeth; Ruffing, Victoria

    2017-02-01

    For as long as there have been immunizations, there have been barriers to them. Immunization rates in the United States are below target. Rheumatologists and rheumatology practitioners need to understand the issues of immunizations in patients with autoimmune inflammatory disease to identify and overcome barriers to immunization. Several strategies for overcoming these barriers are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Therapeutic enhancement of protective immunity during experimental leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Senad Divanovic

    2011-09-01

    Full Text Available Leishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4(+ T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx, a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4(+ T cells.We investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy.These data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline.

  13. Enhancing the Immune Response to Recombinant Plague Antigens

    Science.gov (United States)

    2007-05-01

    protection against rotavirus infection of mice stimulated by intranasal immunization with chimeric VP4 or VP6 protein. J Virol 1999;73(9):7574–81. [13] Choi...McNeal MM, Rae MN, Bean JA, Ward RL. Antibody-dependent and -independent protection following intranasal immunization of mice with rotavirus particles. J...Williamson ED, Sharp GJ, Eley SM, Vesey PM, Pepper TC, Titball RW, et al. Local and systemic immune response to a microencapsu- lated sub-unit vaccine for

  14. Probiotic Enhanced Intestinal Immunity in Broilers against Subclinical Necrotic Enteritis

    Directory of Open Access Journals (Sweden)

    Hesong Wang

    2017-11-01

    positively changing contents and/or mRNA expression levels of apoptosis-related proteins. These findings indicate that BS15 supplementation may prevent SNE-affected growth decline mainly through enhancing intestinal immunity in broilers.

  15. Probiotic Enhanced Intestinal Immunity in Broilers against Subclinical Necrotic Enteritis.

    Science.gov (United States)

    Wang, Hesong; Ni, Xueqin; Qing, Xiaodan; Liu, Lei; Lai, Jing; Khalique, Abdul; Li, Guangyao; Pan, Kangcheng; Jing, Bo; Zeng, Dong

    2017-01-01

    contents and/or mRNA expression levels of apoptosis-related proteins. These findings indicate that BS15 supplementation may prevent SNE-affected growth decline mainly through enhancing intestinal immunity in broilers.

  16. Dengue vaccine safety signal: Immune enhancement, waning immunity, or chance occurrence?

    Science.gov (United States)

    Gessner, Bradford D; Halsey, Neal

    2017-06-14

    A new dengue vaccine was associated with increased risk of hospitalized virologically-confirmed disease during year 3 of follow-up among children age 2-5years. Among hypotheses to explain this finding, we could not distinguish definitively between antibody dependent enhancement, waning immunity, or chance occurrence. However, any theory must account for the following: (a) the signal occurred mainly because of decreased dengue among controls rather than increased dengue among vaccinees; (b) among 48 data points, a statistically significant increase in hospitalization among vaccinated children occurred for only one age group, during one year, and in one region; (c) cumulative risk was similar for vaccinated vs. control children age 2-5years at the end of year 5 and lower for vaccinated vs. control children among older age groups; (d) the protective effect of vaccine against hospitalization decreased from years 1-2 to years 3-5 of follow-up for all age groups and regions. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. HIV-specific CD4+ T cells and viremia: who's in control?

    NARCIS (Netherlands)

    Jansen, Christine A.; van Baarle, Debbie; Miedema, Frank

    2006-01-01

    It has been proposed that HIV-specific CD4+ T cells with a central memory phenotype might be involved in controlling HIV replication. Based on recent data (lack of protective effects of HIV-specific CD4+ T-cell responses in acutely infected patients undergoing treatment interruptions; loss of

  18. Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection versus Immunopathology

    Directory of Open Access Journals (Sweden)

    Dhabhar Firdaus S

    2008-03-01

    Full Text Available It is widely believed that stress suppresses immune function and increases susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate allergic, autoimmune, and inflammatory diseases. These observations suggest that stress may have bidirectional effects on immune function, being immunosuppressive in some instances and immunoenhancing in others. It has recently been shown that in contrast to chronic stress that suppresses or dysregulates immune function, acute stress can be immunoenhancing. Acute stress enhances dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function and has been shown to augment innate and adaptive immune responses. Acute stress experienced prior to novel antigen exposure enhances innate immunity and memory T-cell formation and results in a significant and long-lasting immunoenhancement. Acute stress experienced during antigen reexposure enhances secondary/adaptive immune responses. Therefore, depending on the conditions of immune activation and the immunizing antigen, acute stress may enhance the acquisition and expression of immunoprotection or immunopathology. In contrast, chronic stress dysregulates innate and adaptive immune responses by changing the type 1-type 2 cytokine balance and suppresses immunity by decreasing leukocyte numbers, trafficking, and function. Chronic stress also increases susceptibility to skin cancer by suppressing type 1 cytokines and protective T cells while increasing suppressor T-cell function. We have suggested that the adaptive purpose of a physiologic stress response may be to promote survival, with stress hormones and neurotransmitters serving as beacons that prepare the immune system for potential challenges (eg, wounding or infection perceived by the brain (eg, detection of an attacker. However, this system may exacerbate immunopathology if the enhanced immune response is directed against innocuous or self-antigens or

  19. Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses

    DEFF Research Database (Denmark)

    Buggert, M.; Norström, M.; Lundegaard, Claus

    2011-01-01

    Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However......, the functional and immunodominant discrepancies of CD4+ T cell responses targeting promiscuous MHC II restricted HIV epitopes remains poorly defined. Thus, utilization of interdisciplinary approaches might aid revealing broadly- reactive peptides eliciting CD4 + T cell responses. Methods: We utilized the novel...... epitopes improved the polyfunctionality compared with overlapping HIV Gag (p55) peptides. Conclusion: Using an unbiased approach where we have predicted peptides with same prerequisites, we demonstrate that HIV-specific CD4 + T cell immunodominance is heavily skewed, targeting particularly Gag and Nef....

  20. Autologous Immune Enhancement Therapy for Cancer - Our experience since 2004

    Directory of Open Access Journals (Sweden)

    Hiroshi Terunuma

    2012-01-01

    Full Text Available Cancer, the major killer disease of the century requires a multi-pronged approach and among the latest modalities of treatments, Immunotherapy occupies a promising role. Immunotherapy for cancer was first started to be practised in the NIH and cell based immunotherapy for cancer is in practice for the past three decades. [1, 2] There are several literatures from various countries on the successful application of cell based Immunotherapies for various solid tumours and haematological malignancies. [3-8] Our team’s association with immune cells started when I was working on RNA transcriptome analysis to understand the immune system in HIV carriers which in turn required in vitro expansion of human Natural Killer (NK cells. [9] This led to the customization of protocols which has resulted in successful in vitro expansion, activation of NK cells and T cells for Immunotherapy. The purpose of Biotherapy institute of Japan (BIJ is to support research and clinical application of immune cells like NK cells, γδT cells, αβT cells, Cytotoxic T lymphocytes (CTL and Dendritic cells (DC for application as Autologous Immune Enhancement Therapy (AIET to fight against cancer. AIET using NK cells, CTLs, DCs etc have been administered for more than 5000 patients since 2004 till date by BIJ. Principle of AIET: For AIET using NK cells, the process involves separation of lymphocytes from the peripheral blood of the patient followed by selective NK cell expansion using the expansion kit (BINKIT, BIJ, JAPAN without feeder layers and then infusion of the expanded-activated NK cells. [10,11] As reports suggest that the activity of peripheral blood NK cells are lower in cancer patients compared to normal individuals [12] and as in vitro expansion of NK cells increases the cytotoxic ability 5 to 10 fold, [13] the NK cells are expanded in vivo and then infused to the patient in AIET. We are also working on combination immunotherapy using NK cells and CTLs and also NK

  1. Cross-infection enhancement among African flaviviruses by immune mouse ascitic fluids.

    Science.gov (United States)

    Fagbami, A H; Halstead, S B; Marchette, N J; Larsen, K

    1987-01-01

    Cross-infection enhancement of seven African flaviviruses by subneutralising concentrations of antibody in immune ascitic fluids was investigated in P388D1 cell culture. Infection by all the seven flaviviruses tested was enhanced by homologous and at least one of six heterologous immune mouse ascitic fluids (IMAF) tested. Enhancement ratios and enhancing antibody titres were higher in homologous than in heterologous enhancement. Zika, Wesselsbron, Uganda S and West Nile viruses were enhanced in culture by all the IMAF tested. Enhancement of Dakar bat and Yellow fever viruses was produced by five heterologous IMAF, but Potiskum virus was enhanced by one heterologous flavivirus antibody. The antibody to Potiskum virus was the most potent mediator of heterologous infection enhancement; all six heterologous flaviviruses were markedly enhanced by this antibody.

  2. Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines

    Energy Technology Data Exchange (ETDEWEB)

    Weir, Genevieve M. [Suite 411, 1344 Summer St., Immunovaccine Inc., Halifax, NS, B3H 0A8 (Canada); Room 11-L1, Sir Charles Tupper Building, Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS, B3H 1X5 (Canada); Liwski, Robert S. [Room 11-L1, Sir Charles Tupper Building, Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS, B3H 1X5 (Canada); Room 206E, Dr. D. J. Mackenzie Building, Department of Pathology, Dalhousie University, 5788 University Avenue, Halifax, NS, B3H 2Y9 (Canada); Mansour, Marc [Suite 411, 1344 Summer St., Immunovaccine Inc., Halifax, NS, B3H 0A8 (Canada)

    2011-08-05

    Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.

  3. Enhancement and abrogation : modifications of host immune status influence IL-2 and LAK cell immunotherapy

    NARCIS (Netherlands)

    E.P. Steller (Erick)

    1988-01-01

    textabstractThis thesis will discuss the role immune cells and the host immune system can play in enhancement and abrogation of this novel immunotherapy with interleukin 2 and lymphokine-activated killer cells. Chapter 3 and 4 will discuss the scoring methods in this intraperitoneal cancer and

  4. c-di-GMP enhances protective innate immunity in a murine model of pertussis.

    Directory of Open Access Journals (Sweden)

    Shokrollah Elahi

    Full Text Available Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.

  5. Adjuvant properties of thermal component of hyperthermia enhanced transdermal immunization: effect on dendritic cells.

    Directory of Open Access Journals (Sweden)

    Neha Joshi

    Full Text Available Hyperthermia enhanced transdermal (HET immunization is a novel needle free immunization strategy employing application of antigen along with mild local hyperthermia (42°C to intact skin resulting in detectable antigen specific Ig in serum. In the present study, we investigated the adjuvant effect of thermal component of HET immunization in terms of maturation of dendritic cells and its implication on the quality of the immune outcome in terms of antibody production upon HET immunization with tetanus toxoid (TT. We have shown that in vitro hyperthermia exposure at 42°C for 30 minutes up regulates the surface expression of maturation markers on bone marrow derived DCs. This observation correlated in vivo with an increased and accelerated expression of maturation markers on DCs in the draining lymph node upon HET immunization in mice. This effect was found to be independent of the antigen delivered and depends only on the thermal component of HET immunization. In vitro hyperthermia also led to enhanced capacity to stimulate CD4+ T cells in allo MLR and promotes the secretion of IL-10 by BMDCs, suggesting a potential for Th2 skewing of T cell response. HET immunization also induced a systemic T cell response to TT, as suggested by proliferation of splenocytes from immunized animal upon in vitro stimulation by TT. Exposure to heat during primary immunization led to generation of mainly IgG class of antibodies upon boosting, similar to the use of conventional alum adjuvant, thus highlighting the adjuvant potential of heat during HET immunization. Lastly, we have shown that mice immunized by tetanus toxoid using HET route exhibited protection against challenge with a lethal dose of tetanus toxin. Thus, in addition to being a painless, needle free delivery system it also has an immune modulatory potential.

  6. Immune-enhancing activity of extracellular polysaccharides isolated from Rhizopus nigricans.

    Science.gov (United States)

    Yu, Zhidan; Kong, Mengli; Zhang, Pengying; Sun, Qingjie; Chen, Kaoshan

    2016-09-05

    Extracellular polysaccharides (EPS1-1) was extracted from fermentation liquor of Rhizopus nigricans and evaluated its immune-enhancing activities in vitro and in vivo. Results suggested that the proliferation of lymphocyte was stimulated after treated with EPS1-1. Moreover, the activities of macrophages were enhanced by increasing the activities of phagocytosis and acid phosphatase, the production of NO and the mRNA levels of IL-2, TNF-α and iNOS. Furthermore, EPS1-1 could significantly boost the immunity of normal and immunosuppressed mice, which included the increase of loaded swimming time, footpad swelling, organ index and the secretion of IL-2 and TNF-α in serum, thus suggesting that EPS1-1 could improve the body immunity through cellular immunity and humoral immunity. These findings provided further insights into the potential use of EPS1-1 as immunopotentiator or new function food. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Natural killer cells enhance the immune surveillance of cancer

    African Journals Online (AJOL)

    Faisal Nouroz

    2015-09-11

    Sep 11, 2015 ... All the cells of the immune sys- tem cooperatively work against infectious agents and cancerous cells but Natural killer (NK) cells ..... Cancer stem cells (CSCs) retain the growth of tumor and resist chemotherapy [25]. ... radiation therapy and mushroom beta glucans showed only 1 nodule. The experiments ...

  8. Novel Strategies to Enhance Vaccine Immunity against Coccidioidomycosis

    Science.gov (United States)

    2013-12-19

    coccidioidal infection remain skin -test positive and likely acquire life-long immunity to the disease. Both clinical data and results of experimental...inner wall that can conjugate with EP67 via S4BHyNic linkers (succinimidyl-4- benzoylhydrazino- nicotinamide ). The concept is that the engineered

  9. Hemagglutinating virus of Japan envelope (HVJ-E) can enhance the immune responses of swine immunized with killed PRRSV vaccine

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Zhihong [State Key Laboratory of Agrobiotechnology, College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China); China Institute of Veterinary Drug Control, Beijing 100081 (China); Zhang, Quan [College of Veterinary Medicine, Yangzhou University, Yangzhou 225009 (China); Wang, Zaishi [China Institute of Veterinary Drug Control, Beijing 100081 (China); Zhang, Zhongqiu [State Key Laboratory of Agrobiotechnology, College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China); Veterinary Bureau, Ministry of Agriculture of the People' s Republic of China, Beijing 100125 (China); Guo, Pengju [Institute of Veterinary Medicine, Guangdong Academy of Agricultural Sciences, Guangdong 510640 (China); Zhao, Deming, E-mail: zhaodm@cau.edu.cn [State Key Laboratory of Agrobiotechnology, College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China)

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer We investigated the immunoadjuvant effects of HVJ-E on killed PRRSV vaccine. Black-Right-Pointing-Pointer HVJ-E enhanced the humoral and cellular responses of the piglets to PRRSV. Black-Right-Pointing-Pointer It is suggested that HVJ-E could be developed as a new-type adjuvant for mammals. -- Abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically detrimental pig pathogen that causes significant losses for the pig industry. The immunostimulatory effects of hemagglutinating virus of Japan envelope (HVJ-E) in cancer therapy and the adjuvant efficacy of HVJ-E have been previously evaluated. The objective of this study was to investigate the adjuvant effects of HVJ-E on immunization with killed PRRSV vaccine, and to evaluate the protective effects of this immunization strategy against virulent PRRSV infection in piglets. Next, the PRRSV-specific antibody response, lymphocyte proliferation, PRRSV-specific IL-2, IL-10 and IFN-{gamma} production, and the overall protection efficacy were evaluated to assess the immune responses of the piglets. The results showed that the piglets inoculated simultaneously with killed PRRSV vaccine and HVJ-E had a significantly stronger immune response than those inoculated with killed PRRSV vaccine alone. Our results suggest that HVJ-E could be employed as an effective adjuvant to enhance the humoral and cellular responses of piglets to PRRSV.

  10. Enhancement of Immune Memory Responses to Respiratory Infection

    Science.gov (United States)

    2017-08-01

    epigenetic mechanisms in the regulation of autophagy gene expression in healthy donors. Completion of these studies will provide novel insights into...induction of highly specific B and T cell responses against viral infections. Despite recent progress in vaccine development, the molecular mechanisms ...BMI 31±8 36±5 The purpose of this application is to find mechanisms that could improve B cell mediated immune response to influenza. This

  11. Stimulation of dendritic cells enhances immune response after photodynamic therapy

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

    2009-02-01

    Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

  12. Jungle Honey Enhances Immune Function and Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Miki Fukuda

    2011-01-01

    Full Text Available Jungle honey (JH is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal. After seven injections, peritoneal cells (PC were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2 cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261.

  13. Immunization

    Science.gov (United States)

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  14. Parasites suppress immune-enhancing effect of methionine in nestling great tits.

    Science.gov (United States)

    Wegmann, Michèle; Voegeli, Beatrice; Richner, Heinz

    2015-01-01

    After birth, an organism needs to invest both in somatic growth and in the development of efficient immune functions to counter the effects of pathogens, and hence an investment trade-off is predicted. To explore this trade-off, we simultaneously exposed nestling great tits (Parus major) to a common ectoparasite, while stimulating immune function. Using a 2 × 2 experimental design, we first infested half of the nests with hen fleas (Ceratophyllus gallinae) on day 3 post-hatch and later, on day 9-13 post-hatch, and then supplemented half of the nestlings within each nest with an immuno-enhancing amino acid (methionine). We then assessed the non-specific immune response by measuring both the inflammatory response to a lipopolysaccharide (LPS) and assessing the levels of acute phase proteins (APP). In parasite-infested nestlings, methionine had a negative effect on body mass close to fledging. Methionine had an immune-enhancing effect in the absence of ectoparasites only. The inflammatory response to LPS was significantly lower in nestlings infested with fleas and was also lower in nestlings supplemented with methionine. These patterns of immune responses suggest an immunosuppressive effect of ectoparasites that could neutralise the immune-enhancing effect of methionine. Our study thus suggests that the trade-off between investment in life history traits and immune function is only partly dependent on available resources, but shows that parasites may influence this trade-off in a more complex way, by also inhibiting important physiological functions.

  15. Immunizations

    Science.gov (United States)

    ... Why Exercise Is Wise Are Detox Diets Safe? Immunizations KidsHealth > For Teens > Immunizations Print A A A What's in this article? ... fault if you don't have all the immunizations (vaccinations) you need. Shots that doctors recommend today ...

  16. Crosstalk between immune cell and oncolytic vaccinia therapy enhances tumor trafficking and antitumor effects.

    Science.gov (United States)

    Sampath, Padma; Li, Jun; Hou, Weizhou; Chen, Hannah; Bartlett, David L; Thorne, Steve H

    2013-03-01

    The combination of an oncolytic virus, that directly destroys tumor cells and mediates an acute immune response, with an immune cell therapy, capable of further enlisting and enhancing the host immune response, has the potential to create a potent therapeutic effect. We have previously developed several strategies for optimizing the delivery of oncolytic vaccinia virus vectors to their tumor targets, including the use of immune cell-based carrier vehicles and the incorporation of mutations that increase production of the enveloped form of vaccinia (extracellular enveloped viral (EEV)) that is better adapted to spread within a host. Here, we initially combine these approaches to create a novel therapeutic, consisting of an immune cell (cytokine-induced killer, CIK) preloaded with an oncolytic virus that is EEV enhanced. This resulted in direct interaction between the viral and immune cell components with each assisting the other in directing the therapy to the tumor and so enhancing the antitumor effects. This effect could be further improved through CCL5 expression from the virus. The resulting multicomponent therapy displays the ability for synergistic crosstalk between components, so significantly enhancing tumor trafficking and antitumor effects.

  17. Improving vaccine registries through mobile technologies: a vision for mobile enhanced Immunization information systems.

    Science.gov (United States)

    Wilson, Kumanan; Atkinson, Katherine M; Deeks, Shelley L; Crowcroft, Natasha S

    2016-01-01

    Immunization registries or information systems are critical to improving the quality and evaluating the ongoing success of immunization programs. However, the completeness of these systems is challenged by a myriad of factors including the fragmentation of vaccine administration, increasing mobility of individuals, new vaccine development, use of multiple products, and increasingly frequent changes in recommendations. Mobile technologies could offer a solution, which mitigates some of these challenges. Engaging individuals to have more control of their own immunization information using their mobile devices could improve the timeliness and accuracy of data in central immunization information systems. Other opportunities presented by mobile technologies that could be exploited to improve immunization information systems include mobile reporting of adverse events following immunization, the capacity to scan 2D barcodes, and enabling bidirectional communication between individuals and public health officials. Challenges to utilizing mobile solutions include ensuring privacy of data, access, and equity concerns, obtaining consent and ensuring adoption of technology at sufficiently high rates. By empowering individuals with their own health information, mobile technologies can also serve as a mechanism to transfer immunization information as individuals cross local, regional, and national borders. Ultimately, mobile enhanced immunization information systems can help realize the goal of the individual, the healthcare provider, and public health officials always having access to the same immunization information. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. STAT6 Deletion Enhances Immunity to Mammary Carcinoma

    Science.gov (United States)

    2005-06-01

    diabetes in D.G. Quiiceno, J. B. choa, and A. C. Ochoa. 2003. L-Arginine consumption by neonatal mice. J. hinininol. 157:978. 17. Ho, W. Y., M. P. Cooke...bottomed plates with 5 X 10’ DOI 1.10 T cells, the is 1 o indicated number of DCs, and 10 ).g ovalbumin (Sigma) orl p.g ova peptide 0 is o 323-339...CD4+CD25’ immnoregulatory T cells that control autoimmune diabetes . In- munit., 12:431. immunity to 4T1 (Clements and Ostrand-Rosenberg, unpublished

  19. Hemagglutinating virus of Japan envelope (HVJ-E) can enhance the immune responses of swine immunized with killed PRRSV vaccine.

    Science.gov (United States)

    Dai, Zhihong; Zhang, Quan; Wang, Zaishi; Zhang, Zhongqiu; Guo, Pengju; Zhao, Deming

    2011-11-11

    Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically detrimental pig pathogen that causes significant losses for the pig industry. The immunostimulatory effects of hemagglutinating virus of Japan envelope (HVJ-E) in cancer therapy and the adjuvant efficacy of HVJ-E have been previously evaluated. The objective of this study was to investigate the adjuvant effects of HVJ-E on immunization with killed PRRSV vaccine, and to evaluate the protective effects of this immunization strategy against virulent PRRSV infection in piglets. Next, the PRRSV-specific antibody response, lymphocyte proliferation, PRRSV-specific IL-2, IL-10 and IFN-γ production, and the overall protection efficacy were evaluated to assess the immune responses of the piglets. The results showed that the piglets inoculated simultaneously with killed PRRSV vaccine and HVJ-E had a significantly stronger immune response than those inoculated with killed PRRSV vaccine alone. Our results suggest that HVJ-E could be employed as an effective adjuvant to enhance the humoral and cellular responses of piglets to PRRSV. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Oral antibiotics enhance antibody responses to keyhole limpet hemocyanin in orally but not muscularly immunized chickens.

    Science.gov (United States)

    Murai, Atsushi; Kitahara, Kazuki; Okumura, Shouta; Kobayashi, Misato; Horio, Fumihiko

    2016-02-01

    Recent studies have emphasized the crucial role of gut microbiota in triggering and modulating immune response. We aimed to determine whether the modification of gut microbiota by oral co-administration of two antibiotics, ampicillin and neomycin, would lead to changes in the antibody response to antigens in chickens. Neonatal chickens were given or not given ampicillin and neomycin (0.25 and 0.5 g/L, respectively) in drinking water. At 2 weeks of age, the chicks were muscularly or orally immunized with antigenic keyhole limpet hemocyanin (KLH), and then serum anti-KLH antibody levels were examined by ELISA. In orally immunized chicks, oral antibiotics treatment enhanced antibody responses (IgM, IgA, IgY) by 2-3-fold compared with the antibiotics-free control, while the antibiotics did not enhance antibody responses in the muscularly immunized chicks. Concomitant with their enhancement of antibody responses, the oral antibiotics also lowered the Lactobacillus species in feces. Low doses of antibiotics (10-fold and 100-fold lower than the initial trial), which failed to change the fecal Lactobacillus population, did not modify any antibody responses when chicks were orally immunized with KLH. In conclusion, oral antibiotics treatment enhanced the antibody response to orally exposed antigens in chickens. This enhancement of antibody response was associated with a modification of the fecal Lactobacillus content, suggesting a possible link between gut microbiota and antibody response in chickens. © 2015 Japanese Society of Animal Science.

  1. Transdermal delivery of plasmid encoding truncated nucleocapsid protein enhanced PRRSV-specific immune responses.

    Science.gov (United States)

    Suradhat, Sanipa; Wongyanin, Piya; Sirisereewan, Chaitawat; Nedumpun, Teerawut; Lumyai, Mongkol; Triyarach, Sittikorn; Chaturavittawong, Damnoen; Paphavasit, Termsit; Panyatong, Raphee; Thanawongnuwech, Roongroje

    2016-01-27

    Porcine Reproductive and Respiratory Syndrome virus (PRRSV) induces several immunomodulatory mechanisms that resulted in delayed and ineffective anti-viral immune responses. Recently, it has been shown that intradermal immunization of plasmid encoding truncated nucleocapsid protein (pORF7t) could reduce PRRSV-induced immunomodulatory activities and enhances anti-PRRSV immunity in vaccinated pigs. However, intradermal immunization may not be practical for farm setting. Currently, there are several transdermal delivery systems available in the market, although they were not originally designed for plasmid delivery. To investigate the potential use of a transdermal delivery system for delivering of pORF7t and its immunological outcomes. The immunomodulatory effects induced by transdermal delivery of pORF7t were compared with intradermal immunization in an experimental pig model. In addition, immunomodulatory effects of the DNA vaccine were determined in the fattening pigs kept in a PRRSV-positive farm environment, and in the experimental pigs receiving heterologous prime-boost, pORF7t-modified live vaccine (MLV) immunization. The patterns of PRRSV-specific cellular responses induced by transdermal and intradermal immunizations of pORF7t were similar. Interestingly, the pigs transdermally immunized with pORF7t exhibited higher number of PRRSV-specific CD8(+)IFN-γ(+) cells. Pigs immunized with pORF7t and kept at PRRSV-positive environment exhibited enhanced PRRSV-specific IFN-γ(+) production, reduced numbers of regulatory T lymphocytes (Tregs) and lower lung scores at the end of the finishing period. In the heterologous prime-boost experiment, priming with pORF7t prior to MLV vaccination resulted in significantly higher numbers of CD3(+)IFN-γ(+) subpopulations, lower numbers of PRRSV-specific CD3(+)IL-10(+) cells and Tregs, and rapid antibody responses in immunized pigs. Transdermal immunization with pORF7t reduced PRRRSV-induced immunomodulatory effects and enhanced

  2. The immune enhancer, thymoquinone, and the hope of utilizing the ...

    African Journals Online (AJOL)

    USER

    2010-05-24

    May 24, 2010 ... thymoquinone enhanced the humoral activity against B. cereus but not against B. thuringiensis. On the other hand ... quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, which showed a relatively higher ... Insect haemolymph contains a number of proteins, which are involved in ...

  3. Merck Ad5/HIV induces broad innate immune activation that predicts CD8⁺ T-cell responses but is attenuated by preexisting Ad5 immunity.

    Science.gov (United States)

    Zak, Daniel E; Andersen-Nissen, Erica; Peterson, Eric R; Sato, Alicia; Hamilton, M Kristina; Borgerding, Joleen; Krishnamurty, Akshay T; Chang, Joanne T; Adams, Devin J; Hensley, Tiffany R; Salter, Alexander I; Morgan, Cecilia A; Duerr, Ann C; De Rosa, Stephen C; Aderem, Alan; McElrath, M Juliana

    2012-12-11

    To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

  4. Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity.

    Directory of Open Access Journals (Sweden)

    David Aebischer

    Full Text Available Contact hypersensitivity (CHS induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC migration to draining lymph nodes (dLNs. On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40 and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function.

  5. ‘Trans-generational immune priming’: specific enhancement of the antimicrobial immune response in the mealworm beetle, Tenebrio molitor

    Science.gov (United States)

    Moret, Yannick

    2006-01-01

    Encounters with parasites and pathogens are often unpredictable in time. However, experience of an infection may provide the host with reliable cues about the future risk of infection for the host itself or for its progeny. If the parental environment predicts the quality of the progeny's environment, then parents may further enhance their net reproductive success by differentially providing their offspring with phenotypes to cope with potential hazards such as pathogen infection. Here, I test for the occurrence of such an adaptive transgenerational phenotypic plasticity in the mealworm beetle, Tenebrio molitor. A pathogenic environment was mimicked by injection of bacterial lipopolysaccharides for two generations of insects. I found that parental challenge enhanced offspring immunity through the inducible production of antimicrobial peptides in the haemolymph. PMID:16777729

  6. Helminth Protein Vaccine Induced Follicular T Helper Cell for Enhancement of Humoral Immunity against Schistosoma japonicum

    Directory of Open Access Journals (Sweden)

    Jingyao Zhang

    2013-01-01

    Full Text Available Protein vaccines combined with adjuvants have been widely used to induce immune responses, especially the humoral immune response, against molecular targets including parasites. Follicular T helper (Tfh cells are the specialized providers of B-cell help, however, the induction of Tfh cells in protein vaccination has been rarely studied. Here, we report that the Schistosoma japonicum recombinant protein (SjGST-32 combined with tacrolimus (FK506 augmented the induction of Tfh cells, which expressed the canonical markers CXCR5, BCL6, and IL-21, and enhanced the humoral immune responses in BALB/c mice. Furthermore, the expression of IL-21R on germinal center (GC B cells and memory B cells increased in immunized mice, which indicated that IL-21 from the induced Tfh cells interacted with IL-21R for activation of B cells and maintenance of long-lived humoral immunity. Our results suggest that helminth protein vaccine combined with FK506 induces Tfh cell for stimulating humoral immune responses and inducing long-lived humoral immunity.

  7. Vaccination Enhances Early Immune Responses in White Shrimp Litopenaeus vannamei after Secondary Exposure to Vibrio alginolyticus

    Science.gov (United States)

    Lin, Yong-Chin; Chen, Jiann-Chu; Morni, Wan Zabidii W.; Putra, Dedi Fazriansyah; Huang, Chien-Lun; Li, Chang-Che; Hsieh, Jen-Fang

    2013-01-01

    Background Recent work suggested that the presence of specific memory or some form of adaptive immunity occurs in insects and shrimp. Hypervariable pattern recognition molecules, known as Down syndrome cell adhesion molecules, are able to mount specific recognition, and immune priming in invertebrates. In the present study, we attempted to understand the immune response pattern of white shrimp Litopenaeus vannamei which received primary (PE) and secondary exposure (SE) to Vibrio alginolyticus. Methodology Immune parameters and proliferation of haematopoietic tissues (HPTs) of shrimp which had received PE and SE to V. alginolyticus were measured. In the PE trial, the immune parameters and proliferation of HPTs of shrimp that received heat-killed V. alginolyticus (HVa) and formalin-inactivated V. alginolyticus (FVa) were measured. Mortality, immune parameters and proliferation of HPTs of 7-day-HVa-PE shrimp (shrimp that received primary exposure to HVa after 7 days) and 7-day-FVa-PE shrimp (shrimp that received primary exposure to FVa after 7 days) following SE to live V. alginolyticus (LVa) were measured. Phagocytic activity and clearance efficiency were examined for the 7∼35-day-HVa-PE and FVa-PE shrimp. Results HVa-receiving shrimp showed an earlier increase in the immune response on day 1, whereas FVa-receiving shrimp showed a late increase in the immune response on day 5. The 7-day-FVa-PE shrimp showed enhancement of immunity when encountering SE to LVa, whereas 7-day-HVa-PE shrimp showed a minor enhancement in immunity. 7-day-FVa-PE shrimp showed higher proliferation and an HPT mitotic index. Both phagocytic activity and clearance maintained higher for both HVa-PE and FVa-PE shrimp after 28 days. Conclusions HVa- and FVa-receiving shrimp showed the bacteria agglutinated prior to being phagocytised. FVa functions as a vaccine, whereas HVa functions as an inducer and can be used as an immune adjuvant. A combined mixture of FVa and HVa can serve as a

  8. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.

    Science.gov (United States)

    Fulci, Giulia; Breymann, Laura; Gianni, Davide; Kurozomi, Kazuhiko; Rhee, Sarah S; Yu, Jianhua; Kaur, Balveen; Louis, David N; Weissleder, Ralph; Caligiuri, Michael A; Chiocca, E Antonio

    2006-08-22

    Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68+ and CD163+ cells and intratumoral IFN-gamma. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.

  9. Antibiotic Treatment Suppresses Rotavirus Infection and Enhances Specific Humoral Immunity

    Science.gov (United States)

    Uchiyama, Robin; Chassaing, Benoit; Zhang, Benyue; Gewirtz, Andrew T.

    2014-01-01

    Background. Rotavirus causes 500 000 deaths and millions of physician visits and hospitalizations per year, with worse outcomes and reduced vaccine efficacy in developing countries. We hypothesized that the gut microbiota might modulate rotavirus infection and/or antibody response and thus potentially play a role in such regional differences. Methods. The microbiota was ablated via germ-free or antibiotic approaches. Enhanced exposure to microbiota was achieved via low-dose dextran sodium sulfate (DSS) treatment. Rotavirus infection and replication was assessed by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcription polymerase chain reaction. Diarrhea was scored visually. Humoral responses to rotavirus were measured by ELISA and enzyme-linked immunosorbent spot assay. Results. Microbiota elimination delayed infection and reduced infectivity by 42%. Antibiotics did not alter ratios of positive-sense to negative-sense strands, suggesting that entry rather than replication was influenced. Antibiotics reduced the diarrhea incidence and duration, indicating that the reduction in the level of rotavirus antigen was biologically significant. Despite lowered antigen level, antibiotics resulted in a more durable rotavirus mucosal/systemic humoral response. Increased rotavirus antibody response durability correlated with increased small intestinal rotavirus-specific, immunoglobulin A–producing antibody-secreting cell concentration in antibiotic-treated mice. Conversely, DSS treatment impaired generation of rotavirus-specific antibodies. Conclusions. Microbiota ablation resulted in reduced rotavirus infection/diarrhea and a more durable rotavirus antibody response, suggesting that antibiotic administration before rotavirus vaccination could raise low seroconversion rates that correlate with the vaccine's inefficacy in developing regions. PMID:24436449

  10. Lack of microbiota reduces innate responses and enhances adaptive immunity against Listeria monocytogenes infection.

    Science.gov (United States)

    Mittrücker, Hans-Willi; Seidel, Daniel; Bland, Paul W; Zarzycka, Agnieszka; Kaufmann, Stefan H E; Visekruna, Alexander; Steinhoff, Ulrich

    2014-06-01

    The intestinal microbiota influences not only metabolic processes, but also the mucosal and systemic immune systems. Here, we compare innate and adaptive immune responses against the intracellular pathogen Listeria monocytogenes in germfree (GF) and conventional mice. We show that animals without endogenous microbiota are highly susceptible to primary infection with impaired activation and accumulation of phagocytes to the site of infection. Unexpectedly, secondary infection with otherwise lethal dose resulted in survival of all GF animals which cleared bacteria more rapidly and developed a stronger antilisterial CD8(+) memory T-cell response compared to conventional mice. In summary, lack of the intestinal microbiota impairs early innate immunity, but enhances activation and expansion of memory T cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Enhancing immunomodulation on innate immunity by shape transition among RNA triangle, square and pentagon nanovehicles

    Science.gov (United States)

    Khisamutdinov, Emil F.; Li, Hui; Jasinski, Daniel L.; Chen, Jiao; Fu, Jian; Guo, Peixuan

    2014-01-01

    Modulation of immune response is important in cancer immunotherapy, vaccine adjuvant development and inflammatory or immune disease therapy. Here we report the development of new immunomodulators via control of shape transition among RNA triangle, square and pentagon. Changing one RNA strand in polygons automatically induced the stretching of the interior angle from 60° to 90° or 108°, resulting in self-assembly of elegant RNA triangles, squares and pentagons. When immunological adjuvants were incorporated, their immunomodulation effect for cytokine TNF-α and IL-6 induction was greatly enhanced in vitro and in animals up to 100-fold, while RNA polygon controls induced unnoticeable effect. The RNA nanoparticles were delivered to macrophages specifically. The degree of immunostimulation greatly depended on the size, shape and number of the payload per nanoparticles. Stronger immune response was observed when the number of adjuvants per polygon was increased, demonstrating the advantage of shape transition from triangle to pentagon. PMID:25092921

  12. Immune response and insulin signalling alter mosquito feeding behaviour to enhance malaria transmission potential.

    Science.gov (United States)

    Cator, Lauren J; Pietri, Jose E; Murdock, Courtney C; Ohm, Johanna R; Lewis, Edwin E; Read, Andrew F; Luckhart, Shirley; Thomas, Matthew B

    2015-07-08

    Malaria parasites alter mosquito feeding behaviour in a way that enhances parasite transmission. This is widely considered a prime example of manipulation of host behaviour to increase onward transmission, but transient immune challenge in the absence of parasites can induce the same behavioural phenotype. Here, we show that alterations in feeding behaviour depend on the timing and dose of immune challenge relative to blood ingestion and that these changes are functionally linked to changes in insulin signalling in the mosquito gut. These results suggest that altered phenotypes derive from insulin signalling-dependent host resource allocation among immunity, blood feeding, and reproduction in a manner that is not specific to malaria parasite infection. We measured large increases in mosquito survival and subsequent transmission potential when feeding patterns are altered. Leveraging these changes in physiology, behaviour and life history could promote effective and sustainable control of female mosquitoes responsible for transmission.

  13. Strategies to enhance immune function for marathon runners : what can be done?

    DEFF Research Database (Denmark)

    Åkerström, Thorbjörn; Pedersen, Bente K

    2007-01-01

    Marathoners are at an increased risk of developing upper respiratory tract infections (URTIs) following races and periods of hard training, which are associated with temporary changes in the immune system. The majority of the reported changes are decreases in function or concentration of certain...... function and reduce the risk of URTIs have been sought. This paper focuses on the effect of glutamine, vitamin C, bovine colostrum and glucose. Although, some of these supplements can affect the physiological and immune changes associated with marathon racing, none of the supplements discussed have...... consistently been shown to reduce the risk of URTIs and therefore cannot be recommended for use as enhancers of immune function in marathon runners....

  14. The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin β7 but not CCR6 and regulated by retinoic acid.

    Directory of Open Access Journals (Sweden)

    Vanessa Sue Wacleche

    Full Text Available CD4(+ T-cells from gut-associated lymphoid tissues (GALT are major targets for HIV-1 infection. Recruitment of excess effector CD8(+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8(+ and CD4(+ T-cells into the GALT and explored the role of retinoic acid (RA in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a "signature" for HIV-specific but not CMV-specific CD4(+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8(+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4(+ versus CD8(+ T-cells. All trans RA (ATRA upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8(+ T-cells may colocalize in excess with CD4(+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6(+CD4(+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8(+ T-cells to migrate in the vicinity of CCR6(+CD4(+ T-cells may facilitate HIV replication and dissemination at mucosal sites.

  15. A gold-nanoparticle-enhanced immune sensor based on fiber optic interferometry

    Science.gov (United States)

    Tseng, Yuan-Tai; Chuang, Yun-Ju; Wu, Yi-Chien; Yang, Chung-Shi; Wang, Mu-Chun; Tseng, Fan-Gang

    2008-08-01

    A method using gold nanoparticles (GNPs) to enhance fiber optic interferometry (GNPFOI) for immune-sensing is reported in this paper. It is suggested that an enlarged index mismatch and an elongated optical path by GNPs conjugated on recognition proteins will contribute most to signal enhancement in the interference fringe shift. Theoretical and experimental results show that the interference fringe shift is linearly related to both the amount and size of the GNPs binding on the sensor surface. The detected signal for 30 nm GNPs can reach a lowest detection limit of 18 pM (1010 particles ml-1). Immune-sensing for rabbit IgG as the antigen to anti-rabbit IgG has been demonstrated and a detection cycle has been completed by elution buffer for surface regeneration. The repeatability of the immune-sensing on one GNPFOI sensor has also been verified by three identical cycles, and the detection limit for 13 nm GNPs conjugated anti-rabbit IgG reaches 0.17 nM (~25.5 ng ml-1). The sensory mechanism has the potential to be engineered on the tip of a needle-type micro-device, which would allow it to monitor immune recognition signals in the future.

  16. Implantable silk composite microneedles for programmable vaccine release kinetics and enhanced immunogenicity in transcutaneous immunization.

    Science.gov (United States)

    DeMuth, Peter C; Min, Younjin; Irvine, Darrell J; Hammond, Paula T

    2014-01-01

    Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local inflammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profiles present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1-2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in >10-fold increases in antigen-specific T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Implantable silk composite microneedles for programmable vaccine release kinetics and enhanced immunogenicity in transcutaneous immunization

    Science.gov (United States)

    Irvine, Darrell J.; Hammond, Paula T.

    2014-01-01

    Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local inflammatory responses in the skin, which are correlated with enhanced immune responses. Here we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profiles present during natural acute infections. We report an approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1-2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in >10-fold increases in antigen-specific T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. PMID:23847143

  18. Cationic amino acid transporter 2 enhances innate immunity during Helicobacter pylori infection.

    Directory of Open Access Journals (Sweden)

    Daniel P Barry

    Full Text Available Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2 is essential for transport of L-arginine (L-Arg into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO produced from inducible NO synthase (iNOS, or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2(-/- mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2(-/- mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2(-/- mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection.

  19. A Cross-Reactive Monoclonal Antibody to Nematode Haemoglobin Enhances Protective Immune Responses to Nippostrongylus brasiliensis

    Science.gov (United States)

    Nieuwenhuizen, Natalie E.; Meter, Jeanne M.; Horsnell, William G.; Hoving, J. Claire; Fick, Lizette; Sharp, Michael F.; Darby, Matthew G.; Parihar, Suraj P.; Brombacher, Frank; Lopata, Andreas L.

    2013-01-01

    Background Nematode secreted haemoglobins have unusually high affinity for oxygen and possess nitric oxide deoxygenase, and catalase activity thought to be important in protection against host immune responses to infection. In this study, we generated a monoclonal antibody (48Eg) against haemoglobin of the nematode Anisakis pegreffii, and aimed to characterize cross-reactivity of 4E8g against haemoglobins of different nematodes and its potential to mediate protective immunity against a murine hookworm infection. Methodology/Principal Findings Immunoprecipitation was used to isolate the 4E8g-binding antigen in Anisakis and Ascaris extracts, which were identified as haemoglobins by peptide mass fingerprinting and MS/MS. Immunological cross-reactivity was also demonstrated with haemoglobin of the rodent hookworm N. brasiliensis. Immunogenicity of nematode haemoglobin in mice and humans was tested by immunoblotting. Anisakis haemoglobin was recognized by IgG and IgE antibodies of Anisakis-infected mice, while Ascaris haemoglobin was recognized by IgG but not IgE antibodies in mouse and human sera. Sequencing of Anisakis haemoglobin revealed high similarity to haemoglobin of a related marine nematode, Psuedoterranova decipiens, which lacks the four –HKEE repeats of Ascaris haemoglobin important in octamer assembly. The localization of haemoglobin in the different parasites was examined by immunohistochemistry and associated with the excretory-secretary ducts in Anisakis, Ascaris and N. brasiliensis. Anisakis haemoglobin was strongly expressed in the L3 stage, unlike Ascaris haemoglobin, which is reportedly mainly expressed in adult worms. Passive immunization of mice with 4E8g prior to infection with N. brasiliensis enhanced protective Th2 immunity and led to a significant decrease in worm burdens. Conclusion The monoclonal antibody 4E8g targets haemoglobin in broadly equivalent anatomical locations in parasitic nematodes and enhances host immunity to a hookworm

  20. Supplementation transgenic cow's milk containing recombinant human lactoferrin enhances systematic and intestinal immune responses in piglets.

    Science.gov (United States)

    Li, Qiuling; Hu, Wenping; Zhao, Jie; Wang, Jianwu; Dai, Yunping; Zhao, Yaofeng; Meng, Qingyong; Li, Ning

    2014-01-01

    Lactoferrin (LF) plays an important role in the body's immune system. However, the immunomodulatory effects of supplementation transgenic cow's milk containing recombinant human LF (rhLF) on the systemic and intestinal immune systems in infants remain unclear. Our laboratory has used genetic engineer to produce transgenic cow secreted rhLF. To assess the immune responses we took piglets as an animal model for infants. Eighteen piglets at 7 days of age were fed ordinary milk, 1:1 mix of ordinary and rhLF milk, or rhLF milk (LFM) for 30 days. The incidence of diarrhea in piglets in natural condition was observed. The protein abundances of immunoglobulin (Ig)G, IgA, IgM, IgE, histamine, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12 interferon, tumor necrosis factor in the plasma, spleen or intestine were measured by enzyme-linked immunosorbent assay. Intestinal structure was assessed by hematoxylin and eosin. The mRNA levels of immune and allergy-related genes were measured by quantitative reverse transcription-polymerase chain reaction. The results showed that LFM-fed significantly reduced incidence of diarrhea, enhanced humoral immunity, T helper (Th) 1, and Th2 cell responses, improved the structure of the intestinal mucosal and did not induce food allergy. LFM increased mRNA levels of toll-like receptor 2 and nuclear factor-κB p65 and decreased that of FCεRI β. In conclusion, rhLF-enriched formula could improve systematic and intestinal immune responses and did not elicit food allergies in neonatal piglets.

  1. Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin.

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    Rachael J Borg

    Full Text Available Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells - a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

  2. Camellia sinensis Mediated Enhancement of Humoral Immunity to Particulate and Non-particulate Antigens.

    Science.gov (United States)

    Khan, Adnan; Ali, Nafisa Hassan; Santercole, Viviana; Paglietti, Bianca; Rubino, Salvatore; Kazmi, Shahana Urooj; Farooqui, Amber

    2016-01-01

    The most common drinking beverage in large portion of the world is Camellia sinensis (green tea). In the present study, we evaluated the adjuvant effect of green tea and tea polyphenols to particulate and non-particulate antigens. BALB/c mice were immunized with particulate and non-particulate antigens. Modulation of immunoglobulin-secreting splenocytes, IgG-mediated and IgM-mediated immunity, was evaluated by hemolytic plaque assay and enzyme-linked immunosorbent assay, respectively. Dose-dependent response of tea polyphenols was also assayed. Phenolic content was measured in crude preparations of green tea. We observed a stimulatory effect of green tea preparations on humoral immune response mediated by the increased number of antibody-secreted cells in spleen. A significant increase in IgM-mediated and IgG-mediated immune response to non-particulate antigen was also observed in green tea-treated animals. A dose-dependent adjuvant effect was seen in the case of tea polyphenols for a longer period of time compared with crude tea preparations. This study indicates polyphenols as major constituents responsible for the enhanced and sustained adjuvant activity of green tea. We suggest that tea polyphenols might be considered for real-life evaluation during adjuvant-mediated vaccination trial programs. Copyright © 2015 John Wiley & Sons, Ltd.

  3. Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages.

    Science.gov (United States)

    Jang, Hyo-Eun; Mok, Hyejung

    2016-11-01

    Polydopamine-coated porous microsphere (PPM) is investigated as a simple and versatile immobilization strategy for immune-stimulating biomolecules to enhance delivery efficiency and immune-stimulating effects such as cytokine induction in macrophages. The PPMs, with diameters of about 2 μm, exhibit simultaneous and efficient incorporation of biomolecules (nucleotides and proteins), which is comparable to that achieved using microspheres carrying biomolecules internally by virtue of their porous structure. Ovalbumin-conjugated PPMs are internalized into macrophages efficiently and selectively via the phagocytic pathway, without any noticeable toxicity. Internalized CpG oligodeoxynucleotide (ODN)-conjugated PPMs (PPM-CpG) greatly enhance the induction of selected cytokines (TNF-α and IL-6) in RAW 264.7 cells compared to that by the soluble CpG ODN and ionic complexes. Therefore, PPMs generated in this study may serve as effective carriers of immune-stimulating biomolecules such as diverse toll-like receptor agonists. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes

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    Halstead, Scott B; Mahalingam, Prof Suresh; Marovich, Mary A; Ubol, Sukathida; Mosser, Prof David M

    2011-01-01

    A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fcγ-receptor signalling. The activation of Fcγ receptors usually leads to phagocytosis. Paradoxically, the ligation of monocyte or macrophage Fcγ receptors by IgG immune complexes, rather than aiding host defences, can suppress innate immunity, increase production of interleukin 10, and bias T-helper-1 (Th1) responses to Th2 responses, leading to increased infectious output by infected cells. This intrinsic antibody-dependent enhancement (ADE) of infection modulates the severity of diseases as disparate as dengue haemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fcγ receptors by infectious immune complexes. PMID:20883967

  5. Targeting and retention of HPV16 E7 to the endoplasmic reticulum enhances immune tumour protection

    Science.gov (United States)

    Loera-Arias, MJ; Martínez-Pérez, AG; Barrera-Hernández, A; Ibarra-Obregón, ER; González-Saldívar, G; Martínez-Ortega, JI; Rosas-Taraco, A; Villanueva-Olivo, A; Esparza-González, SC; Villatoro-Hernandez, J; Saucedo-Cárdenas, O; Montes-de-Oca-Luna, R

    2010-01-01

    Abstract The endoplasmic reticulum (ER) is where the major histocompatibility complex (MHC) class I molecules are loaded with epitopes to cause an immune cellular response. Most of the protein antigens are degraded in the cytoplasm to amino acids and few epitopes reach the ER. Antigen targeting of this organelle by Calreticulin (CRT) fusion avoids this degradation and enhances the immune response. We constructed a recombinant adenovirus to express the E7 antigen with an ER-targeting signal peptide (SP) plus an ER retention signal (KDEL sequence). In cell-culture experiments we demonstrated that this new E7 antigen, SP-E7-KDEL, targeted the ER. Infection of mice with this recombinant adenovirus that expresses SP-E7-KDEL showed interferon induction and tumour-protection response, similar to that provided by an adenovirus expressing the E7 antigen fused to CRT. This work demonstrated that just by adding a SP and the KDEL sequence, antigens can be targeted and retained in the ER with a consequent enhancement of immune response and tumour protection. These results will have significant clinical applications. PMID:19818090

  6. Immune disease-associated variants in gene enhancers point to BET epigenetic mechanisms for therapeutic intervention.

    Science.gov (United States)

    Tough, David F; Prinjha, Rab K

    2017-04-01

    Genome-wide association studies have identified thousands of single nucleotide polymorphisms in the human genome that are statistically associated with particular disease traits. In this Perspective, we review emerging data suggesting that most single nucleotide polymorphisms associated with immune-mediated diseases are found in regulatory regions of the DNA - parts of the genome that control expression of the protein encoding genes - rather than causing mutations in proteins. We discuss how the emerging understanding of particular gene regulatory regions, gene enhancers and the epigenetic mechanisms by which they are regulated is opening up new opportunities for the treatment of immune-mediated diseases, focusing particularly on the BET family of epigenetic reader proteins as potential therapeutic targets.

  7. Early skewed distribution of total and HIV-specific CD8+ T-cell memory phenotypes during primary HIV infection is related to reduced antiviral activity and faster disease progression.

    Science.gov (United States)

    Ghiglione, Yanina; Falivene, Juliana; Ruiz, María Julia; Laufer, Natalia; Socías, María Eugenia; Cahn, Pedro; Giavedoni, Luis; Sued, Omar; Gherardi, María Magdalena; Salomón, Horacio; Turk, Gabriela

    2014-01-01

    The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of

  8. Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection.

    Science.gov (United States)

    Feng, Yonghui; Zhu, Xiaotong; Wang, Qinghui; Jiang, Yongjun; Shang, Hong; Cui, Liwang; Cao, Yaming

    2012-08-08

    During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

  9. Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection

    Directory of Open Access Journals (Sweden)

    Feng Yonghui

    2012-08-01

    Full Text Available Abstract Background During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. Methods To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs, macrophages, CD4+ T and regulatory T cells (Treg were assessed by FACS. Results Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Conclusions Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

  10. Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein.

    Science.gov (United States)

    Parra, Marcela; Liu, Xia; Derrick, Steven C; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D; Waldmann, Thomas A; Kumar, Sanjai; Morris, Sheldon L; Perera, Liyanage P

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies.

  11. The Listeria monocytogenes ChiA chitinase enhances virulence through suppression of host innate immunity.

    Science.gov (United States)

    Chaudhuri, Swarnava; Gantner, Benjamin N; Ye, Richard D; Cianciotto, Nicholas P; Freitag, Nancy E

    2013-03-19

    Environmental pathogens survive and replicate within the outside environment while maintaining the capacity to infect mammalian hosts. For some microorganisms, mammalian infection may be a relatively rare event. Understanding how environmental pathogens retain their ability to cause disease may provide insight into environmental reservoirs of disease and emerging infections. Listeria monocytogenes survives as a saprophyte in soil but is capable of causing serious invasive disease in susceptible individuals. The bacterium secretes virulence factors that promote cell invasion, bacterial replication, and cell-to-cell spread. Recently, an L. monocytogenes chitinase (ChiA) was shown to enhance bacterial infection in mice. Given that mammals do not synthesize chitin, the function of ChiA within infected animals was not clear. Here we have demonstrated that ChiA enhances L. monocytogenes survival in vivo through the suppression of host innate immunity. L. monocytogenes ΔchiA mutants were fully capable of establishing bacterial replication within target organs during the first 48 h of infection. By 72 to 96 h postinfection, however, numbers of ΔchiA bacteria diminished, indicative of an effective immune response to contain infection. The ΔchiA-associated virulence defect could be complemented in trans by wild-type L. monocytogenes, suggesting that secreted ChiA altered a target that resulted in a more permissive host environment for bacterial replication. ChiA secretion resulted in a dramatic decrease in inducible nitric oxide synthase (iNOS) expression, and ΔchiA mutant virulence was restored in NOS2(-/-) mice lacking iNOS. This work is the first to demonstrate modulation of a specific host innate immune response by a bacterial chitinase. Bacterial chitinases have traditionally been viewed as enzymes that either hydrolyze chitin as a food source or serve as a defense mechanism against organisms containing structural chitin (such as fungi). Recent evidence indicates

  12. Carbon Nanotubes Enhance CpG Uptake and Potentiate Anti-Glioma Immunity

    Science.gov (United States)

    Zhao, Dongchang; Alizadeh, Darya; Zhang, Leying; Liu, Wei; Farrukh, Omar; Manuel, Edwin; Diamond, Don J.; Badie, Behnam

    2010-01-01

    Purpose Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. Since TLR9 is located intracellularly, we hypothesized that methods that enhance its internalization may also potentiate its immunostimulatory response. The goal of this study was to evaluate carbon nanotubes (CNTs) as a CpG delivery vehicle in brain tumor models. Experimental Design Functionalized single-walled CNTs were conjugated with CpG (CNT-CpG) and evaluated in vitro and in mice bearing intracranial GL261 gliomas. Flow cytometry was used to assess CNT-CpG uptake and anti-glioma immune response. Tumor growth was measured by bioluminescent imaging, histology, and animal survival. Results CNT-CpG was nontoxic and enhanced CpG uptake both in vitro and intracranial gliomas. CNT-mediated CpG delivery also potentiated pro-inflammatory cytokine production by primary monocytes. Interestingly, a single intracranial injection of low-dose CNT-CpG (but not free CpG or blank CNT) eradicated intracranial GL261 gliomas in half of tumor-bearing mice. Moreover, surviving animals exhibited durable tumor-free remission (> 3 months), and were protected from intracranial tumor rechallenge, demonstrating induction of long-term anti-tumor immunity. Conclusions These findings suggest that CNTs can potentiate CpG immunopotency by enhancing its delivery into tumor-associated inflammatory cells. PMID:21088258

  13. Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity.

    Science.gov (United States)

    Zhao, Dongchang; Alizadeh, Darya; Zhang, Leying; Liu, Wei; Farrukh, Omar; Manuel, Edwin; Diamond, Don J; Badie, Behnam

    2011-02-15

    Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. Because TLR9 is located intracellularly, we hypothesized that methods that enhance its internalization may also potentiate its immunostimulatory response. The goal of this study was to evaluate carbon nanotubes (CNT) as a CpG delivery vehicle in brain tumor models. Functionalized single-walled CNTs were conjugated with CpG (CNT-CpG) and evaluated in vitro and in mice bearing intracranial GL261 gliomas. Flow cytometry was used to assess CNT-CpG uptake and antiglioma immune response. Tumor growth was measured by bioluminescent imaging, histology, and animal survival. CNT-CpG was nontoxic and enhanced CpG uptake both in vitro and intracranial gliomas. CNT-mediated CpG delivery also potentiated proinflammatory cytokine production by primary monocytes. Interestingly, a single intracranial injection of low-dose CNT-CpG (but not free CpG or blank CNT) eradicated intracranial GL261 gliomas in half of tumor-bearing mice. Moreover, surviving animals exhibited durable tumor-free remission (>3 months), and were protected from intracranial tumor rechallenge, demonstrating induction of long-term antitumor immunity. These findings suggest that CNTs can potentiate CpG immunopotency by enhancing its delivery into tumor-associated inflammatory cells. ©2010 AACR.

  14. Dietary Supplementation of Phoenix dactylifera Seeds Enhances Performance, Immune Response, and Antioxidant Status in Broilers

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    Ali H. El-Far

    2016-01-01

    Full Text Available The date palm (Phoenix dactylifera seeds were utilized in some traditional medical remedies and have been investigated for their possible health benefits. This proposed study wanted to assess the effect of date palm seeds (DPS dietary supplementation in comparison to mannan-oligosaccharides (Bio-Mos® and β-glucan over antioxidant and immunity events that have effect on growth and carcass performances of broilers. An aggregate of 180, one-day-old, chicks were raised in the wire-floored cages and allotted into control, Bio-Mos (0.1%  Bio-Mos, β-glucan (0.1%  β-glucan, DPS2 (2% date crushed seeds, DPS4 (4% date crushed seeds, and DPS6 (6% date crushed seeds groups. Broilers in DPS2 and DPS4 groups showed significant variations (P<0.05 in relative growth rate (RGR, feed conversion ratio (FCR, and efficiency of energy utilization in comparison to control group. Moreover, all DPS fed groups showed significant increases (P<0.05 in serum reduced glutathione (GSH values. Meanwhile, both serum interferon-gamma (IFN-γ and interleukin-2 (IL-2 levels were significantly increased (P<0.05 in DPS2. Consequently, obtained data revealed a substantial enhancement of performance, immunity, and antioxidant status by DPS supplementation in broiler that might be related to the antioxidant and immune-stimulant constituents of P. dactylifera seeds.

  15. Enhancing immunomodulation on innate immunity by shape transition among RNA triangle, square and pentagon nanovehicles.

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    Khisamutdinov, Emil F; Li, Hui; Jasinski, Daniel L; Chen, Jiao; Fu, Jian; Guo, Peixuan

    2014-09-01

    Modulation of immune response is important in cancer immunotherapy, vaccine adjuvant development and inflammatory or immune disease therapy. Here we report the development of new immunomodulators via control of shape transition among RNA triangle, square and pentagon. Changing one RNA strand in polygons automatically induced the stretching of the interior angle from 60° to 90° or 108°, resulting in self-assembly of elegant RNA triangles, squares and pentagons. When immunological adjuvants were incorporated, their immunomodulation effect for cytokine TNF-α and IL-6 induction was greatly enhanced in vitro and in animals up to 100-fold, while RNA polygon controls induced unnoticeable effect. The RNA nanoparticles were delivered to macrophages specifically. The degree of immunostimulation greatly depended on the size, shape and number of the payload per nanoparticles. Stronger immune response was observed when the number of adjuvants per polygon was increased, demonstrating the advantage of shape transition from triangle to pentagon. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Attenuating Immune Response of Macrophage by Enhancing Hydrophilicity of Ti Surface

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    Xiaohan Dai

    2015-01-01

    Full Text Available Immune responses can determine the in vivo fate of implanted materials. The strategy for developing implants has shifted towards using materials with immunomodulatory activity. However, the immunoregulatory effect of hydrophilicity of titanium surface on the macrophage behavior and its underlying mechanism remain poorly understood. Here, the Ti surface hydrophilicity-dependent behavior of murine RAW264.7 macrophages was investigated in vitro. Two laboratory models with significantly different surface hydrophilicity and similar roughness were established with Ti-polished and Ti-H2O2 surfaces. The results of cell morphology observation showed that the Ti-H2O2 surface yielded enhanced cell adhesion and less multinucleated cell formation. CCK-8 assay indicated that the growth rate of macrophage on Ti-H2O2 surface is higher than that of Ti-polished. ELISA assay result revealed lower level of proinflammatory factor TNF-α and higher level of anti-inflammatory factor IL-10 on the Ti-H2O2 surface compared to Ti-polished. Subsequently, immunofluorescence and western blotting analysis showed that activation of the NF-κB-TNF-α pathway might be involved in the modulation of the immune response by surface hydrophilicity. Together, these results suggested that relative high hydrophilic Ti surface might attenuate the immune response of macrophage by activating NF-κB signaling. These findings could provide new insights into designing implant devices for orthopedic applications.

  17. A synthetic adjuvant to enhance and expand immune responses to influenza vaccines.

    Science.gov (United States)

    Coler, Rhea N; Baldwin, Susan L; Shaverdian, Narek; Bertholet, Sylvie; Reed, Steven J; Raman, Vanitha S; Lu, Xiuhua; DeVos, Joshua; Hancock, Kathy; Katz, Jacqueline M; Vedvick, Thomas S; Duthie, Malcolm S; Clegg, Christopher H; Van Hoeven, Neal; Reed, Steven G

    2010-10-27

    Safe, effective adjuvants that enhance vaccine potency, including induction of neutralizing Abs against a broad range of variant strains, is an important strategy for the development of seasonal influenza vaccines which can provide optimal protection, even during seasons when available vaccines are not well matched to circulating viruses. We investigated the safety and ability of Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE), a synthetic Toll-like receptor (TLR)4 agonist formulation, to adjuvant Fluzone® in mice and non-human primates. The GLA-SE adjuvanted Fluzone vaccine caused no adverse reactions, increased the induction of T helper type 1 (T(H)1)-biased cytokines such as IFNγ, TNF and IL-2, and broadened serological responses against drifted A/H1N1 and A/H3N2 influenza variants. These results suggest that synthetic TLR4 adjuvants can enhance the magnitude and quality of protective immunity induced by influenza vaccines.

  18. A synthetic adjuvant to enhance and expand immune responses to influenza vaccines.

    Directory of Open Access Journals (Sweden)

    Rhea N Coler

    Full Text Available Safe, effective adjuvants that enhance vaccine potency, including induction of neutralizing Abs against a broad range of variant strains, is an important strategy for the development of seasonal influenza vaccines which can provide optimal protection, even during seasons when available vaccines are not well matched to circulating viruses. We investigated the safety and ability of Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE, a synthetic Toll-like receptor (TLR4 agonist formulation, to adjuvant Fluzone® in mice and non-human primates. The GLA-SE adjuvanted Fluzone vaccine caused no adverse reactions, increased the induction of T helper type 1 (T(H1-biased cytokines such as IFNγ, TNF and IL-2, and broadened serological responses against drifted A/H1N1 and A/H3N2 influenza variants. These results suggest that synthetic TLR4 adjuvants can enhance the magnitude and quality of protective immunity induced by influenza vaccines.

  19. Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses.

    Science.gov (United States)

    Li, Man; Li, You; Peng, Ke; Wang, Ying; Gong, Tao; Zhang, Zhirong; He, Qin; Sun, Xun

    2017-10-10

    construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses. Copyright © 2017. Published by Elsevier Ltd.

  20. The role of TLR2 and bacterial lipoprotein in enhancing airway inflammation and immunity

    Directory of Open Access Journals (Sweden)

    Amit A Lugade

    2011-04-01

    Full Text Available Non-typeable Haemophilus influenzae (NTHI colonizes the lower respiratory tract of patients with chronic obstructive pulmonary disease (COPD and also causes exacerbations of the disease. The 16-kDa lipoprotein P6 has been widely studied as a potential vaccine antigen due to its highly conserved expression amongst NTHI strains. Although P6 is known to induce potent inflammatory responses, its role in the pathogenesis of NTHI infection in vivo has not been examined. Additionally, the presence of an amino-terminal lipid motif on P6 serves to activate host TLR2 signaling. The role of host Toll-like receptor 2 (TLR2 and NTHI expression of the lipoprotein P6 on the induction of airway inflammation and generation of adaptive immune responses following chronic NTHI stimulation was evaluated with TLR2-deficient mice and a P6-deficient NTHI strain. Absence of either host TLR2 or bacterial P6 resulted in diminished levels of immune cell infiltration within lungs of mice exposed to NTHI. Pro-inflammatory cytokine secretion was also reduced in lungs that did not express TLR2 or were exposed to NTHI devoid of P6. Induction of specific antibodies to P6 was severely limited in TLR2-deficient mice. Although mice exposed to the P6-deficient NTHI strain were capable of generating antibodies to other surface antigens of NTHI, these levels were lower compared to those observed in mice exposed to P6-expressing NTHI. Therefore, cognate interaction between host TLR2 and bacterial P6 serves to enhance lung inflammation and elicit robust adaptive immune responses during NTHI exposure. Strategies to limit NTHI inflammation while simultaneously promoting robust immune responses may benefit from targeting the TLR2:P6 signaling axis.

  1. Human study of the herbal preparation(HemoHIM) on enhancement of immune and hematopoietic functions

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hee-Jeong; Park, Jong-Nam; Jeon, Sun-Hee [Eulji Univ. Hospital, Daejeon (Korea, Republic of)

    2006-01-15

    This study was aimed to evaluate the human efficacy of the herbal preparation(HemoHIM) on the immune and hematopoiesis enhancement in sub-healthy volunteers. It was conducted as a double-blind, placebo-controlled human study. The sub-healthy volunteers with peripheral White Blood Cell (WBC) counts below 5000/μl were recruited and randomly allocated to 3 groups and administered with HemoHIM 6g/day, HemoHIM 12g/day, or placebo throughout the test. Peripheral blood was collected 4 times before or after the administration and analyzed for the hematological and serum biochemical values, immune cell activities, antioxidant status of plasma. The data of 38 volunteers were finally included in the analysis. Although there were no statistical significances, a trend was observed that the dose and duration of HemoHIM administration was correlated to the increased number of immune cells (white blood cells and lymphocytes). NK cell activity was increased significantly in the male group administered with HemoHIM 6g/day. The cytokines involved in immune activation (IL-2, IFN-γ, IL-6) were significantly increased or showed the trends of increases in HemoHIM administered groups, while IL-4 involved in allergy and asthma was not changed or showed the trends of decreases in HemoHIM administered groups. On the other hand, the antioxidant biomarkers such as total GSH, MDA, and TAS, were not affected by HemoHIM administration. The toxicological safety of HemoHIM administration was confirmed by the serum biochemical analysis of liver and kidney function markers and the questionnaire of HemoHIM administration and the consultation with the doctor, which showed no side effects of HemoHIM administration. The results of this study may provide the basic data for further clinical study on HemoHIM.

  2. How Innate Immune Mechanisms Contribute to Antibody-Enhanced Viral Infections ▿

    Science.gov (United States)

    Ubol, Sukathida; Halstead, Scott B.

    2010-01-01

    Preexisting antibodies may enhance viral infections. In dengue, nonneutralizing antibodies raised by natural infection with one of four dengue viruses (DENVs) may enhance infection with a different virus by a process we term “intrinsic antibody-dependent enhancement” (iADE). In addition, nonprotective antibodies raised by formalin-inactivated respiratory syncytial virus (RSV) and measles virus vaccines have led to enhanced disease during breakthrough infections. Infections under iADE conditions not only facilitate the process of viral entry into monocytes and macrophages but also modify innate and adaptive intracellular antiviral mechanisms, suppressing type 1 interferon (IFN) production and resulting in enhanced DENV replication. The suppression observed in vitro has been documented in patients with severe (dengue hemorrhagic fever [DHF]) but not in patient with mild (dengue fever [DF]) secondary dengue virus infections. Important veterinary viral infections also may exhibit iADE. It is thought that use of formalin deconforms viral epitopes of RSV, resulting in poor Toll-like receptor (TLR) stimulation; suboptimal maturation of dendritic cells with reduced production of activation factors CD40, CD80, and CD86; decreased germinal center formation in lymph nodes; and the production of nonprotective antibodies. These antibodies fail to neutralize RSV, allowing replication with secondary stimulation of RSV-primed Th2 cells producing more low-avidity antibody, resulting in immune complexes deposited into affected tissue. However, when formalin-inactivated RSV was administered with a TLR agonist to mice, they were protected against wild-type virus challenge. Safe and effective vaccines against RSV/measles virus and dengue virus may benefit from a better understanding of how innate immune responses can promote production of protective antibodies. PMID:20876821

  3. HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) - Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART)

    DEFF Research Database (Denmark)

    Jensen, Sanne Skov; Fomsgaard, Anders; Borggren, Marie

    2015-01-01

    Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated...... the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared...... to the individuals initiating ART at a low CD4+ T cell count (ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined...

  4. Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes.

    Science.gov (United States)

    Trujillo, Jonathan A; Gras, Stephanie; Twist, Kelly-Anne; Croft, Nathan P; Channappanavar, Rudragouda; Rossjohn, Jamie; Purcell, Anthony W; Perlman, Stanley

    2014-06-01

    Peptides that bind poorly to MHC class I molecules often elicit low-functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope ("heteroclitic"). This augmented MHC binding is likely to increase the half-life and surface density of the heteroclitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)- and low (S598, RCQIFANI)-functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross-reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope. Copyright © 2014 by The American Association of Immunologists, Inc.

  5. Dietary Supplementation of Honey Bee Larvae with Arginine and Abscisic Acid Enhances Nitric Oxide and Granulocyte Immune Responses after Trauma.

    Science.gov (United States)

    Negri, Pedro; Ramirez, Leonor; Quintana, Silvina; Szawarski, Nicolás; Maggi, Matías; Le Conte, Yves; Lamattina, Lorenzo; Eguaras, Martin

    2017-08-15

    Many biotic and abiotic stressors impact bees' health, acting as immunosupressors and contribute to colony losses. Thus, the importance of studying the immune response of honey bees is central to develop new strategies aiming to enhance bees' fitness to confront the threats affecting them. If a pathogen breaches the physical and chemical barriers, honey bees can protect themselves from infection with cellular and humoral immune responses which represent a second line of defense. Through a series of correlative studies we have previously reported that abscisic acid (ABA) and nitric oxide (NO) share roles in the same immune defenses of Apis mellifera (A. mellifera). Here we show results supporting that the supplementation of bee larvae's diet reared in vitro with l-Arginine (precursor of NO) or ABA enhanced the immune activation of the granulocytes in response to wounding and lipopolysaccharide (LPS) injection.

  6. Mutations in Cas9 Enhance the Rate of Acquisition of Viral Spacer Sequences during the CRISPR-Cas Immune Response.

    Science.gov (United States)

    Heler, Robert; Wright, Addison V; Vucelja, Marija; Bikard, David; Doudna, Jennifer A; Marraffini, Luciano A

    2017-01-05

    CRISPR loci and their associated (Cas) proteins encode a prokaryotic immune system that protects against viruses and plasmids. Upon infection, a low fraction of cells acquire short DNA sequences from the invader. These sequences (spacers) are integrated in between the repeats of the CRISPR locus and immunize the host against the matching invader. Spacers specify the targets of the CRISPR immune response through transcription into short RNA guides that direct Cas nucleases to the invading DNA molecules. Here we performed random mutagenesis of the RNA-guided Cas9 nuclease to look for variants that provide enhanced immunity against viral infection. We identified a mutation, I473F, that increases the rate of spacer acquisition by more than two orders of magnitude. Our results highlight the role of Cas9 during CRISPR immunization and provide a useful tool to study this rare process and develop it as a biotechnological application. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.

    Directory of Open Access Journals (Sweden)

    Henri-Alexandre Michaud

    Full Text Available Antiviral monoclonal antibodies (mAbs represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCas(E murine retrovirus on day 8 after birth die of leukemia within 4-5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC mechanism. In addition, it forms immune complexes (ICs with infected cells that enhance antiviral CTL responses through Fc gammaR-mediated binding to dendritic cells (DCs. Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses

  8. Effects of selenylation modification on immune-enhancing activity of garlic polysaccharide.

    Directory of Open Access Journals (Sweden)

    Shulei Qiu

    Full Text Available The garlic polysaccharide was modified by HNO3-Na2SeO3 method according to orthogonal design L9(3(4 to obtain nine selenizing garlic polysaccharides, sGPS1-sGPS9. Their effects on chicken peripheral lymphocytes proliferation in vitro were compared by MTT assay. The results showed that sGPSs could significantly promote lymphocytes proliferation, sGPS3, sGPS5 and sGPS6 presented stronger efficacy. In vivo experiment, 14-day-old chickens were injected respectively with sGPS3, sGPS5 and sGPS6 when they were vaccinated with ND vaccine taking unmodified GPS as control. The results showed that three sGPSs could significantly promote lymphocyte proliferation, enhance serum antibody titer, IFN-γ and IL-2 contents. These results indicated that selenylation modification could significantly enhance the immune-enhancing activity of GPS, sGPS6 possessed the best efficacy and could be as a candidate drug of immunoenhancer. Its optimal modification conditions were 400 mg of sodium selenite for 500 mg of GPS, reaction temperature of 70°C and reaction time of 6 h.

  9. An endogenous immune adjuvant released by necrotic cells for enhancement of DNA vaccine potency.

    Science.gov (United States)

    Dorostkar, Rohollah; Bamdad, Taravat; Parsania, Masoud; Pouriayevali, Hassan

    2012-12-01

    Improving vaccine potency in the induction of a strong cell-mediated cytotoxicity can enhance the efficacy of vaccines. Necrotic cells and the supernatant of necrotic tumor cells are attractive adjuvants, on account of their ability to recruit antigen-presenting cells to the site of antigen synthesis as well as its ability to stimulate the maturation of dendritic cells. To evaluate the utility of supernatant of necrotic tumor cells as a DNA vaccine adjuvant in a murine model. The supernatant of EL4 necrotic cells was co-administered with a DNA vaccine expressing the glycoprotein B of Herpes simplex virus-1 as an antigen model under the control of Cytomegalovirus promoter. C57BL/6 mice were vaccinated three times at two weeks intervals with glycoprotein B DNA vaccine and supernatant of necrotic EL4 cells. Five days after the last immunization, cell cytotoxicity, IFN-γ and IL-4 were evaluated. The obtained data showed that the production of IFN-γ from the splenocytes after antigenic stimulation in the presence of the supernatant of necrotic EL4 cells was significantly higher than the other groups (pEL4 cells in the mice immunized with DNA vaccine and supernatant of necrotic EL4 cells comparing to the other groups (p<0.001). The supernatant of necrotic cells contains adjuvant properties that can be considered as a candidate for tumor vaccination.

  10. Potential of the Cnidium monnieri fruits as an immune enhancer in Escherichia coli infection model.

    Science.gov (United States)

    Malla, Bindu; Chang, Bo Yoon; Kim, Seon Beom; Park, Hyun; Lee, Mi Kyeong; Kim, Sung Yeon

    2016-11-01

    The Cnidium monnieri fruits (CMF) were studied how they act on immune system as a novel immunostimulator against the infectious disease. Macrophages were treated with CMF, and nitric oxide (NO) and tumour necrosis factor-α (TNF-α) were measured, and phagocytosis of macrophages was detected using FITC-labelled Escherichia coli. The protective effect of CMF against E. coli infection in mice was examined. The survival rate was monitored daily for up to 5 days. And then the viable bacteria count of serum and the immunological mediator (NO, TNF-α, interleukin (IL)-12 and IL-6) of serum, splenocyte and peritoneal macrophages were analysed. The CMF significantly enhanced the concentrations of NO and TNF-α and the phagocytosis activity in macrophages. The oral administration of CMF for five consecutive days before infection prolonged the survival rate. Treatment with CMF significantly stimulated the phagocytosis of peritoneal macrophages and induced the immunological mediator of serum, splenocyte and peritoneal macrophages against the E. coli infection. The host-protective effects of CMF might be archived by improving immune response, and CMF could act to prevent pathogenic microbial infections with immunomodulation. © 2016 Royal Pharmaceutical Society.

  11. NY-ESO-1 protein glycosylated by yeast induces enhanced immune responses.

    Science.gov (United States)

    Wadle, Andreas; Mischo, Axel; Strahl, Sabine; Nishikawa, Hiroyoshi; Held, Gerhard; Neumann, Frank; Wullner, Beate; Fischer, Eliane; Kleber, Sascha; Karbach, Julia; Jager, Elke; Shiku, Hiroshi; Odunsi, Kunle; Shrikant, Protul A; Knuth, Alexander; Cerundolo, Vincenzo; Renner, Christoph

    2010-11-01

    Vaccine strategies that target dendritic cells to elicit potent cellular immunity are the subject of intense research. Here we report that the genetically engineered yeast Saccharomyces cerevisiae, expressing the full-length tumour-associated antigen NY-ESO-1, is a versatile host for protein production. Exposing dendritic cells (DCs) to soluble NY-ESO-1 protein linked to the yeast a-agglutinin 2 protein (Aga2p) protein resulted in protein uptake, processing and MHC class I cross-presentation of NY-ESO-1-derived peptides. The process of antigen uptake and cross-presentation was dependent on the glycosylation pattern of NY-ESO-1-Aga2p protein and the presence of accessible mannose receptors. In addition, NY-ESO-1-Aga2p protein uptake by dendritic cells resulted in recognition by HLA-DP4 NY-ESO-1-specific CD4(+) T cells, indicating MHC class II presentation. Finally, vaccination of mice with yeast-derived NY-ESO-1-Aga2p protein led to an enhanced humoral and cellular immune response, when compared to the bacterially expressed NY-ESO-1 protein. Together, these data demonstrate that yeast-derived full-length NY-ESO-1-Aga2p protein is processed and presented efficiently by MHC class I and II complexes and warrants clinical trials to determine the potential value of S. cerevisiae as a host for cancer vaccine development. Copyright © 2010 John Wiley & Sons, Ltd.

  12. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation

    Science.gov (United States)

    Viswanathan, Kavitha; Dhabhar, Firdaus S.

    2005-04-01

    Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. In contrast to immunosuppressive chronic stressors, short-term acute stressors have immunoenhancing effects. Here, we quantify leukocyte infiltration within a surgical sponge to elucidate the kinetics, magnitude, subpopulation, and chemoattractant specificity of an acute stress-induced increase in leukocyte trafficking to a site of immune activation. Mice acutely stressed before sponge implantation showed 200-300% higher neutrophil, macrophage, natural killer cell, and T cell infiltration than did nonstressed animals. We also quantified the effects of acute stress on lymphotactin- (LTN; a predominantly lymphocyte-specific chemokine), and TNF-- (a proinflammatory cytokine) stimulated leukocyte infiltration. An additional stress-induced increase in infiltration was observed for neutrophils, in response to TNF-, macrophages, in response to TNF- and LTN, and natural killer cells and T cells in response to LTN. These results show that acute stress initially increases trafficking of all major leukocyte subpopulations to a site of immune activation. Tissue damage-, antigen-, or pathogen-driven chemoattractants subsequently determine which subpopulations are recruited more vigorously. Such stress-induced increases in leukocyte trafficking may enhance immunoprotection during surgery, vaccination, or infection, but may also exacerbate immunopathology during inflammatory (cardiovascular disease or gingivitis) or autoimmune (psoriasis, arthritis, or multiple sclerosis) diseases. chemokine | psychophysiological stress | surgical sponge | wound healing | lymphotactin

  13. Yogurt consumption does not enhance immune function in healthy premenopausal women.

    Science.gov (United States)

    Campbell, C G; Chew, B P; Luedecke, L O; Shultz, T D

    2000-01-01

    Fermented milk products may protect against breast cancer by stimulating immunologic activity. Twenty-five women [24.0 +/- 0.7 (SE) yr] were assigned randomly to two groups: control (n = 12) and yogurt treatment (n = 13). Controls refrained from yogurt products for three months, whereas the yogurt treatment group consumed two cups (454 g/day) of commercially produced yogurt for three consecutive months. Prior yogurt consumption did not exceed 4-6 cups/mo, and subjects consumed their usual diet during the study. Three-day diet records and fasting midluteal blood samples were obtained during subjects' first, second, and fourth menstrual cycles (baseline, Month 1, and Month 3, respectively). Macronutrient intakes differed between groups only for carbohydrate. Calcium intake increased for yogurt consumers during intervention. Lymphocyte proliferation induced by concanavalin A, phytohemagglutinin, and pokeweed mitogen, interleukin 2 production, and cytotoxic T lymphocyte-mediated cytotoxicity was assessed after baseline and Months 1 and 3 for both groups. No significant immune differences between the control and yogurt treatment group were observed for concanavalin A, phytohemagglutinin, pokeweed mitogen, interleukin-2, or cytotoxicity. In conclusion, three months of yogurt consumption did not enhance ex vivo cell-mediated immune function in young women.

  14. RNA-guided complex from a bacterial immune system enhances target recognition through seed sequence interactions

    Science.gov (United States)

    Wiedenheft, Blake; van Duijn, Esther; Bultema, Jelle B.; Waghmare, Sakharam P.; Zhou, Kaihong; Barendregt, Arjan; Westphal, Wiebke; Heck, Albert J. R.; Boekema, Egbert J.; Dickman, Mark J.; Doudna, Jennifer A.

    2011-01-01

    Prokaryotes have evolved multiple versions of an RNA-guided adaptive immune system that targets foreign nucleic acids. In each case, transcripts derived from clustered regularly interspaced short palindromic repeats (CRISPRs) are thought to selectively target invading phage and plasmids in a sequence-specific process involving a variable cassette of CRISPR-associated (cas) genes. The CRISPR locus in Pseudomonas aeruginosa (PA14) includes four cas genes that are unique to and conserved in microorganisms harboring the Csy-type (CRISPR system yersinia) immune system. Here we show that the Csy proteins (Csy1–4) assemble into a 350 kDa ribonucleoprotein complex that facilitates target recognition by enhancing sequence-specific hybridization between the CRISPR RNA and complementary target sequences. Target recognition is enthalpically driven and localized to a “seed sequence” at the 5′ end of the CRISPR RNA spacer. Structural analysis of the complex by small-angle X-ray scattering and single particle electron microscopy reveals a crescent-shaped particle that bears striking resemblance to the architecture of a large CRISPR-associated complex from Escherichia coli, termed Cascade. Although similarity between these two complexes is not evident at the sequence level, their unequal subunit stoichiometry and quaternary architecture reveal conserved structural features that may be common among diverse CRISPR-mediated defense systems. PMID:21536913

  15. Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.

    Science.gov (United States)

    Gaiha, Gaurav D; McKim, Kevin J; Woods, Matthew; Pertel, Thomas; Rohrbach, Janine; Barteneva, Natasha; Chin, Christopher R; Liu, Dongfang; Soghoian, Damien Z; Cesa, Kevin; Wilton, Shannon; Waring, Michael T; Chicoine, Adam; Doering, Travis; Wherry, E John; Kaufmann, Daniel E; Lichterfeld, Mathias; Brass, Abraham L; Walker, Bruce D

    2014-12-18

    Decreased HIV-specific CD8(+) T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8(+) T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8(+) T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8(+) T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8(+) T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8(+) T cell proliferation through activation of necroptosis and increased cell death. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Effects of pidotimod soluble powder and immune enhancement of Newcastle disease vaccine in chickens.

    Science.gov (United States)

    Qu, Shaoqi; Dai, Cunchun; Qiu, Mei; Zhang, Ruili; Wang, Chunyuan; Cui, Liangliang; Hao, Zhihui

    2017-07-01

    The aims of this study were to prepare pidotimod (PDM) soluble powder and to investigate the immune enhancement properties of PDM in chickens vaccinated with Newcastle disease virus vaccine. In vivo experiment, 360 6-day-old chickens were averagely divided into 6 groups. The chickens, except blank control (BC) group, were vaccinated with Newcastle disease vaccine (NDV). At the same time of the vaccination, the chickens in three PDM groups were given water with PDM for 5days, respectively, with the PDM at low, medium and high concentrations (0.25g/L, 0.5g/L, 1g/L), in control drug group was treated with 0.2ml/PDM dose via drinking water, in vaccination control (VC) and BC group, with equal volume physiological saline, once a day for five successive days. On days 14, 21 and 28 after the vaccination, the growth performance, the lymphocyte proliferation, serum antibody titer, the CD4/CD8 cell ratios and interleukin-2 (IL-2) and interferon-gamma (IFN-γ) were measured. The results showed that PDM at suitable dose could significantly promote growth performance, lymphocyte proliferation, enhance serum antibody titer, CD4/CD8 cell ratios and improve serum IL-2 and IFN-γ concentrations. It indicated that PDM could significantly improve the immune efficacy of Newcastle disease vaccine using doses of 0.5g/L, these results are consistent with the drug acting as an immunopotentiator. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  17. A bovine whey protein extract can enhance innate immunity by priming normal human blood neutrophils.

    Science.gov (United States)

    Rusu, Daniel; Drouin, Réjean; Pouliot, Yves; Gauthier, Sylvie; Poubelle, Patrice E

    2009-02-01

    Bovine milk-derived products, in particular whey proteins, exhibit beneficial properties for human health, including the acquired immune response. However, their effects on innate immunity have received little attention. Neutrophils are key cells of innate defenses through their primary functions of chemotaxis, phagocytosis, oxidative burst, and degranulation. A whey protein extract (WPE) purified from bovine lactoserum was evaluated for its direct and indirect effects on these primary functions of normal human blood neutrophils in vitro. Although WPE had no direct effects on primary functions, a 24-h pretreatment of neutrophils with WPE was associated with a significant and dose-dependent increase of their chemotaxis, superoxide production, and degranulation in response to N-formyl-methionine-leucine-phenylalanine, as well as of their phagocytosis of bioparticles. The pretreatment increased the surface expression of CD11b, CD16B, and CD32A receptors. The major WPE protein components beta-lactoglobulin (beta-LG) and alpha-lactalbumin (alpha-LA) were the main active fractions having an additive effect on human neutrophils that became more responsive to a subsequent stimulation. This effect on NADPH oxidase activity was associated with translocation of p47(phox) to plasma membrane. Glycomacropeptide, a peptide present in measurable amounts in WPE products, was able to enhance the individual effect of beta-LG or alpha-LA on neutrophils. The present data suggest that WPE, through beta-LG and alpha-LA, has the capacity to enhance or "prime" human neutrophil responses to a subsequent stimulation, an effect that could be associated with increased innate defenses in vivo.

  18. Bacillus Coagulans Enhance the Immune Function of the Intestinal Mucosa of Yellow Broilers

    Directory of Open Access Journals (Sweden)

    L Xu

    Full Text Available ABSTRACT This experiment was conducted to investigate the effects of Bacillus coagulans on the growth performance and immune functions of the intestinal mucosa of yellow broilers. Three hundred and sixty one-day-old yellow chicks were randomly allocated to four treatments groups with six replicates of 15 chicks each. The broilers were randomly subjected to one of the following treatments for 28 days: control group (group1, fed a basal diet and three treatments (group 2, 3, 4 fed the basal diet supplemented with 100, 200, or 300 mg/kg Bacillus coagulans , respectively. The results showed that for 28 days, compared with the control diet, the dietary addition of 200 mg/kg Bacillus coagulans significantly decreased the feed/gain ratio (F/G (p<0.05, improved the thymus index, spleen index and bursa index (p<0.05, increased the villus height to crypt depth ratio (V/C in the duodenum (p<0.05, increased the number of secretory immunoglobulin (sIgA positive cells ( p<0.05. The dietary addition of 200 mg/kg Bacillus coagulans promoted a significant increase in Lactobacillus spp. populations and suppressed Escherichia coli replication in cecum, compared with the control (p<0.05. Moreover, the dietary addition of 200 mg/kg Bacillus coagulans also significantly enhanced the levels of interferon alpha (IFNα, toll-like receptor (TLR3, and melanoma differentiation-associated protein 5(MDA5 in the duodenum (p<0.05. In conclusion, the dietary addition of Bacillus coagulans significantly improved broiler performance, and enhanced the intestinal mucosal barrier and immune function. The optimal dosage of Bacillus coagulans for yellow broilers was determined as 2×108 cfu/kg.

  19. Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response.

    Science.gov (United States)

    Federici Canova, Donata; Pavlov, Anton M; Norling, Lucy V; Gobbetti, Thomas; Brunelleschi, Sandra; Le Fauder, Pauline; Cenac, Nicolas; Sukhorukov, Gleb B; Perretti, Mauro

    2015-11-10

    Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Murine and bovine γδ T cells enhance innate immunity against Brucella abortus infections.

    Directory of Open Access Journals (Sweden)

    Jerod A Skyberg

    Full Text Available γδ T cells have been postulated to act as a first line of defense against infectious agents, particularly intracellular pathogens, representing an important link between the innate and adaptive immune responses. Human γδ T cells expand in the blood of brucellosis patients and are active against Brucella in vitro. However, the role of γδ T cells in vivo during experimental brucellosis has not been studied. Here we report TCRδ(-/- mice are more susceptible to B. abortus infection than C57BL/6 mice at one week post-infection as measured by splenic colonization and splenomegaly. An increase in TCRγδ cells was observed in the spleens of B. abortus-infected C57BL/6 mice, which peaked at two weeks post-infection and occurred concomitantly with diminished brucellae. γδ T cells were the major source of IL-17 following infection and also produced IFN-γ. Depletion of γδ T cells from C57BL/6, IL-17Rα(-/-, and GMCSF(-/- mice enhanced susceptibility to B. abortus infection although this susceptibility was unaltered in the mutant mice; however, when γδ T cells were depleted from IFN-γ(-/- mice, enhanced susceptibility was observed. Neutralization of γδ T cells in the absence of TNF-α did not further impair immunity. In the absence of TNF-α or γδ T cells, B. abortus-infected mice showed enhanced IFN-γ, suggesting that they augmented production to compensate for the loss of γδ T cells and/or TNF-α. While the protective role of γδ T cells was TNF-α-dependent, γδ T cells were not the major source of TNF-α and activation of γδ T cells following B. abortus infection was TNF-α-independent. Additionally, bovine TCRγδ cells were found to respond rapidly to B. abortus infection upon co-culture with autologous macrophages and could impair the intramacrophage replication of B. abortus via IFN-γ. Collectively, these results demonstrate γδ T cells are important for early protection to B. abortus infections.

  1. KIR2DL2 enhances protective and detrimental HLA class I-mediated immunity in chronic viral infection.

    Directory of Open Access Journals (Sweden)

    Nafisa-Katrin Seich Al Basatena

    2011-10-01

    Full Text Available Killer cell immunoglobulin-like receptors (KIRs influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.

  2. Immune enhancing effects of WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts

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    Vetvicka, Vaclav; Vetvickova, Jana

    2011-01-01

    Background: Stress has been found to significantly reduce the abilities of the immune system to fight infections. One of the ways to overcome the defects of the immune system is the strengthening of the defense reactions by nutrition. Aims: To evaluate immune enhancing effects of the following material: WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts. Results: We found that both glucan-rich maitake extract and WB365 caused a similar stimulation of phagocytic activity. Stress-induced increase of corticosterone production was blocked by feeding with Ashwagandha extract and even more by WB365. Cytokine experiments showed that feeding with WB365 helped overcome the stress-related inhibition of IL-6, IL-12 and IFN-γ production. Conclusion: This study clearly demonstrated that WB365, a combination of Maitake mushroom-derived glucan and Ashwagandha extracts, has strong pleiotropic biological effects related to immune health and stress reduction. PMID:22540105

  3. Immune enhancing effects of WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts.

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    Vetvicka, Vaclav; Vetvickova, Jana

    2011-07-01

    Stress has been found to significantly reduce the abilities of the immune system to fight infections. One of the ways to overcome the defects of the immune system is the strengthening of the defense reactions by nutrition. TO EVALUATE IMMUNE ENHANCING EFFECTS OF THE FOLLOWING MATERIAL: WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts. We found that both glucan-rich maitake extract and WB365 caused a similar stimulation of phagocytic activity. Stress-induced increase of corticosterone production was blocked by feeding with Ashwagandha extract and even more by WB365. Cytokine experiments showed that feeding with WB365 helped overcome the stress-related inhibition of IL-6, IL-12 and IFN-γ production. This study clearly demonstrated that WB365, a combination of Maitake mushroom-derived glucan and Ashwagandha extracts, has strong pleiotropic biological effects related to immune health and stress reduction.

  4. Au@Pt nanoparticles as catalase mimics to attenuate tumor hypoxia and enhance immune cell-mediated cytotoxicity

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    Liang, Hong; Wu, Ying; Ou, Xiang-Yu; Li, Jing-Ying; Li, Juan

    2017-11-01

    Hypoxic tumor microenvironment (TME) is closely linked to tumor progression, heterogeneity and immune suppression. Therefore, the development of effective methods to overcome hypoxia and substantially enhance the immunotherapy efficacy remains a desirable goal. Herein, we engineered a biocompatible Au core/Pt shell nanoparticles (Au@Pt NPs) to reoxygenate the TME by reacting with endogenous H2O2. Treatment with Au@Pt NPs appeared to improve oxygen in intracellular environments and decrease hypoxia-inducible factor-1α expression. Furthermore, the integration of high catalytic efficiency of Au@Pt NPs with cytokine-induced killer (CIK) cell immunotherapy, could lead to significantly improve the effect of CIK cell-mediated cytotoxicity. These results suggest great potential of Au@Pt NPs for regulation of the hypoxic TME and enhance immune cell mediated anti-tumor immunity.

  5. Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette-Guérin (BCG) via Synergistic Activation of Innate Immune Receptors.

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    Speth, Martin T; Repnik, Urska; Müller, Elisabeth; Spanier, Julia; Kalinke, Ulrich; Corthay, Alexandre; Griffiths, Gareth

    2017-11-06

    The attenuated live vaccine strain bacille Calmette-Guérin (BCG) is currently the only available vaccine against tuberculosis (TB), but is largely ineffective against adult pulmonary TB, the most common disease form. This is in part due to BCG's ability to interfere with the host innate immune response, a feature that might be targeted to enhance the potency of this vaccine. Here, we investigated the ability of chitosan-based nanoparticles (pIC-NPs) containing polyinosinic-polycytidylic acid (poly(I:C)), an inducer of innate immunity via Toll-like receptor 3 (TLR3), to enhance the immunogenicity of BCG in mouse bone marrow derived macrophages (BMDM) in vitro. Incorporation of poly(I:C) into NPs protected it against degradation by ribonucleases and increased its uptake by mouse BMDM. Whereas soluble poly(I:C) was ineffective, pIC-NPs strongly enhanced the proinflammatory immune response of BCG-infected macrophages in a synergistic fashion, as evident by increased production of cytokines and induction of nitric oxide synthesis. Using macrophages from mice deficient in key signaling molecules involved in the pathogen recognition response, we identified combined activation of MyD88- and TRIF-dependent TLR signaling pathways to be essential for the synergistic effect between BCG and NP. Moreover, synergy was strongly dependent on the order of the two stimuli, with TLR activation by BCG functioning as the priming event for the subsequent pIC-NP stimulus, which acted through an auto-/paracrine type I interferon (IFN) feedback loop. Our results provide a foundation for a promising new approach to enhance BCG-vaccine immunogenicity by costimulation with NPs. They also contribute to a molecular understanding of the observed synergistic interaction between the pIC-NPs and BCG vaccine.

  6. PD-1 blockade enhances the vaccination-induced immune response in glioma.

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    Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Orpilla, Joey; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M

    2016-07-07

    DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.

  7. Enhancing photodynamic therapy of a metastatic mouse breast cancer by immune stimulation

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    Castano, Ana P.; Hamblin, Michael R.

    2006-02-01

    , chemokines and immunoglobulins. Both these novel combinations gave significantly enhanced therapeutic benefit not seen with single treatments alone. Tumors grew more slowly and mice lived significantly longer, although cures were rare. We propose that a rational choice of immune stimulant is an ideal addition to PDT regimens.

  8. A sulfated galactans supplemented diet enhances the expression of immune genes and protects against Vibrio parahaemolyticus infection in shrimp.

    Science.gov (United States)

    Rudtanatip, Tawut; Boonsri, Nantavadee; Asuvapongpatana, Somluk; Withyachumnarnkul, Boonsirm; Wongprasert, Kanokpan

    2017-06-01

    A sulfated galactans (SG) supplemented diet was evaluated for the potential to stimulate immune activity in shrimp Penaeus vannamei (P. vannamei). Shrimp given the SG supplemented diet (0.5, 1 and 2% w/w) for 7 days showed enhanced expression of the downstream signaling mediator of lipopolysaccharide and β-1,3-glucan binding protein (LGBP) and immune related genes including p-NF-κB, IMD, IKKβ and IKKε, antimicrobial peptide PEN-4, proPO-I and II. Following immersion with Vibrio parahaemolyticus (V. parahaemolyticus) for 14 days, the shrimp given the SG supplemented diet (1 and 2% w/w) showed a decrease in bacterial colonies and bacterial toxin gene expression, compared to shrimp given a normal diet, and they reached 50% mortality at day 14. However, shrimp given the normal diet and challenged with the bacteria reached 100% mortality at day 6. SG-fed shrimp increased expression of immune genes related to LGBP signaling at day 1 after the bacterial immersion compared to control (no immersion), which later decreased to control levels. Shrimp on the normal diet also increased expression of immune related genes at day 1 after immersion which however decreased below control levels by day 3. Taken together, the results indicate the efficacy of the SG supplemented diet to enhance the immune activity in shrimp which could offer protection from V. parahaemolyticus infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Immune-enhancing effect of fermented Maesil (Prunus mume Siebold & Zucc.) with probiotics against Bordetella bronchiseptica in mice.

    Science.gov (United States)

    Jung, Bock-Gie; Ko, Jae-Hyung; Cho, Sun-Ju; Koh, Hong-Bum; Yoon, So-Rah; Han, Dong-Un; Lee, Bong-Joo

    2010-09-01

    Maesil (Prunus mume) has long been used as a traditional drug and healthy food in East Asian countries. It possesses a number of beneficial biological activities including potential antimicrobial effects against pathogens. Probiotics also have antibacterial effects. Moreover, some probiotics have an important role in regulating the immune system. The present study evaluated the immune enhancing effects of fermented Maesil with probiotics (Saccharomyces cerevisiae, Bacillus subtilis and Lactobacillus acidophilus) in mice, especially against Bordetella bronchiseptica, as an initial step towards the development of feed supplements for the promotion of immune activity and prevention of disease, especially in pigs. Continuous ingestion of fermented Maesil with probiotics markedly increased the macrophage ratio in peripheral blood and the T lymphocyte ratio in the spleen. In addition, antibody production against formalin-killed B. bronchiseptica significantly increased in the mice fed fermented Maesil compared with the control group. The number of leukocytes was significantly higher in the bronchio-alveolar lavage obtained from the fermented Maesil-fed animals compared to it in the control group at day 3 (maximal peak time) after experimental B. bronchiseptica infection. Moreover, at 7 day post-infection, relative messenger RNA expression levels of tumor necrosis factor- α and interferon-γ were significantly increased in splenocytes of mice fed fermented Maesil compared with those in the control group. Taken together, these findings suggest that feed containing fermented Maesil with probiotics enhances immune activity in mice, especially against B. bronchiseptica, via the potent stimulation of non-specific immune responses.

  10. Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity

    Directory of Open Access Journals (Sweden)

    Mari Hirvinen

    2016-01-01

    Full Text Available In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate—and eventually the long-lasting adaptive immunity against cancer.

  11. [Enhancement of immune responses in rabbits with a targeted anti-caries DNA vaccine pGJA-P].

    Science.gov (United States)

    Jia, Rong; Fan, Ming-wen; Guo, Ji-hua; Bian, Zhuan; Chen, Zhi; Yu, Fei

    2004-05-01

    To detect the immunoreactivity of targeted fusion anti-caries DNA vaccine pGJA-P in vitro, and the ability to enhance the immune responses compared with the non-targeted fusion anti-caries DNA vaccine pGLUA-P. The CHO cells were transfected with pGJA-P and the expression of recombinant protein in cultured supernatants were detected using Western blotting. 5 to 6-month-old female Japanese rabbits were immunized with either pGJA-P or pGLUA-P via either intramuscular injection (i.m.) or intranasal route (i.n.). The sera and saliva were collected and the antibody responses were checked by ELISA. The effect of immune sera on the synthesis of water-insoluble glucan by glucosyltransferase of S. mutans was examined. The expressed protein could response to specific anti-GTF antibody. The antibody responses in serum generated by pGJA-P via i.m. were significantly higher than those generated by pGLUA-P (P vaccine, pGLUA-P. High titres of specific mucosal antibodies were found in rabbits immunized with pGJA-P via i.m. The immune sera of rabbits immunized by pGJA-P via i.m. displayed the ability of inhibiting the synthesis of water-insoluble glucan by glucosyltransferase.

  12. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

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    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Dietary supplementation with lacto-wolfberry enhances the immune response and reduces pathogenesis to influenza infection in mice.

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    Ren, Zhihong; Na, Lixin; Xu, Yanmei; Rozati, Mitra; Wang, Junpeng; Xu, Jianguo; Sun, Changhao; Vidal, Karine; Wu, Dayong; Meydani, Simin Nikbin

    2012-08-01

    Despite the availability of vaccines, influenza is a considerable public health problem, which emphasizes the need for development of additional strategies to enhance host defense against influenza. Wolfberry, or goji berry, long used as a medicinal food in China, has recently been shown to improve immune response in mice. Because immune response plays a key role in the body's defense against pathogens, we hypothesized that wolfberry may increase host resistance to influenza infection by enhancing immune response. To test this hypothesis, we fed adult mice (4 mo old) a milk-based preparation of wolfberry called Lacto-Wolfberry (LWB) for 4 wk and then infected them with influenza A/Puerto Rico/8/34 (H1N1) while continuing the same experimental diets. Viral titer, lung pathology, and immune response were determined at different time points postinfection. LWB supplementation prevented infection-induced weight loss and reduced lung pathology on days 6 and 9 postinfection (P < 0.05). LWB-fed mice showed overall, significantly higher concanavalin A-induced IL-2 production (P < 0.05). Furthermore, we found positive correlations between weight loss and lung viral titer, pathology score, TNFα, and IL-6 production as well as negative correlations with T cell proliferation and IL-2 production (all P ≤ 0.05). These results indicate that LWB supplementation can attenuate symptoms and pathology of influenza infection by decreasing inflammatory cytokines in lungs while enhancing systemic T cell-mediated function as measured by their ability to produce IL-2.

  14. Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Guillain-Barré syndrome (GBS is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO, a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.

  15. Morinda citrifolia edible leaf extract enhanced immune response against lung cancer.

    Science.gov (United States)

    Lim, Swee-Ling; Goh, Yong-Meng; Noordin, M Mustapha; Rahman, Heshu S; Othman, Hemn H; Abu Bakar, Nurul Ain; Mohamed, Suhaila

    2016-02-01

    Lung cancer causes 1.4 million deaths annually. In the search for functional foods as complementary therapies against lung cancer, the immuno-stimulatory properties of the vegetable Morinda citrifolia leaves were investigated and compared with the anti-cancer drug erlotinib. Lung tumour-induced BALB/c mice were fed with 150 mg kg(-1) or 300 mg kg(-1) body weight of the leaf extract, or erlotinib (50 mg kg(-1) body-weight) for 21 days. The 300 mg kg(-1) body weight extract significantly (and dose-dependently) suppressed lung tumour growth; the extract worked more effectively than the 50 mg kg(-1) body weight erlotinib treatment. The extract significantly increased blood lymphocyte counts, and spleen tissue B cells, T cells and natural killer cells, and reduced the epidermal growth factor receptor (EGFR) which is a lung adenocarcinoma biomarker. The extract also suppressed the cyclooxygenase 2 (COX2) inflammatory markers, and enhanced the tumour suppressor gene (phosphatase and tensin homolog, PTEN). It inhibited tumour growth cellular gene (transformed mouse 3T3 cell double minute 2 (MDM2), V-raf-leukemia viral oncogene 1 (RAF1), and mechanistic target of rapamycin (MTOR)) mRNA expression in the tumours. The extract is rich in scopoletin and epicatechin, which are the main phenolic compounds. The 300 mg kg(-1)Morinda citrifolia leaf 50% ethanolic extract showed promising potential as a complementary therapeutic dietary supplement which was more effective than the 50 mg kg(-1) erlotinib in suppressing lung adenocarcinoma. Part of the mechanisms involved enhancing immune responses, suppressing proliferation and interfering with various tumour growth signalling pathways.

  16. Blocking Tumor Necrosis Factor α Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma.

    Science.gov (United States)

    Bertrand, Florie; Rochotte, Julia; Colacios, Céline; Montfort, Anne; Tilkin-Mariamé, Anne-Françoise; Touriol, Christian; Rochaix, Philippe; Lajoie-Mazenc, Isabelle; Andrieu-Abadie, Nathalie; Levade, Thierry; Benoist, Hervé; Ségui, Bruno

    2015-07-01

    TNF plays a dual, still enigmatic role in melanoma, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. Herein, the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels (MHC-I(high)) was dramatically impaired in TNF-deficient mice, and this was associated with enhanced tumor-infiltrating CD8(+) T lymphocytes. Immunodepletion of CD8 T cells fully restored melanoma growth in TNF(-/-) mice. Systemic administration of Etanercept inhibited MHC-I(high) melanoma growth in immunocompetent but not in immunodeficient (IFNγ(-/-), nude, or CD8(-/-)) mice. MHC-I(high) melanoma growth was also reduced in mice lacking TNF-R1, but not TNF-R2. TNF(-/-) and TNF-R1(-/-) mice as well as Etanercept-treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8(+) T-cell density. Adoptive transfer of activated TNF-R1-deficient or -proficient CD8(+) T cells in CD8-deficient mice bearing B16K1 tumors demonstrated that TNF-R1 deficiency facilitates the accumulation of live CD8(+) T cells into the tumors. Moreover, in vitro experiments indicated that TNF triggered activated CD8(+) T cell death in a TNF-R1-dependent manner, likely limiting the accumulation of tumor-infiltrating CD8(+) T cells in TNF/TNF-R1-proficient animals. Collectively, our observations indicate that TNF-R1-dependent TNF signaling impairs tumor-infiltrating CD8(+) T-cell accumulation and may serve as a putative target to favor CD8(+) T-cell-dependent immune response in melanoma. ©2015 American Association for Cancer Research.

  17. Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Kenneth E. Bernstein

    2016-03-01

    Full Text Available Angiotensin-converting enzyme (ACE converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA. Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response.

  18. Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression.

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    Huemer, Hartwig P; Lassnig, Caroline; Nowotny, Norbert; Irschick, Eveline U; Kitchen, Maria; Pavlic, Marion

    2010-08-31

    Benzodiazepines are drugs widely used as tranquilizers and in various other indications. We treated Balb/c mice with diazepam and infected them with cowpox (CPXV) and vaccinia virus (VACV). Disease index, weight loss and the antibody response were determined. Additionally the influence of different benzodiazepines on the mitogen response of human peripheral blood lymphocytes and spleen cells was tested. Diazepam led to earlier disease onset, prolonged duration of symptoms, higher weight loss and overall disease index in VACV infected mice. CPXV infected mice developed poxviral skin lesions only after drug administration and a significant decrease in the specific antibody response was also observed. Diazepam and alprazolam also inhibited the proliferative response of human lymphocytes/spleen cells in vitro but did not show noteworthy apoptotic effects. It is surprising that even a single dose of diazepam has a profound influence on the immune system, sufficient to facilitate symptomatic infectious disease. These data provide first evidence that commonly used drugs like Valium may augment severity of rare poxvirus infections such as CPXV or monkeypox. As VACV is still used as life vaccine against smallpox there is also a risk of enhanced side effects or possible interference with the success of vaccination. (c) 2010 Elsevier Ltd. All rights reserved.

  19. Enhancing the clinical potential of AAV vectors by capsid engineering to evade pre-existing immunity

    Directory of Open Access Journals (Sweden)

    Melissa eBartel

    2011-10-01

    Full Text Available Vectors based on adeno-associated viruses have shown considerable promise in both preclinical models and increasingly in clinical trials. However, one formidable challenge is pre-existing immunity due to widespread exposure to numerous AAV variants and serotypes within the human population, which affect efficacy of clinical trials due to the accompanying high levels of anti-capsid neutralizing antibodies. Transient immunosuppression has promise in mitigating cellular and humoral responses induced by vector application in naïve hosts, but cannot overcome the problem that pre-existing neutralizing antibodies pose towards the goal of safe and efficient gene delivery. Shielding of AAV from antibodies, however, may be possible by covalent attachment of polymers to the viral capsid or by encapsulation of vectors inside biomaterials. In addition, there has been considerable progress in using rational mutagenesis, combinatorial libraries, and directed evolution approaches to engineer capsid variants that are not recognized by anti-AAV antibodies generally present in the human population. While additional progress must be made, such strategies, alone or in combination with immunosuppression to avoid de novo induction of antibodies, have strong potential to significantly enhance the clinical efficacy of AAV vectors.

  20. Immune-enhancing activities of low molecular weight {beta}-glucan depolymerized by gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Nak-Yun [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Byun, Eui-Hong [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Laboratory of Food Chemistry, Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 (Japan); Kwon, Sun-Kyu; Song, Beom-Seok; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Yoo, Young-Choon [Department of Microbiology, College of Medicine, Konyang University, Daejeon 302-718 (Korea, Republic of); Kim, Mee-Ree [Department of Food and Nutrition, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Ju-Woon [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: sjwlee@kaeri.re.kr

    2009-07-15

    {beta}-glucans are structural cell wall polymers of many microorganisms and cereals which possess immunomodulatory properties and have been used in the food, cosmetic and medical industry. In our previous study, {beta}-glucan was depolymerized by gamma irradiation and leads to improve the solubility and viscosity. This study was carried out to evaluate the functional properties, mainly immune-enhancing activities of low molecular weight {beta}-glucan fragmented by gamma irradiation. The results showed that RAW 264.7 macrophage cell stimulation activities of irradiated {beta}-glucan were higher than that of non-irradiated {beta}-glucan. In addition, the oral administration of gamma-irradiated {beta}-glucan significantly increased the proliferation and cytokine (IFN-{gamma} and IL-2) release of spleen and Peyer's patch cells compared with non-irradiated {beta}-glucan. In conclusion, gamma irradiation could be used as an effective method for the production of depolymerized {beta}-glucan improved functional property such as immunomodulatory activity.

  1. Enhancing immune responses to inactivated porcine parvovirus oil emulsion vaccine by co-inoculating porcine transfer factor in mice.

    Science.gov (United States)

    Wang, Rui-ning; Wang, Ya-bin; Geng, Jing-wei; Guo, Dong-hui; Liu, Fang; Chen, Hong-ying; Zhang, Hong-ying; Cui, Bao-an; Wei, Zhan-yong

    2012-07-27

    Inactivated porcine parvovirus (PPV) vaccines are available commercially and widely used in the breeding herds. However, inactivated PPV vaccines have deficiencies in induction of specific cellular immune response. Transfer factor (TF) is a material that obtained from the leukocytes, and is a novel immune-stimulatory reagent that as a modulator of the immune system. In this study, the immunogenicity of PPV oil emulsion vaccine and the immuno-regulatory activities of TF were investigated. The inactivated PPV oil emulsion vaccines with or without TF were inoculated into BALB/c mice by subcutaneous injection. Then humoral and cellular immune responses were evaluated by indirect enzyme-linked immunosorbent assays (ELISA), fluorescence-activated cell sorter analyses (FACS). The results showed that the PPV specific immune responses could be evoked in mice by inoculating with PPV oil emulsion vaccine alone or by co-inoculation with TF. The cellular immune response levels in the co-inoculation groups were higher than those groups receiving the PPV oil emulsion vaccine alone, with the phenomena of higher level of IFN-γ, a little IL-6 and a trace of IL-4 in serum, and a vigorous T-cell response. However, there was no significant difference in antibody titers between TF synergy inactivated vaccine and the inactivated vaccine group (P>0.05). In conclusion, these results suggest that TF possess better cellular immune-enhancing capability and would be exploited into an effective immune-adjuvant for inactivated vaccines. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis.

    Science.gov (United States)

    Mueller, Tobias; Beutler, Claudia; Picó, Almudena Hurtado; Shibolet, Oren; Pratt, Daniel S; Pascher, Andreas; Neuhaus, Peter; Wiedenmann, Bertram; Berg, Thomas; Podolsky, Daniel K

    2011-11-01

    Pattern recognition receptors (PRRs) orchestrate the innate immune defence in human biliary epithelial cells (BECs). Tight control of PRR signalling provides tolerance to physiological amounts of intestinal endotoxins in human bile to avoid constant innate immune activation in BECs. We wanted to determine whether inappropriate innate immune responses to intestinal endotoxins contribute to the development and perpetuation of chronic biliary inflammation. We examined PRR-mediated innate immune responses and protective endotoxin tolerance in primary BECs isolated from patients with primary sclerosing cholangitis (PSC), alcoholic liver disease and patients without chronic liver disease. Expression studies comprised northern blots, RT-PCR, Western blots and immunocytochemistry. Functional studies comprised immuno-precipitation Western blots, FACS for endotoxin uptake, and NF-κB activation assays and ELISA for secreted IL-8 and tumour necrosis factor (TNF)-α. Primary BECs from explanted PSC livers showed reversibly increased TLR and NOD protein expression and activation of the MyD88/IRAK signalling complex. Consecutively, PSC BECs exhibited inappropriate innate immune responses to endotoxins and did not develop immune tolerance after repeated endotoxin exposures. This endotoxin hyper-responsiveness was probably because of the stimulatory effect of abundantly expressed IFN-γ and TNF-α in PSC livers, which stimulated TLR4-mediated endotoxin signalling in BECs, leading to increased TLR4-mediated endotoxin incorporation and impaired inactivation of the TLR4 signalling cascade. As TNF-α inhibition partly restored protective innate immune tolerance, endogenous TNF-α secretion probably contributed to inappropriate endotoxin responses in BECs. Inappropriate innate immune responses to intestinal endotoxins and subsequent endotoxin intolerance because of enhanced PRR signalling in BECs probably contribute to chronic cholangitis. © 2011 John Wiley & Sons A/S.

  3. Neural Network Enhanced Structure Determination of Osteoporosis, Immune System, and Radiation Repair Proteins Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The proposed innovation will utilize self learning neural network technology to determine the structure of osteoporosis, immune system disease, and excess radiation...

  4. Alphavirus replicon-based enhancement of mucosal and systemic immunity is linked to the innate response generated by primary immunization.

    Science.gov (United States)

    Tonkin, Daniel R; Jorquera, Patricia; Todd, Tracie; Beard, Clayton W; Johnston, Robert E; Barro, Mario

    2010-04-19

    Venezuelan equine encephalitis virus replicon particles (VRP) function as an effective systemic, cellular and mucosal adjuvant when codelivered with antigen, and show promise for use as a component in new and existing human vaccine formulations. We show here that VRP are effective at low dose and by intramuscular delivery, two useful features for implementation of VRP as a vaccine adjuvant. In mice receiving a prime and boost with antigen, we found that VRP are required in prime only to produce a full adjuvant effect. This outcome indicates that the events triggered during prime with VRP are sufficient to establish the nature and magnitude of the immune response to a second exposure to antigen. Events induced by VRP in the draining lymph node after prime include robust secretion of many inflammatory cytokines, upregulation of CD69 on leukocytes, and increased cellularity, with a disproportionate increase of a cell population expressing CD11c, CD11b, and F4/80. We show that antigen delivered 24h after administration of VRP does not benefit from an adjuvant effect, indicating that the events which are critical to VRP-mediated adjuvant activity occur within the first 24h. Further studies of the events induced by VRP will help elucidate the mechanism of VRP adjuvant activity and will advance the safe implementation of this adjuvant in human vaccines. Copyright 2010 Elsevier Ltd. All rights reserved.

  5. Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus.

    Science.gov (United States)

    Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye; Ko, Eun-Ju; Lee, Youri; Kwon, Young-Man; Kang, Sang-Moo

    2017-11-01

    Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. Copyright © 2017. Published by Elsevier Inc.

  6. Dietary supplementation of mannan-oligosaccharide enhances neonatal immune responses in chickens during natural exposure to Eimeria spp

    Directory of Open Access Journals (Sweden)

    Nava Gerardo M

    2009-03-01

    Full Text Available Abstract Background Control and eradication of intestinal infections caused by protozoa are important biomedical challenges worldwide. Prophylactic control of coccidiosis has been achieved with the use of anticoccidial drugs; however, the increase in anticoccidial resistance has raised concerns about the need for new alternatives for the control of coccidial infections. In fact, new strategies are needed to induce potent protective immune responses in neonatal individuals. Methods The effects of a dietary supplementation of mannan-oligosaccharide (yeast cell wall; YCW on the local, humoral and cell-mediated immune responses, and intestinal replication of coccidia were evaluated in a neonatal animal model during natural exposure to Eimeria spp. A total of 840 one-day-old chicks were distributed among four dietary regimens: A Control diet (no YCW plus anticoccidial vaccine; B Control diet plus coccidiostat; C YCW diet plus anticoccidial vaccination; and D YCW diet plus coccidiostat. Weight gain, feed consumption and immunological parameters were examined within the first seven weeks of life. Results Dietary supplementation of 0.05% of YCW increased local mucosal IgA secretions, humoral and cell-mediated immune responses, and reduced parasite excretion in feces. Conclusion Dietary supplementation of yeast cell wall in neonatal animals can enhance the immune response against coccidial infections. The present study reveals the potential of YCW as adjuvant for modulating mucosal immune responses.

  7. Reduction of splenic immunosuppressive cells and enhancement of anti-tumor immunity by synergy of fish oil and selenium yeast.

    Directory of Open Access Journals (Sweden)

    Hang Wang

    Full Text Available Growing evidence has shown that regulatory T cells (Tregs and myeloid-derived suppressor cells (MDSCs abnormally increase in cancer cachectic patients. Suppressions of Tregs and MDSCs may enhance anti-tumor immunity for cancer patients. Fish oil and selenium have been known to have many biological activities such as anti-inflammation and anti-oxidation. Whether fish oil and/or selenium have an additional effect on population of immunosuppressive cells in tumor-bearing hosts remained elusive and controversial. To gain insights into their roles on anti-tumor immunity, we studied the fish oil- and/or selenium-mediated tumor suppression and immunity on lung carcinoma, whereof cachexia develops. Advancement of cachexia in a murine lung cancer model manifested with such indicative symptoms as weight loss, chronic inflammation and disturbed immune functionality. The elevation of Tregs and MDSCs in spleens of tumor-bearing mice was positively correlated with tumor burdens. Consumption of either fish oil or selenium had little or no effect on the levels of Tregs and MDSCs. However, consumption of both fish oil and selenium together presented a synergistic effect--the population of Tregs and MDSCs decreased as opposed to increase of anti-tumor immunity when both fish oil and selenium were supplemented simultaneously, whereby losses of body weight and muscle/fat mass were alleviated significantly.

  8. Enhanced immune response to a dual-promoter anti-caries DNA vaccine orally delivered by attenuated Salmonella typhimurium.

    Science.gov (United States)

    Jiang, Hao; Hu, Yijun; Yang, Mei; Liu, Hao; Jiang, Guangshui

    2017-05-01

    The strength of immune responses induced by DNA vaccine is closely associated with the expression level of cloned antigens available to the antigen presenting cells (APCs). To acquire a larger and more persistent amount of antigen, a dual-promoter, which could double the target antigen output through its expression both in prokaryotic and eukaryotic cells, was employed in the constructed anti-caries DNA vaccine with attenuated Salmonella as mucosal delivery vector in this study. Here, both CMV and nirB promoters were included in the plasmid that harbors the genes encoding the functional epitopes of two virulence factors of S. mutans, i.e. the saliva-binding region (SBR) of PAc and the glucan-binding region (GBR) of glucosyltransferase-I (GTF-I). Delivered by attenuated Salmonella Typhimurium strain SL3261, the anti-caries vaccine was administered intragastrointestinally to BALB/c mice for evaluation of the effectiveness of this immune regime. Specific anti-SBR and anti-GBR antibodies were detected in the serum and saliva of experimental animals by week 3 after immunization. These immune responses were further enhanced after a booster vaccination at week 16. However, in mice receiving Salmonella expressing SBR and GBR under the control of nirB alone these antibody responses were significantly (Pcaries DNA vaccine when employing attenuated Salmonella as delivering vehicle for mucosal immunization. Copyright © 2017 Elsevier GmbH. All rights reserved.

  9. Immunostimulatory properties and enhanced TNF- α mediated cellular immunity for tumor therapy by C60(OH)20 nanoparticles

    Science.gov (United States)

    Liu, Ying; Jiao, Fang; Qiu, Yang; Li, Wei; Qu, Ying; Tian, Chixia; Li, Yufeng; Bai, Ru; Lao, Fang; Zhao, Yuliang; Chai, Zhifang; Chen, Chunying

    2009-10-01

    Publications concerning the mechanism of biological activity, especially the immunological mechanism of C60(OH)20 nanoparticles, are relatively limited. However, the structure and characteristics of this carbon allotrope have been widely investigated. In this paper, we have demonstrated that water-soluble C60(OH)20 nanoparticles have an efficient anti-tumor activity in vivo, and show specific immunomodulatory effects to the immune cells, such as T cells and macrophages, both in vivo and in vitro. For example, C60(OH)20 nanoparticles can increase the production of T-helper cell type 1 (Th1) cytokines (IL-2, IFN- γ and TNF-α), and decrease the production of Th2 cytokines (IL-4, IL-5 and IL-6) in serum samples. On the other hand, C60(OH)20 nanoparticles show almost no adverse effect to the viability of immune cells in vitro but stimulate the immune cells to release more cytokines, in particular TNF- α, which plays a key role in the cellular immune process to help eliminate abnormal cells. TNF- α production increased almost three-fold in treated T lymphocytes and macrophages. Accordingly, we conclude that C60(OH)20 nanoparticles have an efficient anti-tumor activity and this effect is associated with an increased CD4+/CD8+ lymphocyte ratio and the enhancement of TNF- α production. The data suggest that C60(OH)20 nanoparticles can improve the immune response to help to scavenge and kill tumor cells.

  10. Enhanced mucosal and systemic immune response with squalane oil-containing multiple emulsions upon intranasal and oral administration in mice.

    Science.gov (United States)

    Shahiwala, Aliasgar; Amiji, Mansoor M

    2008-05-01

    The objective of this study was to develop and evaluate squalane oil-containing water-in-oil-in-water (W/O/W) multiple emulsion for mucosal administration of ovalbumin (OVA) as a model candidate vaccine in BALB/c mice. Control and optimized OVA-containing W/O/W emulsion (OVA-Emul) and chitosan-modified W/O/W emulsion (OVA-Emul-Chi) formulations were administered intranasally and orally at an OVA dose of 100 mug. The mucosal and systemic immune responses were evaluated after the first and second immunization. The OVA-Emul formulations resulted in higher immunoglobulin-G (IgG) and immunoglobulin-A (IgA) responses as compared with aqueous solution. In addition, significant IgG and IgA responses were observed after the second immunization dose using the emulsions with both routes of administration. Intranasal vaccination was more effective in generating the systemic OVA-specific IgG response than the mucosal OVA-specific IgA response. Oral immunizations, on the other hand, showed a much higher systemic IgG and mucosal IgA responses as compared with the nasally treated groups. The results of this study show that squalane oil-containing W/O/W multiple emulsion formulations can significantly enhance the local and systemic immune responses, especially after oral administration, and may be adopted as a better alternative in mucosal delivery of prophylactic and therapeutic vaccines.

  11. Does larch arabinogalactan enhance immune function? A review of mechanistic and clinical trials.

    Science.gov (United States)

    Dion, Carine; Chappuis, Eric; Ripoll, Christophe

    2016-01-01

    The common cold is a viral infection with important economic burdens in Western countries. The research and development of nutritional solutions to reduce the incidence and severity of colds today is a major focus of interest, and larch arabinogalactan seems to be a promising supportive agent. Arabinogalactan has been consumed by humans for thousands of years and is found in a variety of common vegetables as well as in medicinal herbs. The major commercial sources of this long, densely branched, high-molecular-weight polysaccharide are North American larch trees. The aim of this article is to review the immunomodulatory effects of larch arabinogalactan derived from Larix laricina and Larix occidentalis (North American Larix species) and more specifically its role in the resistance to common cold infections. In cell and animal models, larch arabinogalactan is capable of enhancing natural killer cells and macrophages as well as the secretion of pro-inflammatory cytokines. In humans a clinical study demonstrated that larch arabinogalactan increased the body's potential to defend against common cold infection. Larch arabinogalactan decreased the incidence of cold episodes by 23 %. Improvements of serum antigen-specific IgG and IgE response to Streptococcus pneumoniae and tetanus vaccination suggesting a B cell dependent mechanism have been reported in vaccination studies with larch arabinogalactan, while the absence of response following influenza vaccination suggests the involvement of a T cell dependent mechanism. These observations suggest a role for larch arabinogalactan in the improvement of cold infections, although the mode of action remains to be further explored. Different hypotheses can be envisaged as larch arabinogalactan can possibly act indirectly through microbiota-dependent mechanisms and/or have a direct effect on the immune system via the gut-associated lymphoid tissue (GALT).

  12. Upgrading food wastes by means of bromelain and papain to enhance growth and immunity of grass carp (Ctenopharyngodon idella).

    Science.gov (United States)

    Choi, W M; Lam, C L; Mo, W Y; Wong, M H

    2016-04-01

    The fast growing of global aquaculture industry accompanied with increasing pressure on the supply and price of traditional feed materials (e.g., fish meal and soy bean meal). This circumstance has urged the need to search alternative sources of feed stuff. Food waste was used as feed stuff in rearing fish which possess substantial protein and lipid. Grass carp are major species reared in Hong Kong with lower nutritional requirements; it is also an ideal species for investigating the feasibility of using food waste as fish feeds for local aquaculture industry. The growth and immunity, reflected by total protein, total immunologlobulin (IgI), and nitroblue tetrazolium (NBT) activity of grass carp blood, were depressed when feeding with food waste feeds without enzymes. However, the supplementation of bromelain and papain in fish feed enhanced the efficient use of food waste by grass carp, which in turn improved the fish immunity. The present results indicated that the addition of those enzymes could enhance the feed utilization by fish and hematological parameters of grass carp, and the improvement on growth and immunity superior to the control (commercial feed) was observed with the addition of bromelain and papain supplement. Addition of 1 and 2 % mixture of bromelain and papain could significantly enhance the lipid utilization in grass carp.

  13. Proteomic identification of the related immune-enhancing proteins in shrimp Litopenaeus vannamei stimulated with vitamin C and Chinese herbs.

    Science.gov (United States)

    Qiao, Jie; Du, Zhiheng; Zhang, Yueling; Du, Hong; Guo, Lingling; Zhong, Mingqi; Cao, Jingsong; Wang, Xiuying

    2011-12-01

    Recently, strong interest has been focused on immunostimulants to reducing the diseases in shrimp aquaculture. However, information regarding to the related immune-enhancing proteins in shrimps is not available yet. In this study, vitamin C (Vc), Chinese herbs (CH), and the mixture of vitamin C and Chinese herbs (Mix) were tested for their enhancement on shrimp's immune activity. Compared with those in the control group, values of phenoloxidase (PO), superoxide dismutase (SOD) and antibacterial (Ua) activity in the Mix-treated group were improved significantly 12 or 24 days after the treatment. The cumulative mortality was also lower in the Mix-treated group after infection with Vibrio parahemolyticus. Furthermore, comparative proteomic approach was used to assess the protein expression profile in shrimps. Approximately 220-290 and 300-400 protein spots were observed in the 2-DE gels. Among them, 29 and 28 altered proteins from hemocytes and hepatopancreas, respectively, were subjected to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. The results revealed that the main altered proteins showed high homologies with Litopenaeus vannamei hemocyanin, hemolymph clottable protein, hemoglobin beta, cytosolic MnSOD, trypsin, cathepsin I(L) and zinc proteinase Mpc1. Together, these studies found Vc and CH were suitable immunostimulants to shrimp L. vannamei, and 7 altered proteins could be involved in the enhanced immune activities. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant.

    Science.gov (United States)

    Murugappan, Senthil; Frijlink, Henderik W; Petrovsky, Nikolai; Hinrichs, Wouter L J

    2015-01-23

    Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However, pulmonary administration of whole inactivated influenza virus (WIV) vaccine induces a Th2 dominant systemic immune response while a more balanced Th1/Th2 vaccine response may be preferred and only induces modest nasal immunity. This study evaluated immunity elicited by pulmonary versus intramuscular (i.m.) delivery of WIV, and tested whether the immune response could be improved by co-administration of delta (δ)-inulin, a novel carbohydrate-based particulate adjuvant. After pulmonary administration both unadjuvanted and δ-inulin adjuvanted WIV induced a potent systemic immune response, inducing higher serum anti-influenza IgG titers and nasal IgA titers than i.m. administration. Moreover, the addition of δ-inulin induced a more balanced Th1/Th2 response and induced higher nasal IgA titers versus pulmonary WIV alone. Pulmonary WIV alone or with δ-inulin induced hemagglutination inhibition (HI) titers>40, titers which are considered protective against influenza virus. In conclusion, in this study we have shown that δ-inulin adjuvanted WIV induces a better immune response after pulmonary administration than vaccine alone. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet.

    Science.gov (United States)

    Lussier, Danielle M; Woolf, Eric C; Johnson, John L; Brooks, Kenneth S; Blattman, Joseph N; Scheck, Adrienne C

    2016-05-13

    Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response. The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells. We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells. The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.

  16. HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells.

    Science.gov (United States)

    Veenhuis, Rebecca T; Freeman, Zachary T; Korleski, Jack; Cohen, Laura K; Massaccesi, Guido; Tomasi, Alessandra; Boesch, Austin W; Ackerman, Margaret E; Margolick, Joseph B; Blankson, Joel N; Chattergoon, Michael A; Cox, Andrea L

    2017-10-30

    Type I IFN production is essential for innate control of acute viral infection; however, prolonged high-level IFN production is associated with chronic immune activation in HIV-infected individuals. Although plasmacytoid DCs (pDCs) are a primary source of IFN, the mechanisms that regulate IFN levels following the acute phase are unknown. We hypothesized that HIV-specific Ab responses regulate late IFN production. We evaluated the mechanism through which HIV-activated pDCs produce IFN as well as how both monoclonal HIV-specific Abs and Abs produced in natural HIV infection modulated normal pDC sensing of HIV. We found that HIV-induced IFN production required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or HIV life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding markedly enhanced the IFN response, irrespective of their ability to neutralize CD4+ T cell infection. Ab-mediated enhancement of IFN production required Fc γ receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized in the absence of Ab. Polyclonal Abs isolated from HIV-infected subjects also enhanced pDC production of IFN in response to HIV. Our data provide an explanation for high levels of IFN production and immune activation in chronic HIV infection.

  17. Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant

    NARCIS (Netherlands)

    Murugappan, Senthil; Frijlink, Henderik W.; Petrovsky, Nikolai; Hinrichs, Wouter L. J.

    2015-01-01

    Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However,

  18. Enterococcus faecium SF68 Enhances the Immune Response to Giardia intestinalis in Mice1

    National Research Council Canada - National Science Library

    J Benyacoub; P F Pérez; F Rochat; K Y Saudan

    2005-01-01

    .... The improvement of specific immune responses in probiotic-fed mice was associated with a diminution in the number of active trophozoites in the small intestine as well as decreased shedding of fecal Giardia antigens (GSA65 protein...

  19. Salidroside liposome formulation enhances the activity of dendritic cells and immune responses.

    Science.gov (United States)

    Zhao, Xiaojuan; Lu, Yu; Tao, Yang; Huang, Yee; Wang, Deyun; Hu, Yuanliang; Liu, Jiaguo; Wu, Yi; Yu, Yun; Liu, Cui

    2013-12-01

    Salidroside, the important composition, of Rhodiola rosea L. has been reported to have various pharmacological properties. Liposome is known to be effective as drug carriers and immune adjuvant. Therefore, the aim of this study is to investigate immunological adjuvant activity of salidroside liposome. Here we reported the preparation, the effect on DCs in vitro and the immune response in vivo. The immunological adjuvant activity of salidroside liposome formulation was compared with that of salidroside and liposome. The result showed that salidroside liposome formulation not only could promote the maturation of DCs, the stimulation of DCs on MLR proliferation and the antigen presenting ability, but also induced the sustained cellular immune and humoral immune response. Overall, the results showed that salidroside liposome formulation had the potential to act as effective sustained release vaccine delivery systems. © 2013.

  20. Critical Role for CCAAT/Enhancer Binding Protein β in Immune Complex-Induced Acute Lung Injury

    Science.gov (United States)

    Yan, Chunguang; Wu, Min; Cao, Jay; Tang, Huifang; Zhu, Mei; Johnson, Peter F.; Gao, Hongwei

    2012-01-01

    The CCAAT/enhancer-binding proteins (C/EBPs), particularly C/EBPβ and C/EBPδ, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPβ and C/EBPδ in acute lung inflammation and injury. Here we show that both C/EBPβ and C/EBPδ activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPβ gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (MPO activity), total number of white blood cells, and neutrophils in bronchial alveolar lavage (BAL) fluids compared to wild-type mice. Moreover, the mutant mice expressed considerably less TNF-α, IL-6, and CXC/CC chemokine and sICAM-1 proteins in BAL fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared to wild-type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPδ deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPβ-deficient alveolar macrophages released significantly less TNF-α, IL-6, macrophage inflammatory protein (MIP)-2, keratinocyte cell-derived chemokine (KC), and MIP-1α compared to wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following siRNA ablation of C/EBPβ in a murine alveolar macrophage cell line. These findings implicate C/EBPβ as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung. PMID:22732594

  1. Enhanced responses to tumor immunization following total body irradiation are time-dependent.

    Directory of Open Access Journals (Sweden)

    Adi Diab

    Full Text Available The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8(+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8(+ T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference

  2. Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load.

    Science.gov (United States)

    Oxenius, Annetie; Sewell, Andrew K; Dawson, Sara J; Günthard, Huldrych F; Fischer, Marek; Gillespie, Geraldine M; Rowland-Jones, Sarah L; Fagard, Catherine; Hirschel, Bernard; Phillips, Rodney E; Price, David A

    2002-11-01

    The potent ability of current antiretroviral drug regimens to control human immunodeficiency Virus-1 (HIV-1) replication, in conjunction with the clinical practice of structured therapeutic interruptions, provides a system in which virus levels are manipulated during a persistent infection in humans. Here, we exploit this system to examine the impact of variable plasma virus load (pVL) on the functionality of HIV-specific CD8+ T-lymphocyte populations. Using both ELISpot methodology and intracellular cytokine staining for interferon (IFN)-gamma to assess functional status, together with fluorochrome-labeled peptide-major histocompatibility complex (pMHC) class I tetramer analysis to detect the physical presence of CD8+ T lymphocytes expressing cognate T-cell receptors (TCRs), we observed that the proportion of HIV-specific CD8+ T lymphocytes capable of mounting an effector response to antigen challenge directly ex vivo is related to the kinetics of virus exposure. Specifically, (a) after prolonged suppression of pVL with antiretroviral therapy (ART), physical and functional measures of HIV-specific CD8+ T-lymphocyte frequencies approximated; and (b) the percentage of functionally responsive cells in the HIV-specific CD8+ T lymphocyte populations declined substantially when therapy was discontinued and pVL recrudesced in the same patients. These results corroborate and extend observations in animal models that describe nonresponsive CD8+ T lymphocytes in the presence of high levels of antigen load and have implications for the interpretation of quantitative data generated by methods that rely on functional readouts.

  3. Unanticipated Mycobacterium tuberculosis complex culture inhibition by immune modulators, immune suppressants, a growth enhancer, and vitamins A and D: clinical implications.

    Science.gov (United States)

    Greenstein, Robert J; Su, Liya; Shahidi, Azra; Brown, William D; Clifford, Anya; Brown, Sheldon T

    2014-09-01

    The development of novel antibiotics to treat multidrug-resistant (MDR) tuberculosis is time-consuming and expensive. Multiple immune modulators, immune suppressants, anti-inflammatories, and growth enhancers, and vitamins A and D, inhibit Mycobacterium avium subspecies paratuberculosis (MAP) in culture. We studied the culture inhibition of Mycobacterium tuberculosis complex by these agents. Biosafety level two M. tuberculosis complex (ATCC 19015 and ATCC 25177) was studied in radiometric Bactec or MGIT culture. Agents evaluated included clofazimine, methotrexate, 6-mercaptopurine, cyclosporine A, rapamycin, tacrolimus, monensin, and vitamins A and D. All the agents mentioned above caused dose-dependent inhibition of the M. tuberculosis complex. There was no inhibition by the anti-inflammatory 5-aminosalicylic acid, which causes bacteriostatic inhibition of MAP. We conclude that, at a minimum, studies with virulent M. tuberculosis are indicated with the agents mentioned above, as well as with the thioamide 5-propothiouricil, which has previously been shown to inhibit the M. tuberculosis complex in culture. Our data additionally emphasize the importance of vitamins A and D in treating mycobacterial diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Clostridium perfringens beta toxin DNA prime-protein boost elicits enhanced protective immune response in mice.

    Science.gov (United States)

    Solanki, Amit Kumar; Bhatia, Bharati; Kaushik, Himani; Deshmukh, Sachin K; Dixit, Aparna; Garg, Lalit C

    2017-07-01

    Clostridium perfringens beta toxin (CPB) is the primary pathogenic factor responsible for necrotic enteritis in sheep, cattle and humans. Owing to rapid progression of the disease, vaccination is the only possible recourse to avoid high mortality in animal farms and huge economic losses. The present study reports evaluation of a cpb gene-based DNA vaccine encoding the beta toxin of C. perfringens with homologous as well as heterologous booster strategy. Immunization strategy employing heterologous booster with heat-inactivated rCPB mounted stronger immune response when compared to that generated by homologous booster. Antibody isotyping and cytokine ELISA demonstrated the immune response to be Th1-biased mixed immune response. While moderate protection of immunized BALB/c and C57BL/6 mice against rCPB challenge was observed with homologous booster strategy, heterologous booster strategy led to complete protection. Thus, beta toxin-based DNA vaccine using the heterologous prime-boosting strategy was able to generate better immune response and conferred greater degree of protection against high of dose rCPB challenge than homologous booster regimen, making it an effective vaccination approach against C. perfringens beta toxin.

  5. HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) -Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART).

    Science.gov (United States)

    Jensen, Sanne Skov; Fomsgaard, Anders; Borggren, Marie; Tingstedt, Jeanette Linnea; Gerstoft, Jan; Kronborg, Gitte; Rasmussen, Line Dahlerup; Pedersen, Court; Karlsson, Ingrid

    2015-01-01

    Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART.

  6. Co-infection with Mycobacterium tuberculosis impairs HIV-Specific CD8+ and CD4+ T cell functionality.

    Science.gov (United States)

    Chetty, Shivan; Govender, Pamla; Zupkosky, Jennifer; Pillay, Mona; Ghebremichael, Musie; Moosa, Mahomed-Yunus S; Ndung'u, Thumbi; Porichis, Filippos; Kasprowicz, Victoria O

    2015-01-01

    The ability of antigen-specific T cells to simultaneously produce multiple cytokines is thought to correlate with the functional capacity and efficacy of T cells. These 'polyfunctional' T cells have been associated with control of HIV. We aimed to assess the impact of co-infection with Mycobacterium tuberculosis (MTB) on HIV-specific CD8+ and CD4+ T cell function. We assessed T cell functionality in 34 South African adults by investigating the IFN-y, IL-2, TNF-α, IL-21 and IL-17 cytokine secretion capacity, using polychromatic flow cytometry, following HIV Gag-specific stimulation of peripheral blood mononuclear cells. We show that MTB is associated with lower HIV-specific T cell function in co-infected as compared to HIV mono-infected individuals. This decline in function was greatest in co-infection with active Tuberculosis (TB) compared to co-infection with latent MTB (LTBI), suggesting that mycobacterial load may contribute to this loss of function. The described impact of MTB on HIV-specific T cell function may be a mechanism for increased HIV disease progression in co-infected subjects as functionally impaired T cells may be less able to control HIV.

  7. Deletion of PPAR-γ in immune cells enhances susceptibility to antiglomerular basement membrane disease

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    Cristen Chafin

    2010-10-01

    Full Text Available Cristen Chafin2, Sarah Muse2, Raquel Hontecillas5, Josep Bassaganya-Riera5, David L Caudell2, Samuel K Shimp III4, M Nichole Rylander4, John Zhang6, Liwu Li3, Christopher M Reilly1,21Virginia College of Osteopathic Medicine, 2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 3Department of Biological Sciences, 4Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 5Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 6Medical University of SC, Charleston, SC, USAAbstract: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR-γ has been shown to be immunoregulatory in autoimmune diseases by inhibiting production of a number of inflammatory mediators. We investigated whether PPAR-γ gene deletion in hematopoietic cells would alter disease pathogenesis in the antiglomerular basement membrane (anti-GBM mouse model. PPAR-γ+/+ and PPAR-γ-/- mice were immunized with rabbit antimouse GBM antibodies and lipopolysaccharide and evaluated for two weeks. Although both the PPAR-γ+/+ and PPAR-γ-/- mice had IgG deposition in the glomerulus and showed proteinuria two weeks after injection, glomerular and tubulointerstitial disease in PPAR-γ-/- mice were significantly more severe compared with the PPAR-γ+/+ animals. We observed that the PPAR-γ-/- mice had decreased CD4+CD25+ regulatory T cells and an increased CD8+:CD4+ ratio as compared with the PPAR-γ+/+ mice, suggesting that PPAR-γ has a role in the regulation of T cells. Furthermore, plasma interleukin-6 levels were significantly increased in the PPAR-γ-/- mice at two weeks as compared with the PPAR-γ+/+ animals. Taken together, these studies show that

  8. Increased hepatic blood flow during enteral immune-enhancing diet gavage requires intact enterohepatic bile cycling.

    Science.gov (United States)

    Nagengast, Andrea K; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, R Neal; Matheson, Paul J

    2014-03-01

    Total hepatic blood flow (HBF) via the hepatic artery and portal vein is highly dependent on gastrointestinal perfusion. During postprandial hyperemia, intestinal blood flow depends on nutrient composition, gastrointestinal location, and time. Immune-enhancing diets (IEDs) containing n-3 polyunsaturated fatty acids (PUFAs) selectively augment blood flow in the ileum at 60-120 min via a bile-dependent mechanism. My colleagues and I hypothesized that liver blood flow would be similarly affected by IEDs containing n-3 PUFAs. Mean arterial blood pressure, heart rate, and effective HBF (galactose clearance) were measured in anesthetized male Sprague-Dawley rats after gastric gavage of either a control diet (CD, Boost, Novartis) or an IED (Impact, Nestle Nutrition), with or without bile-duct ligation (BDL), and with or without supplemental bile (bovine, dried, unfractionated). Significance was assessed by 2-way ANOVA for repeated measures with the Tukey-Kramer honestly significant difference test. Compared with baseline levels, a CD increased HBF (peak at 40 min , *P < 0.05) whereas an IED increased HBF in two distinct peaks at 40 min (*P < 0.05) and 120 min (*P < 0.05), but BDL prevented both the early (CD and IED, †P < 0.05) and late peaks (IED, †P < 0.05). Bile supplementation in the CD + BDL or IED + BDL groups restored neither the CD peak nor the early or late IED peaks. HBF during absorptive intestinal hyperemia is modulated by a mechanism that requires an intact enterohepatic circulation. The early peaks at 40 min (CD or IED) were prevented by BDL, even though fat absorption in the proximal gut occurs by bile-independent direct absorption. Bile supplementation with the diet (CD + BDL or IED + BDL) was insufficient to restore HBF hyperemia, which implies that a relationship exists between intestinal and hepatic blood flow that is not solely dependent on bile-mediated intestinal fat absorption and bile recirculation. Copyright © 2014 Elsevier Inc. All rights

  9. Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major.

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    Romain Ballet

    2014-12-01

    Full Text Available The recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to T cells. In the present study, we showed that antibody blockade of junctional adhesion molecule C (JAM-C on endothelial cells removed JAM-C away from junctions and increased vascular permeability after L. major infection. This has multiple consequences on the output of the immune response. In resistant C57BL/6 and susceptible BALB/c mice, we found higher numbers of innate immune cells migrating from blood to the site of infection. The subsequent migration of dendritic cells (DCs from the skin to the draining lymph node was also improved, thereby boosting the induction of the adaptive immune response. In C57BL/6 mice, JAM-C blockade after L. major injection led to an enhanced IFN-γ dominated T helper 1 (Th1 response with reduced skin lesions and parasite burden. Conversely, anti JAM-C treatment increased the IL-4-driven T helper 2 (Th2 response in BALB/c mice with disease exacerbation. Overall, our results show that JAM-C blockade can finely-tune the innate cell migration and accelerate the consequent immune response to L. major without changing the type of the T helper cell response.

  10. Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major.

    Science.gov (United States)

    Ballet, Romain; Emre, Yalin; Jemelin, Stéphane; Charmoy, Mélanie; Tacchini-Cottier, Fabienne; Imhof, Beat A

    2014-12-01

    The recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to T cells. In the present study, we showed that antibody blockade of junctional adhesion molecule C (JAM-C) on endothelial cells removed JAM-C away from junctions and increased vascular permeability after L. major infection. This has multiple consequences on the output of the immune response. In resistant C57BL/6 and susceptible BALB/c mice, we found higher numbers of innate immune cells migrating from blood to the site of infection. The subsequent migration of dendritic cells (DCs) from the skin to the draining lymph node was also improved, thereby boosting the induction of the adaptive immune response. In C57BL/6 mice, JAM-C blockade after L. major injection led to an enhanced IFN-γ dominated T helper 1 (Th1) response with reduced skin lesions and parasite burden. Conversely, anti JAM-C treatment increased the IL-4-driven T helper 2 (Th2) response in BALB/c mice with disease exacerbation. Overall, our results show that JAM-C blockade can finely-tune the innate cell migration and accelerate the consequent immune response to L. major without changing the type of the T helper cell response.

  11. Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition.

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    Sarah L Sherrington

    2017-05-01

    Full Text Available Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C. albicans by macrophages and neutrophils, and induced a stronger proinflammatory cytokine response, driven through the C-type lectin-like receptor, Dectin-1. This enhanced inflammatory response resulted in significant recruitment of neutrophils in an intraperitoneal model of infection, a hallmark of symptomatic vaginal colonisation. Enhanced chitin exposure resulted from reduced expression of the cell wall chitinase Cht2, via a Bcr1-Rim101 dependent signalling cascade, while increased β-glucan exposure was regulated via a non-canonical signalling pathway. We propose that this "unmasking" of the cell wall may induce non-protective hyper activation of the immune system during growth in acidic niches, and may attribute to symptomatic vaginal infection.

  12. Regular Exercise Enhances the Immune Response Against Microbial Antigens Through Up-Regulation of Toll-like Receptor Signaling Pathways

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    Qishi Zheng

    2015-09-01

    Full Text Available Background/Aims: Regular physical exercise can enhance resistance to many microbial infections. However, little is known about the mechanism underlying the changes in the immune system induced by regular exercise. Methods: We recruited members of a university badminton club as the regular exercise (RE group and healthy sedentary students as the sedentary control (SC group. We investigated the distribution of peripheral blood mononuclear cell (PBMC subsets and functions in the two groups. Results: There were no significant differences in plasma cytokine levels between the RE and SC groups in the true resting state. However, enhanced levels of IFN-γ, TNF-α, IL-6, IFN-α and IL-12 were secreted by PBMCs in the RE group following microbial antigen stimulation, when compared to the SC group. In contrast, the levels of TNF-α and IL-6 secreted by PBMC in the RE group were suppressed compared with those in SC group following non-microbial antigen stimulation (concanavalin A or α-galactosylceramide. Furthermore, PBMC expression of TLR2, TLR7 and MyD88 was significantly increased in the RE group in response to microbial antigen stimulation. Conclusion: Regular exercise enhances immune cell activation in response to pathogenic stimulation leading to enhanced cytokine production mediated via the TLR signaling pathways.

  13. β-1,3/1,6-Glucan-supplemented diets antagonize immune inhibitory effects of hypoxia and enhance the immune response to a model vaccine.

    Science.gov (United States)

    Rodríguez, Felipe E; Valenzuela, Beatriz; Farías, Ana; Sandino, Ana María; Imarai, Mónica

    2016-12-01

    The diets of farmed salmon are usually supplemented with immunostimulants to improve health status. Because β-glucan is one of the most common immunostimulants used in diets, here we examined the effect of two β-1,3/1,6-glucan-supplemented diets on the expression of immune response genes of Atlantic salmon. The relative abundances of IFN-α1, Mx, IFN-γ, IL-12, TGF-β1, IL-10, and CD4 transcripts were evaluated in head kidney by qRT-PCR. We assessed the effects of the diets under normoxia and acute hypoxia, as salmon are especially sensitive to changes in the concentration of dissolved oxygen, which can also affect immunity. These effects were also tested on vaccinated fish, as we expected that β-1,3/1,6-glucan-supplemented diets would enhance the adaptive immune response to the vaccine. We found that administration of the Bg diet (containing β-1,3/1,6-glucan) under normoxia had no effects on the expression of the analyzed genes in the kidney of the diet-fed fish, but under hypoxia/re-oxygenation (90 min of acute hypoxia), the βg diet affected the expression of the antiviral genes, IFN-α1 and Mx, preventing their decrease caused by hypoxia. The Bax diet, which in addition to β-1,3/1,6-glucan, contained astaxanthin, increased IL-12 and IFN-γ in kidneys. With fish exposed to hypoxia/reoxygenation, the diet prevented the decrease of IFN-α1 and Mx levels observed after hypoxia. When fish were vaccinated, only the levels of IL-12 and CD4 transcripts increased, but interestingly if fish were also fed the Bax diet, the vaccination induced a significant increase in all the analyzed transcripts. Finally, when vaccinated fish were exposed to hypoxia, the effect of the Bax diet was greatly reduced for all genes tested and moreover, inducible effects completely disappeared for IL-12, IFN-α, and Mx. Altogether, these results showed that the tested β-1,3/1,6-glucan diets increased the levels of transcripts of key genes involved in innate and adaptive immune response

  14. Recombinant TgHSP70 Immunization Protects against Toxoplasma gondii Brain Cyst Formation by Enhancing Inducible Nitric Oxide Expression

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    Neide M. Silva

    2017-04-01

    Full Text Available Toxoplasma gondii is known to cause congenital infection in humans and animals and severe disease in immunocompromised individuals; consequently development of vaccines against the parasite is highly necessary. Under stress conditions, T. gondii expresses the highly immunogenic heat shock protein 70 (TgHSP70. Here, we assessed the protective efficacy of rTgHSP70 immunization combined with Alum in oral ME-49 T. gondii infection and the mechanisms involved on it. It was observed that immunized mice with rTgHSP70 or rTgHSP70 adsorbed in Alum presented a significantly reduced number of cysts in the brain that was associated with increased iNOS+ cell numbers in the organ, irrespective the use of the adjuvant. Indeed, ex vivo experiments showed that peritoneal macrophages pre-stimulated with rTgHSP70 presented increased NO production and enhanced parasite killing, and the protein was able to directly stimulate B cells toward antibody producing profile. In addition, rTgHSP70 immunization leads to high specific antibody titters systemically and a mixed IgG1/IgG2a response, with predominance of IgG1 production. Nonetheless, it was observed that the pretreatment of the parasite with rTgHSP70 immune sera was not able to control T. gondii internalization and replication by NIH fibroblast neither peritoneal murine macrophages, nor anti-rTgHSP70 antibodies were able to kill T. gondii by complement-mediated lysis, suggesting that these mechanisms are not crucial to resistance. Interestingly, when in combination with Alum, rTgHSP70 immunization was able to reduce inflammation in the brain of infected mice and in parallel anti-rTgHSP70 immune complexes in the serum. In conclusion, immunization with rTgHSP70 induces massive amounts of iNOS expression and reduced brain parasitism, suggesting that iNOS expression and consequently NO production in the brain is a protective mechanism induced by TgHSP70 immunization, therefore rTgHSP70 can be a good candidate for

  15. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish.

    Science.gov (United States)

    Martinez, Rebeca; Ubieta, Kenia; Herrera, Fidel; Forellat, Alina; Morales, Reynold; de la Nuez, Ania; Rodriguez, Rolando; Reyes, Osvaldo; Oliva, Ayme; Estrada, Mario P

    2012-09-01

    In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae.

  16. Levamisole enhances immune response by affecting the activation and maturation of human monocyte-derived dendritic cells

    Science.gov (United States)

    Chen, L-Y; Lin, Y-L; Chiang, B-L

    2008-01-01

    Levamisole is a synthetic phenylimidazolthiazole that was first introduced in 1966 as an anti-helmintic agent. Current studies have been focused upon its effect on immune response and on cancer treatment. We examined the molecular mechanisms of levamisole in the activation and maturation of human monocyte-derived dendritic cells (DC) and human T cells. Treatment of DC with levamisole increased the presentation of CD80, CD86, CD83 and human leucocyte antigen D-related (HLA-DR) molecules on the cell membrane, as well as the production of interleukin (IL)-12 p40 and IL-10. Levamisole-treated human DC also enhanced T cell activation towards type 1 T helper immune response by inducing interferon-γ secretion. Neutralization with antibodies against Toll-like receptor (TLR)-2 inhibited levamisole-induced production of IL-12 p40 and IL-10, suggesting a vital role for TLR-2 in signalling DC upon incubation with levamisole. The inhibition of nuclear factor-κB, extracellular signal-regulated kinases 1/2 or c-Jun N-terminal kinases pathways also prevented the effects of levamisole on DC in producing IL-12 p40 or IL-10. Taken together, levamisole could enhance immune response towards T helper 1 development through the activation of dendritic cells or T cell aspects. PMID:18005262

  17. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.

    Science.gov (United States)

    Günaltay, Sezin; Kumawat, Ashok Kumar; Nyhlin, Nils; Bohr, Johan; Tysk, Curt; Hultgren, Olof; Hultgren Hörnquist, Elisabeth

    2015-01-01

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

  18. Heterologous Prime-Boost Vaccination Enhances TsPmy’s Protective Immunity against Trichinella spiralis Infection in a Murine Model

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    Lei Wang

    2017-07-01

    Full Text Available TsPmy is a paramyosin expressed by parasitic Trichinella spiralis and confers a protective immunity when its recombinant protein or DNA was used as an immunogen. To improve its immunogenicity and vaccine efficacy, we conducted a heterologous prime-boost strategy by orally delivering one dose of TsPmy DNA carried by attenuated Salmonella typhimurium (SL7207, followed by two doses of recombinant TsPmy intramuscularly. This strategy effectively induced intestinal mucosal sIgA response and an enhanced and balanced Th1/Th2 immune responses that improve protection against T. spiralis larval challenge, with 55.4% muscle larvae reduction and 41.8% adult worm reduction compared to PBS control. The muscle larvae reduction induced by heterologous prime-boost regimen was significant higher than that induced by the homologous DNA or protein prime-boost regimens, which could act as a practical prophylactic approach to prevent T. spiralis infection.

  19. Immune-enhancing effects of Maitake (Grifola frondosa) and Shiitake (Lentinula edodes) extracts

    Science.gov (United States)

    Vetvickova, Jana

    2014-01-01

    Background The role of glucan in stimulation of immune reactions has been studied for several decades. In this report, we focused on the effects of orally administered glucan Maitake and Shiitake on immune reactions. Materials and methods We measured phagocytosis, NK cell activity, and secretion of IL-6, IL-12, IFN-γ as well as C-reactive protein (CRP) after 14 days of oral application of tested glucans. For comparison, active hexose correlated compound (AHCC) was used in all reactions. Results We found significant stimulation of defense reaction. In all cases, the most active was the Maitake-Shiitake combination, with Maitake alone being the second strongest, followed by Shiitake on its own and AHCC. Conclusions Short-term oral application of natural immunomodulating glucans from Maitake and Shiitake mushrooms strongly stimulated both the cellular and humoral branch of immune reactions. These activities were significantly higher than those of AHCC. PMID:25332990

  20. Dammarane triterpenes from the leaves of Panax ginseng enhance cellular immunity

    DEFF Research Database (Denmark)

    Tran, Tien-Lam; Kim, Young-Ran; Yang, Jun-Li

    2014-01-01

    In our search for immune stimulating materials from natural source, bioassay-guided fractionation of a methanol extract of Panax ginseng leaves led to the isolation of three dammarane triterpenes (1-3), including two previously unknown compounds 27-demethyl-(E,E)-20(22),23-dien-3β,6α,12β-trihydro......In our search for immune stimulating materials from natural source, bioassay-guided fractionation of a methanol extract of Panax ginseng leaves led to the isolation of three dammarane triterpenes (1-3), including two previously unknown compounds 27-demethyl-(E,E)-20(22),23-dien-3β,6α,12β...

  1. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies.

    Science.gov (United States)

    Evans, Elizabeth E; Jonason, Alan S; Bussler, Holm; Torno, Sebold; Veeraraghavan, Janaki; Reilly, Christine; Doherty, Michael A; Seils, Jennifer; Winter, Laurie A; Mallow, Crystal; Kirk, Renee; Howell, Alan; Giralico, Susan; Scrivens, Maria; Klimatcheva, Katya; Fisher, Terrence L; Bowers, William J; Paris, Mark; Smith, Ernest S; Zauderer, Maurice

    2015-06-01

    Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2(+) mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression. ©2015 American Association for Cancer Research.

  2. Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand.

    Science.gov (United States)

    Liljenfeldt, Lina; Gkirtzimanaki, Katerina; Vyrla, Dimitra; Svensson, Emma; Loskog, Angelica Si; Eliopoulos, Aristides G

    2014-03-01

    Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.

  3. Enhancement of innate immune system in monocot rice by transferring the dicotyledonous elongation factor Tu receptor EFR.

    Science.gov (United States)

    Lu, Fen; Wang, Huiqin; Wang, Shanzhi; Jiang, Wendi; Shan, Changlin; Li, Bin; Yang, Jun; Zhang, Shiyong; Sun, Wenxian

    2015-07-01

    The elongation factor Tu (EF-Tu) receptor (EFR) in cruciferous plants specifically recognizes the N-terminal acetylated elf18 region of bacterial EF-Tu and thereby activates plant immunity. It has been demonstrated that Arabidopsis EFR confers broad-spectrum bacterial resistance in the EFR transgenic solanaceous plants. Here, the transgenic rice plants (Oryza sativa L. ssp. japonica cv. Zhonghua 17) and cell cultures with constitutive expression of AtEFR were developed to investigate whether AtEFR senses EF-Tu and thus enhances bacterial resistance in the monocot plants. We demonstrated that the Xanthomonas oryzae-derived elf18 peptide induced oxidative burst and mitogen-activated protein kinase activation in the AtEFR transgenic rice cells and plants, respectively. Pathogenesis-related genes, such as OsPBZ1, were upregulated dramatically in transgenic rice plant and cell lines in response to elf18 stimulation. Importantly, pretreatment with elf18 triggered strong resistance to X. oryzae pv. oryzae in the transgenic plants, which was largely dependent on the AtEFR expression level. These plants also exhibited enhanced resistance to rice bacterial brown stripe, but not to rice fungal blast. Collectively, the results indicate that the rice plants with heterologous expression of AtEFR recognize bacterial EF-Tu and exhibit enhanced broad-spectrum bacterial disease resistance and that pattern recognition receptor-mediated immunity may be manipulated across the two plant classes, dicots and monocots. © 2014 Institute of Botany, Chinese Academy of Sciences.

  4. Enhancement of humoral immunity in mice by coupling pUCpGs10 and aluminium to the HCV recombinant immunogen

    Directory of Open Access Journals (Sweden)

    Zhan Na

    2011-11-01

    Full Text Available Abstract Aim To investigate the enhancement of humoral immunity when CpG ODN (cytidine phosphate guanosine oligodeoxynucleotides and aluminium adjuvants are complexed with the HCV (Hepatitis C virus recombinant immunogen in mice. Methods After immunizing Balb/c mice with the recombination HCV antigen adjuvanted with pUCpGs10 and/or aluminium(antigen+CpG+alum, antigen+CpG, antigen+alum, antigen+PBS, enzyme-linked immunosorbent assay (ELISA was used to measure the specific serum antibody titers of IgG, to determine the neutralization response to various peptide genotypes, and to determine the concentration of IL-6 and IL-10 in supernatants of in vitro cultured splenic lymphocytes. Enzyme-linked immunospot assay (ELISPOT was used to quantify the non-specific and specific splenic antibody-secreting cells (ASCs, and flow cytometry (FCM determined the ratio of different splenic lymphocytes. The serum of rabbits immunized with the recombinant pBVGST/HVR1 antigen immunoprecipitated the HCV isolated from 12 patients' serum. Results The sera antibody titers were 1:51200, 1:9051, 1:18102, 1:6400 respectively after the final immunization and demonstrated good neutralization responses to the six gene peptide containing 1a, 1b, 2a, 3a, 4a and 6a. The aluminum adjuvant increased the population of both specific ASCs (P +CD27+ (P +CD38+ splenic lymphocytes with the aluminum and pUCpGs10 adjuvant present compared to the control group(P Conclusions 1. The aluminum adjuvant induces a potent Th2-biased immune response by increasing both the populations of specific and total ASCs and the ratio of CD19+CD27+ cells. 2. The pUCpGs10 complexed with the aluminum adjuvant boosts the population of plasma cells and increase the efficiency of the immune response. 3. The two adjuvants have synergistic effects on humoral immunity. 4. The recombinant HVR1 protein has the possibility of generating broadly reactive anti-HVR1 antibody.

  5. Enhanced host immune recognition of E.coli causing mastitis in CD-14 transgenic mice.

    Science.gov (United States)

    Escherchia coli causes mastitis, an economically significant disease in dairy animals. E. coli endotoxin (lipopolysaccharide, LPS) when bound by host membrane proteins such as CD-14, causes release of pro-inflammatory cytokines recruiting neutrophils as a early innate immune response. Excessive pr...

  6. Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats.

    Science.gov (United States)

    Lu, Linlin; Yuan, Jiangshui; Zhang, Shicui

    2013-06-01

    It is well known that immune response decreases with aging. Salidroside (SDS), an antioxidant component isolated from the traditional Chinese medicine roseroot Rhodiola rosea, has been demonstrated to possess potent anti-aging and health-promoting activities. However, the mechanism underlying these activities is poorly understood. In this study, we clearly demonstrated that (1) dietary intake of SDS induced a considerable increase in total T cells (CD3(+)) and T helper cells (CD4(+)) in aged (21 months old) Wistar male rats; (2) SDS supplementation significantly increased the DTH response, a T cell-mediated immune response, in aged rats; and (3) SDS supplementation remarkably promoted the production of total anti-KLH IgG, anti-KLH IgG1, and anti-KLH IgG2α in aged rats without disturbing immune homeostasis. These indicate that SDS is able to counteract immunosenescence, thereby resulting in rejuvenation. Practically, SDS may be used to help the elderly to generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.

  7. Mycobacterium tuberculosis Rv1987 induces Th2 immune responses and enhances Mycobacterium smegmatis survival in mice.

    Science.gov (United States)

    Sha, Shanshan; Shi, Xiaoxia; Deng, Guoying; Chen, Lina; Xin, Yi; Ma, Yufang

    2017-04-01

    Mycobacterium tuberculosis can interfere with host immune response and escape clearance through its specific antigens. M. tuberculosis Rv1987 encoded by region of difference (RD)-2 gene is a secretory protein with immunogenic potency. Here, we investigated the impact of Rv1987 on host cytokine responses and T cell polarization in mouse aerosol model. A recombinant M. smegmatis mc2155 strain that overexpressed Rv1987 protein (named MS1987) was constructed and used to infect C57BL/6 mice. The mc2155 harbored the empty vector (named MSVec) was as a control. The results showed that MS1987 challenged mice promoted Th2-biased cytokine responses with lower secretion of IFN-γ but higher production of IL-4 and Rv1987-specific IgG antibody compared to MSVec infected mice. Neutrophilic inflammation and high bacterial burden were observed in the lung tissues of MS1987 infected mice probably own to the failed Th1 cell immunity. Besides, subcutaneous injection of Rv1987 protein could mediate the Th1 cytokine responses caused by M. bovis BCG in mice. These results indicated that M. tuberculosis Rv1987 protein could modulate host immune response towards Th2 profile, which probably contributed to the immune evasion of bacteria from host elimination. Copyright © 2017 Elsevier GmbH. All rights reserved.

  8. Enhancement of feline immunodeficiency virus infection after immunization with envelope glycoprotein subunit vaccines.

    NARCIS (Netherlands)

    C.H.J. Siebelink (Kees); E.J. Tijhaar (Edwin); R.C. Huisman (Robin); W. Huisman (Willem); A. de Ronde; I.H. Darby; M.J. Francis; G.F. Rimmelzwaan (Guus); A.D.M.E. Osterhaus (Albert)

    1995-01-01

    textabstractCats were immunized three times with different recombinant feline immunodeficiency virus (FIV) candidate vaccines. Recombinant vaccinia virus (rVV)-expressed envelope glycoprotein with (vGR657) or without (vGR657 x 15) the cleavage site and an FIV envelope bacterial fusion protein

  9. Enhanced innate immune responses in a brood parasitic cowbird species: degranulation and oxidative burst

    Science.gov (United States)

    Hahn, D. Caldwell; Summers, Scott G.; Genovese, Kenneth J.; He, Haiqi; Kogut, Michael H.

    2013-01-01

    We examined the relative effectiveness of two innate immune responses in two species of New World blackbirds (Passeriformes, Icteridae) that differ in resistance to West Nile virus (WNV). We measured degranulation and oxidative burst, two fundamental components of phagocytosis, and we predicted that the functional effectiveness of these innate immune responses would correspond to the species' relative resistance to WNV. The brown-headed cowbird (Molothrus ater), an obligate brood parasite, had previously shown greater resistance to infection with WNV, lower viremia and faster recovery when infected, and lower subsequent antibody titers than the red-winged blackbird (Agelaius phoeniceus), a close relative that is not a brood parasite. We found that cowbird leukocytes were significantly more functionally efficient than those of the blackbird leukocytes and 50% more effective at killing the challenge bacteria. These results suggest that further examination of innate immunity in the cowbird may provide insight into adaptations that underlie its greater resistance to WNV. These results support an eco-immunological interpretation that species like the cowbird, which inhabit ecological niches with heightened exposure to parasites, experience evolutionary selection for more effective immune responses.

  10. Impact of Making Textile Handcrafts on Mood Enhancement and Inflammatory Immune Changes

    Science.gov (United States)

    Futterman Collier, Ann D.; Wayment, Heidi A.; Birkett, Melissa

    2016-01-01

    The authors hypothesized that a textile art-making activity that was high in arousal, engagement, and positive mood and low in rumination and negative affect would be most effective for mood repair and would buffer inflammatory immune reactions. Forty-seven experienced textile handcrafters were asked to recall an upsetting situation before random…

  11. Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis.

    Science.gov (United States)

    Yang, Ru; Zhang, Yingzi; Wang, Lin; Hu, Ji; Wen, Jian; Xue, Leixi; Tang, Mei; Liu, Zhichun; Fu, Jinxiang

    2017-02-28

    The incidence of rheumatoid arthritis (RA) has been reported to be correlated with a disorder of immunregulation. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) play an important role in regulating the local immune microenvironment. However, the potential mechanism of RA-FLS in regulating the immnue response is not clearly understood. In this study, we demonstrated that the expression of HIF-1α was significantly up-regulated in rheumatoid arthritis tissue which indicated that the hypoxia condition in the microenvironment. We also observed that RA-FLSs demonstrated the potential to up-regulate immune activation. Meanwhile, the level of autophagy increased in RA-FLSs compared with control group. Besides that, the expression of IL-6 was up-regulated not only in RA-FLSs but also in the fibroblasts that treated with hypoxia condition. Accordingly, we found that autophagy inhibitiors could effectively inhibit the immune activation function of RA-FLSs medicated by IL-6. Taken together, the results we demonstrated above indicated that the hypoxia microenvironment could effectively induce the incidence of autophagy and then lead to the immune activation function of RA-FLSs medicated by IL-6.

  12. Nanoparticle Vaccines Adopting Virus-like Features for Enhanced Immune Potentiation

    Science.gov (United States)

    Chattopadhyay, Saborni; Chen, Jui-Yi; Chen, Hui-Wen; Hu, Che-Ming Jack

    2017-01-01

    Synthetic nanoparticles play an increasingly significant role in vaccine design and development as many nanoparticle vaccines show improved safety and efficacy over conventional formulations. These nanoformulations are structurally similar to viruses, which are nanoscale pathogenic organisms that have served as a key selective pressure driving the evolution of our immune system. As a result, mechanisms behind the benefits of nanoparticle vaccines can often find analogue to the interaction dynamics between the immune system and viruses. This review covers the advances in vaccine nanotechnology with a perspective on the advantages of virus mimicry towards immune potentiation. It provides an overview to the different types of nanomaterials utilized for nanoparticle vaccine development, including functionalization strategies that bestow nanoparticles with virus-like features. As understanding of human immunity and vaccine mechanisms continue to evolve, recognizing the fundamental semblance between synthetic nanoparticles and viruses may offer an explanation for the superiority of nanoparticle vaccines over conventional vaccines and may spur new design rationales for future vaccine research. These nanoformulations are poised to provide solutions towards pressing and emerging human diseases. PMID:29071191

  13. Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine

    National Research Council Canada - National Science Library

    Frahm, Nicole; DeCamp, Allan C; Friedrich, David P; Carter, Donald K; Defawe, Olivier D; Kublin, James G; Casimiro, Danilo R; Duerr, Ann; Robertson, Michael N; Buchbinder, Susan P; Huang, Yunda; Spies, Gregory A; De Rosa, Stephen C; McElrath, M Juliana

    2012-01-01

    .... Here, we have identified and compared adenovirus-specific and HIV-specific T cell responses in subjects participating in two HIV-1 vaccine trials using a vaccine vectored by adenovirus serotype 5 (Ad5...

  14. Immune-enhancing effect of nanometricLactobacillus plantarumnF1 (nLp-nF1) in a mouse model of cyclophosphamide-induced immunosuppression.

    Science.gov (United States)

    Choi, Dae-Woon; Jung, Sun Young; Kang, Jisu; Nam, Young-Do; Lim, Seong-Il; Kim, Ki Tae; Shin, Hee Soon

    2017-11-15

    Nanometric Lactobacillus plantarum nF1 (nLp-nF1) is a biogenics consisting of dead L. plantarum pre-treated with heat and a nanodispersion process. In this study, we investigated the immune-enhancing effects of nLp-nF1 in vivo and in vitro . To evaluate the immunostimulatory effects of nLp-nF1, mice immunosuppressed by cyclophosphamide (CPP) treatment were administered with nLp-nF1. As expected, CPP restricted the immune response of mice, whereas oral administration of nLp-nF1 significantly increased total IgG in serum, and cytokine production [interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α)] in bone marrow cells. Furthermore, nLp-nF1 enhanced the production of splenic cytokines such as IL-12, TNF-α, and interferon gamma (IFN-γ). In vitro , nLp-nF1 stimulated the immune response by enhancing the production of cytokines such as IL-12, TNF-α, and IFN-γ. Moreover, nLp-nF1 given a food additive enhanced the immune responses when combined with various food materials on in vitro . These results suggest that nLp-nF1 could be used to strengthen the immune system and recover normal immunity in people with a weaker immune system, such as children, the elderly, and patients.

  15. Cationic micelle based vaccine induced potent humoral immune response through enhancing antigen uptake and formation of germinal center.

    Science.gov (United States)

    Luo, Zichao; Shi, Shuai; Jin, Ling; Xu, Lu; Yu, Jing; Chen, Hao; Li, Xingyi

    2015-11-01

    Nanoparticles have been proven to be an effective vaccine delivery system that can boost immune responses to subunit vaccines. Herein, we developed and characterized a cationic polymeric polyethylene glycol2000-poly ϵ-caprolactone2000-polyethylenimine2000 (mPEG2000-PCL2000-g-PEI2000) micelle as a potent vaccine delivery system to boost the immune response in vivo. The micelles that we developed exhibited great antigen-loading capability and minimal cytotoxicity in vitro. Meanwhile, micelles facilitated OVA antigen uptake by dendritic cells both in vitro and in vivo. More importantly, a micelle-formulated OVA vaccine could significantly promote anti-OVA antibody production by 190-fold and potently enhance T cell proliferation and the secretion of IL-5 and IFN-γ. We attributed these effects to its ability to promote antigen uptake, antigen deposition, and germinal center formation. In conclusion, the mPEG2000-PCL2000-PEI2000 micelle that we developed has potential as potent vaccine delivery system to induce Th2 immune response. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Dietary Supplementation of Astragalus Polysaccharides Enhanced Immune Components and Growth Factors EGF and IGF-1 in Sow Colostrum

    Directory of Open Access Journals (Sweden)

    Lunbo Tan

    2017-01-01

    Full Text Available Colostrum is the main external resource providing piglets with nutrients and maternal immune molecules. Astragalus polysaccharides (APS have been used as immunopotentiators in vitro and several animal models. This study aimed to determine the effects of APS on immune factors in sow colostrum and milk. The sow diet was supplemented with APS one week before the expected delivery date. Colostrum and milk were collected and designated as 0 h- (onset of parturition, 12 h-, and 24 h-colostrum and 36 h-milk postpartum. Samples were measured using porcine immunoglobulin (Ig G, IgM, classical swine fever virus antibody (CSFV Ab, epidermal growth factor (EGF, and insulin-like growth factor- (IGF- 1 ELISA Quantitation Kits. Dietary supplementation of APS significantly enhanced the presence of IgG, IgM, EGF, and IGF-1 in 0 h-colostrum (P<0.001. The blocking rates of CSFV Ab were increased in samples from APS-supplemented sow when compared to those from the matched samples without APS treatment. The results indicate that supplement of APS could improve the immune components in sow colostrum and/or milk; and status of some specific vaccination could be determined through using colostrum or early milk in sow.

  17. Marek's disease virus VP22 enhances potentially the immune response of ESAT-6/CFP-10 against Mycobacterium bovis infection.

    Science.gov (United States)

    Chen, Hongjun; Wang, Wei; Song, Cuiping; Yu, Shengqing; Ding, Chan

    2010-05-15

    Currently available vaccines against Mycobacterium bovis, the causative agent of tuberculosis, do not provide reliable efficacy and there is therefore a need for a novel vaccine with improved efficacy. Here, we use protein transduction technology to deliver DNA vaccines expressing mycobacterial antigens directly to target cells. We used various protein transduction domain (PTD) proteins including the VP22 conjugate from Marek's disease virus serotype 1 (MDV-1), as delivery systems for DNA constructs encoding the antigens early secretory antigenic target-6 kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10) of M. bovis. The eukaryotic expression plasmid pZ106, encoding antigens ESAT-6 and CFP-10, conjugated to various PTDs, was used to construct experimental preparations. Our findings demonstrated that VP22 alone or in combination with CFP-10:ESAT-6 fusion protein could spread into all the nuclei of the cell monolayer surrounding the transfected cells. Whereas trans-activating transcriptional PTD showed limited delivery of the fusion protein and 8R peptide was unable to deliver the fusion protein into any untransfected cells. We have demonstrated that immunization with a preparation fused to VP22 leads to a higher antibody and interferon-gamma titer (P<0.05). Taken together, our results demonstrated that MDV-1 VP22 serves as a potential immune enhancer in gene therapy and immunization using DNA vaccines, offering a novel approach for the prevention of M. bovis infection.

  18. Oreochromis mossambicus diet supplementation with Psidium guajava leaf extracts enhance growth, immune, antioxidant response and resistance to Aeromonas hydrophila.

    Science.gov (United States)

    Gobi, Narayanan; Ramya, Chinnu; Vaseeharan, Baskaralingam; Malaikozhundan, Balasubramanian; Vijayakumar, Sekar; Murugan, Kadarkarai; Benelli, Giovanni

    2016-11-01

    In this research, we focused on the efficacy of aqueous and ethanol leaf extracts of Psidium guajava L. (guava) based experimental diets on the growth, immune, antioxidant and disease resistance of tilapia, Oreochromis mossambicus following challenge with Aeromonas hydrophila. The experimental diets were prepared by mixing powdered (1, 5 and 10 mg/g) aqueous and ethanol extract of guava leaf with commercial diet. The growth (FW, FCR and SGR), non-specific cellular immune (myeloperoxidase activity, reactive oxygen activity and reactive nitrogen activity) humoral immune (complement activity, antiprotease, alkaline phosphatase activity and lysozyme activity) and antioxidant enzyme responses (SOD, GPX, and CAT) were examined after 30 days of post-feeding. A significant enhancement in the biochemical and immunological parameters of fish were observed fed with experimental diets compared to control. The dietary supplementation of P. guajava leaf extract powder for 30 days significantly reduced the mortality and increased the disease resistance of O. mossambicus following challenge with A. hydrophila at 50 μl (1 × 10 7  cells ml -1 ) compared to control after post-infection. The results suggest that the guava leaf extract could be used as a promising feed additive in aquaculture. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines

    Directory of Open Access Journals (Sweden)

    Daniel H. Libraty

    2014-01-01

    Full Text Available Neonatal Bacille Calmette Guérin (BCG vaccination has been reported to have beneficial effects beyond preventing infantile tuberculous meningitis and miliary disease. We hypothesized that BCG vaccine given at birth would enhance T-helper 1 (Th1 immune responses to the first vaccines given later in infancy. We conducted a nested case-control study of neonatal BCG vaccination and its heterologous Th1 immune effects in 2–3 months old infants. BCG vaccination at birth was associated with an increased frequency of interferon-γ (IFN-γ producing spot-forming cells (SFC to tetanus toxoid 2–3 months later. The frequency of IFN-γ producing SFC to polioviruses 1–3 also trended higher among infants who received BCG vaccination at birth. The frequency of IFN-γ+/tumor necrosis factor-α (TNF-α+CD45RO+CD4+ T-cells upon stimulation with phorbol myristate acetate (PMA/Ionomycin was higher in 2–3 months old infants who received BCG vaccination at birth compared to those who did not. The circulating frequency of forkhead box P3 (FoxP3+ CD45RO+ regulatory CD4+ T-cells also trended lower in these infants. Neonatal BCG vaccination is associated with heterologous Th1 immune effects 2–3 months later.

  20. The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response.

    Science.gov (United States)

    Schneider, Bradley S; Higgs, Stephen

    2008-05-01

    Arthropod-borne (arbo-) viruses have emerged as a major human health concern. Viruses transmitted by mosquitoes are the cause of the most serious and widespread arbovirus diseases worldwide and are ubiquitous in both feral and urban settings. Arboviruses, including dengue and West Nile virus, are injected into vertebrates within mosquito saliva during mosquito feeding. Mosquito saliva contains anti-haemostatic, anti-inflammatory and immunomodulatory molecules that facilitate the acquisition of a blood meal. Collectively, studies investigating the effects of mosquito saliva on the vertebrate immune response suggest that at high concentrations salivary proteins are immmunosuppressive, whereas lower concentrations modulate the immune response; specifically, T(H)1 and antiviral cytokines are downregulated, while T(H)2 cytokines are unaffected or amplified. As a consequence, mosquito saliva can impair the antiviral immune response, thus affecting viral infectiousness and host survival. Mounting evidence suggests that this is a mechanism whereby arbovirus pathogenicity is enhanced. In a range of disease models, including various hosts, mosquito species and arthropod-borne viruses, mosquito saliva and/or feeding is associated with a potentiation of virus infection. Compared with arbovirus infection initiated in the absence of the mosquito or its saliva, infection via mosquito saliva leads to an increase in virus transmission, host susceptibility, viraemia, disease progression and mortality.

  1. Ozone Enhances Pulmonary Innate Immune Response to a Toll-Like Receptor–2 Agonist

    Science.gov (United States)

    Oakes, Judy L.; O’Connor, Brian P.; Warg, Laura A.; Burton, Rachel; Hock, Ashley; Loader, Joan; LaFlamme, Daniel; Jing, Jian; Hui, Lucy; Schwartz, David A.

    2013-01-01

    Previous work demonstrated that pre-exposure to ozone primes innate immunity and increases Toll-like receptor–4 (TLR4)–mediated responses to subsequent stimulation with LPS. To explore the pulmonary innate immune response to ozone exposure further, we investigated the effects of ozone in combination with Pam3CYS, a synthetic TLR2/TLR1 agonist. Whole-lung lavage (WLL) and lung tissue were harvested from C57BL/6 mice after exposure to ozone or filtered air, followed by saline or Pam3CYS 24 hours later. Cells and cytokines in the WLL, the surface expression of TLRs on macrophages, and lung RNA genomic expression profiles were examined. We demonstrated an increased WLL cell influx, increased IL-6 and chemokine KC (Cxcl1), and decreased macrophage inflammatory protein (MIP)-1α and TNF-α in response to Pam3CYS as a result of ozone pre-exposure. We also observed the increased cell surface expression of TLR4, TLR2, and TLR1 on macrophages as a result of ozone alone or in combination with Pam3CYS. Gene expression analysis of lung tissue revealed a significant increase in the expression of genes related to injury repair and the cell cycle as a result of ozone alone or in combination with Pam3CYS. Our results extend previous findings with ozone/LPS to other TLR ligands, and suggest that the ozone priming of innate immunity is a general mechanism. Gene expression profiling of lung tissue identified transcriptional networks and genes that contribute to the priming of innate immunity at the molecular level. PMID:23002100

  2. RNA-guided complex from a bacterial immune system enhances target recognition through seed sequence interactions

    OpenAIRE

    Wiedenheft, Blake; van Duijn, Esther; Bultema, Jelle; Waghmare, Sakharam; Zhou, Kaihong; Barendregt, Arjan; Westphal, Wiebke; Heck, Albert; Boekema, Egbert; Dickman, Mark; Doudna, Jennifer A.

    2011-01-01

    Prokaryotes have evolved multiple versions of an RNA-guided adaptive immune system that targets foreign nucleic acids. In each case, transcripts derived from clustered regularly interspaced short palindromic repeats (CRISPRs) are thought to selectively target invading phage and plasmids in a sequence-specific process involving a variable cassette of CRISPR-associated (cas) genes. The CRISPR locus in Pseudomonas aeruginosa (PA14) includes four cas genes that are unique to and conserved in micr...

  3. Immune enhancement of Taishan Robinia pseudoacacia polysaccharide on recombinant Proteus mirabilis OmpA in chickens.

    Science.gov (United States)

    Zhang, Yongbing; Yang, Shifa; Zhao, Xue; Yang, Ya; Li, Bing; Zhu, Fujie; Zhu, Ruiliang

    2014-09-01

    This study was conducted to evaluate the effects of Taishan Robinia pseudoacacia polysaccharide (TRPPS) on immune responses of chickens immunized with Proteus mirabilis outer membrane protein A (OmpA) recombinant protein vaccine. OmpA was expressed in Pichia pastoris and mixed with TRPPS. 360 chickens were randomly divided into six groups. Groups I to IV were treated with OmpA which contained TRPPS of three different dosages, Freund's adjuvant, respectively. Groups V and VI were treated with pure OmpA and physiological saline, respectively. The data showed that the antibody titers against OmpA, the concentration of IL-2, CD4 +, and CD8 +, T lymphocyte proliferation rate in Group II were significantly higher (P < 0.05) than those in the other groups, little difference in SIgA content was observed among groups I to VI. These results indicated that TRPPS strengthened humoral and cellular immune responses against recombinant OmpA vaccine. Moreover, 200 mg/mL TRPPS showed significance (P < 0.05) compared with Freund's adjuvant. Therefore, TRPPS can be developed into an adjuvant for recombinant subunit vaccine. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Lin Wang

    2017-11-01

    Full Text Available Background/Aims: Cetuximab is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of epidermal growth factor receptor. This antibody is widely used for colorectal cancer (CRC treatment but its influence on the immune system is incompletely understood. Methods: The immune influence of cetuximab therapy in CRC patients was investigated by analyzing peripheral blood mononuclear cells using flow cytometry. We undertook in vitro cytotoxicity and cytokine-profile assays to ascertain the immunomodulatory effect of cetuximab treatment. Results: The number of CD3+ T, CD8+ T, and natural killer (NK cells was increased significantly and T-regulatory cells reduced gradually after cetuximab treatment. Percentage of CD4+ T, natural killer T (NKT-like, invariant NKT, and dendritic cells was similar between baseline patients and cetuximab patients. Expression of CD137 on NK and CD8+ T cells was increased significantly after 4 weeks of cetuximab therapy. In vitro cetuximab treatment markedly increased expression of CD137 and CD107a on NK and CD8+ T cells. Cetuximab treatment promoted the cytotoxic activity of NK and CD8+ T cells against tumor cells. Conclusion: Cetuximab treatment promotes activation of the immune response but alleviates immunosuppression: this might be the underlying anti-CRC effect of cetuximab.

  5. In pulmonary paracoccidioidomycosis IL-10 deficiency leads to increased immunity and regressive infection without enhancing tissue pathology.

    Directory of Open Access Journals (Sweden)

    Tânia A Costa

    Full Text Available BACKGROUND: Cellular immunity is the main defense mechanism in paracoccidioidomycosis (PCM, the most important systemic mycosis in Latin America. Th1 immunity and IFN-γ activated macrophages are fundamental to immunoprotection that is antagonized by IL-10, an anti-inflammatory cytokine. Both in human and experimental PCM, several evidences indicate that the suppressive effect of IL-10 causes detrimental effects to infected hosts. Because direct studies have not been performed, this study was aimed to characterize the function of IL-10 in pulmonary PCM. METHODOLOGY/PRINCIPAL FINDINGS: Wild type (WT and IL-10(-/- C57BL/6 mice were used to characterize the role of IL-10 in the innate and adaptive immunity against Paracoccidioides brasiliensis (Pb infection. We verified that Pb-infected peritoneal macrophages from IL-10(-/- mice presented higher phagocytic and fungicidal activities than WT macrophages, and these activities were associated with elevated production of IFN-γ, TNF-α, nitric oxide (NO and MCP-1. For in vivo studies, IL-10(-/- and WT mice were i.t. infected with 1×10(6 Pb yeasts and studied at several post-infection periods. Compared to WT mice, IL-10(-/- mice showed increased resistance to P. brasiliensis infection as determined by the progressive control of pulmonary fungal loads and total clearance of fungal cells from dissemination organs. This behavior was accompanied by enhanced delayed-type hypersensitivity reactions, precocious humoral immunity and controlled tissue pathology resulting in increased survival times. In addition, IL-10(-/- mice developed precocious T cell immunity mediated by increased numbers of lung infiltrating effector/memory CD4(+ and CD8(+ T cells. The inflammatory reactions and the production of Th1/Th2/Th17 cytokines were reduced at late phases of infection, paralleling the regressive infection of IL-10(-/- mice. CONCLUSIONS/SIGNIFICANCE: Our work demonstrates for the first time that IL-10 plays a

  6. A booster vaccine expressing a latency-associated antigen augments BCG induced immunity and confers enhanced protection against tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bappaditya Dey

    Full Text Available BACKGROUND: In spite of a consistent protection against tuberculosis (TB in children, Mycobacterium bovis Bacille Calmette-Guerin (BCG fails to provide adequate protection against the disease in adults as well as against reactivation of latent infections or exogenous reinfections. It has been speculated that failure to generate adequate memory T cell response, elicitation of inadequate immune response against latency-associated antigens and inability to impart long-term immunity against M. tuberculosis infections are some of the key factors responsible for the limited efficiency of BCG in controlling TB. METHODS/PRINCIPAL FINDINGS: In this study, we evaluated the ability of a DNA vaccine expressing α-crystallin--a key latency antigen of M. tuberculosis to boost the BCG induced immunity. 'BCG prime-DNA boost' regimen (B/D confers robust protection in guinea pigs along with a reduced pathology in comparison to BCG vaccination (1.37 log(10 and 1.96 log(10 fewer bacilli in lungs and spleen, respectively; p<0.01. In addition, B/D regimen also confers enhanced protection in mice. Further, we show that B/D immunization in mice results in a heightened frequency of PPD and antigen specific multi-functional CD4 T cells (3(+ simultaneously producing interferon (IFNγ, tumor necrosis factor (TNFα and interleukin (IL2. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of α-crystallin based B/D regimen over BCG. Our study, also demonstrates that protection against TB is predictable by an increased frequency of 3(+ Th1 cells with superior effector functions. We anticipate that this study would significantly contribute towards the development of superior booster vaccines for BCG vaccinated individuals. In addition, this regimen can also be expected to reduce the risk of developing active TB due to reactivation of latent infection.

  7. Enhancing Routine Immunization Performance using Innovative Technology in an Urban Area of Nigeria.

    Science.gov (United States)

    Eze, G U; Adeleye, O O

    2015-01-01

    Routine Immunization (RI)is known to beone of the most cost-effective public health strategies ever, and a cornerstone among all primary healthcare efforts but has been bedevilledin Low and Middle Income Countries (LMICs) in the last two decadesby poor coverage and lack of timeliness -both due, among other factors, to clients forgetting appointments. These setback RI effectiveness from ensuring herd immunity and preventing disease. Across the world, different cost-effective mobile telephone-based reminder systems are currently in use as strategies for improving coverage and compliance in various health interventions.Their application to RI is thereforehighly recommended. This study sought to provide evidence validating the need for development and deployment of automated client Reminder-Recall systems for the Nigerian National Routine Immunisation Program and to compare its projected cost withthe cost of a health personnel-based defaulter tracking system. A multi-centre, parallel-group, Randomized Controlled Trial was carried outusing multi-stage sampling.Nine hundred and five child-caregivers were followed-upat 8 health facilities in an urban/sub-urban area in South-South Nigeria.Text messagereminders were sent to the Intervention group only, with concurrent weekly data collection, including that for controls, at each of the enrolled health facilities. Recall messages were sent to defaulters and their responses (presence at immunization session) assessed the next RI session. Receipt of DPT3 vaccine on or before the 18th week was categorized early, while receiptafter was categorized delayed. Clients in the Interventiongroup were1.5times earlier than Controls intheir receipt of DPT3. Immunization coverage was also 8.7%better in the Interventiongroup. A first year estimate of cost of deploying this strategy was less than a quarter ofthe estimated cost of using home-visits which is the defaulter tracking method currently recommended by regulatory authorities. Routine

  8. Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach.

    Science.gov (United States)

    Lu, Yao; Wang, Yuhua; Miao, Lei; Haynes, Matthew; Xiang, Guangya; Huang, Leaf

    2016-08-28

    Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p nanomedicine by establishing effect synergy in host-specific immunotherapy following chemotherapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

  9. Helical carbon nanotubes enhance the early immune response and inhibit macrophage-mediated phagocytosis of Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Brent E Walling

    Full Text Available Aerosolized or aspirated manufactured carbon nanotubes have been shown to be cytotoxic, cause pulmonary lesions, and demonstrate immunomodulatory properties. CD-1 mice were used to assess pulmonary toxicity of helical carbon nanotubes (HCNTs and alterations of the immune response to subsequent infection by Pseudomonas aeruginosa in mice. HCNTs provoked a mild inflammatory response following either a single exposure or 2X/week for three weeks (multiple exposures but were not significantly toxic. Administering HCNTs 2X/week for three weeks resulted in pulmonary lesions including granulomas and goblet cell hyperplasia. Mice exposed to HCNTs and subsequently infected by P. aeruginosa demonstrated an enhanced inflammatory response to P. aeruginosa and phagocytosis by alveolar macrophages was inhibited. However, clearance of P. aeruginosa was not affected. HCNT exposed mice depleted of neutrophils were more effective in clearing P. aeruginosa compared to neutrophil-depleted control mice, accompanied by an influx of macrophages. Depletion of systemic macrophages resulted in slightly inhibited bacterial clearance by HCNT treated mice. Our data indicate that pulmonary exposure to HCNTs results in lesions similar to those caused by other nanotubes and pre-exposure to HCNTs inhibit alveolar macrophage phagocytosis of P. aeruginosa. However, clearance was not affected as exposure to HCNTs primed the immune system for an enhanced inflammatory response to pulmonary infection consisting of an influx of neutrophils and macrophages.

  10. Equol Inhibits LPS-Induced Oxidative Stress and Enhances the Immune Response in Chicken HD11 Macrophages

    Directory of Open Access Journals (Sweden)

    Zhongyong Gou

    2015-05-01

    Full Text Available Background/Aims: There has been increasing recent attention on the antioxidative capacity of equol. This study tested the effect of equol on oxidative stress induced by lipopolysaccharide (LPS and regulation of immunity in chicken macrophages. Methods: Chicken HD11 macrophages were challenged with LPS (100 ng/mL alone or with LPS (100 ng/mL and (±equol (10, 20, 40, 80, 160 μmol/L together for 24h. Evaluated responses included the contents of malondialdehyde (MDA and reduced glutathione (GSH, activities of total superoxide dismutase (T-SOD and inducible nitric oxide synthase (iNOS, transcript abundance of superoxide dismutase 2 (SOD2, catalase (CAT, glutathione transferase (GST, Toll-like receptor 4 (TLR4, tumor necrosis factor alpha (TNFα and interleukin-1 beta (IL-1β, and contents of the cytokines TNFα, IL-1β, interleukin-2 (IL-2 and interferon beta (IFNβ. Results: Exposure to LPS induced oxidative stress as contents of MDA increased and GSH decreased in LPS-treated cells (P SOD2 and GST transcripts (P TLR4, TNFα and IL-1β (P < 0.05. And there were similar changes in contents of IL-1β, IL-2, IFNβ and TNFα in the cells (P < 0.05. Conclusions: It concluded that equol can protect chicken HD11 macrophages from oxidative stress induced by LPS through reducing lipid peroxidation products and enhancing contents of antioxidants, and activities of relevant antioxidase enzymes; effects were also seen in gene expression related to the immune response and increased contents of cytokines. The optimal concentration of equol on antioxidation and immune enhancement in chicken macrophages was 40 μmol/L.

  11. Equol Inhibits LPS-Induced Oxidative Stress and Enhances the Immune Response in Chicken HD11 Macrophages.

    Science.gov (United States)

    Gou, Zhongyong; Jiang, Shouqun; Zheng, Chuntian; Tian, Zhimei; Lin, Xiajing

    2015-01-01

    There has been increasing recent attention on the antioxidative capacity of equol. This study tested the effect of equol on oxidative stress induced by lipopolysaccharide (LPS) and regulation of immunity in chicken macrophages. Chicken HD11 macrophages were challenged with LPS (100 ng/mL) alone or with LPS (100 ng/mL) and (±)equol (10, 20, 40, 80, 160 μmol/L) together for 24h. Evaluated responses included the contents of malondialdehyde (MDA) and reduced glutathione (GSH), activities of total superoxide dismutase (T-SOD) and inducible nitric oxide synthase (iNOS), transcript abundance of superoxide dismutase 2 (SOD2), catalase (CAT), glutathione transferase (GST), Toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β), and contents of the cytokines TNFα, IL-1β, interleukin-2 (IL-2) and interferon beta (IFNβ). Exposure to LPS induced oxidative stress as contents of MDA increased and GSH decreased in LPS-treated cells (P equol (20 μmol/L, 40 μmol/L or 80 μmol/L) reduced contents of MDA and increased those of GSH (both P equol (80 μmol/L or 160 μmol/L), however, all concentrations (20 μmol/L to 160 μmol/L) increased activity of iNOS (P equol (160 μmol/L) increased SOD2 and GST transcripts (P Equol treatment increased transcripts of TLR4, TNFα and IL-1β (P equol can protect chicken HD11 macrophages from oxidative stress induced by LPS through reducing lipid peroxidation products and enhancing contents of antioxidants, and activities of relevant antioxidase enzymes; effects were also seen in gene expression related to the immune response and increased contents of cytokines. The optimal concentration of equol on antioxidation and immune enhancement in chicken macrophages was 40 μmol/L. © 2015 S. Karger AG, Basel.

  12. Levamisole enhances the innate immune response and prevents increased cortisol levels in stressed pacu (Piaractus mesopotamicus).

    Science.gov (United States)

    Pahor-Filho, Eduardo; Castillo, Adriana Soliris Corredor; Pereira, Nycolas Levy; Pilarski, Fabiana; Urbinati, Elisabeth Criscuolo

    2017-06-01

    We analyzed the effects of levamisole on stress and the innate immune responses of pacu (Piaractus mesopotamicus). A total of 300 fish (180 ± 1.27 g) were fed a diet containing levamisole hydrochloride (LHC) for 15 days, then distributed into the following groups: T0 (control group); T1 (100), T2 (150), T3 (300) and T4 (500) mg kg -1 LHC (15 fish per group and four replicates per treatment). After this, fish (n = 8 per treatment) were exposed to air for three minutes to simulate stress conditions and were then challenged with the bacterium Aeromonas hydrophila to stimulate the immune system. Fish were sampled at 1, 3 and 24 h after bacterial inoculation to measure plasma cortisol and glucose concentrations, the leukocyte respiratory burst (LRB), hemolytic activity of the complement system (HAC 50 ) and serum lysozyme activity (SLA). LHC attenuated the increase in plasma cortisol at 1 h (500 mg kg -1 ) and 3 h (300 mg kg -1 ) after air exposure and bacterial inoculation compared to control fish. The highest glucose concentrations were observed at 1 and 3 h after stress, which then returned to initial levels after 24 h, without any effect of LHC. The LHC 100 mg kg -1 dose increased LRB 1 h after inoculation and activated the HAC 50 3 h later. At 24 h, all LHC concentrations increased the HAC 50 . SLA was reduced after inoculation, throughout the experimental period, without an effect of levamisole. Our results indicate that the oral administration of levamisole for 15 days modulated circulating cortisol levels during the stress response and improved the innate immune response against A. hydrophila infection in pacu. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils.

    Science.gov (United States)

    Spinner, Daryl S; Kascsak, Regina B; Lafauci, Giuseppe; Meeker, Harry C; Ye, Xuemin; Flory, Michael J; Kim, Jae Il; Schuller-Levis, Georgia B; Levis, William R; Wisniewski, Thomas; Carp, Richard I; Kascsak, Richard J

    2007-06-01

    Prion diseases are characterized by conversion of the cellular prion protein (PrP(C)) to a protease-resistant conformer, the srapie form of PrP (PrP(Sc)). Humoral immune responses to nondenatured forms of PrP(Sc) have never been fully characterized. We investigated whether production of antibodies to PrP(Sc) could occur in PrP null (Prnp(-/-)) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti-PrP(Sc) antibody levels in wild-type (Prnp(+/+)) mice was also investigated. Prnp(-/-) and Prnp(+/+) mice were immunized with nondenatured 139A scrapie-associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP-specific antibodies. In Prnp(-/-) mice, inclusion of ODN 1826 in the immunization regime increased anti-PrP titers more than 13-fold after two immunizations and induced, among others, antibodies to an N-terminal epitope, which were only present in the immune repertoire of mice receiving ODN 1826. mAb 6D11, derived from such a mouse, reacts with the N-terminal epitope QWNK in native and denatured forms of PrP(Sc) and recombinant PrP and exhibits a K(d) in the 10(-)(11) M range. In Prnp(+/+) mice, ODN 1826 increased anti-PrP levels as much as 84% after a single immunization. Thus, ODN 1826 potentiates adaptive immune responses to PrP(Sc) in 139A SAF-immunized mice. These results represent the first characterization of humoral immune responses to nondenatured, infectious PrP(Sc) and suggest methods for optimizing the generation of mAbs to PrP(Sc), many of which could be used for diagnosis and treatment of prion diseases.

  14. IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis

    Science.gov (United States)

    Rovetta, Ana I; Peña, Delfina; Hernández Del Pino, Rodrigo E; Recalde, Gabriela M; Pellegrini, Joaquín; Bigi, Fabiana; Musella, Rosa M; Palmero, Domingo J; Gutierrez, Marisa; Colombo, María I; García, Verónica E

    2015-01-01

    Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen. PMID:25426782

  15. TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response.

    Science.gov (United States)

    Han, Jianfeng; Chen, Xilin; Chu, Jianhong; Xu, Bo; Meisen, Walter H; Chen, Lichao; Zhang, Lingling; Zhang, Jianying; He, Xiaoming; Wang, Qi-En; Chiocca, E Antonio; Kaur, Balveen; Caligiuri, Michael A; Yu, Jianhua

    2015-12-15

    Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes. ©2015 American Association for Cancer Research.

  16. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.

    Directory of Open Access Journals (Sweden)

    Ruth J Napier

    2015-03-01

    Full Text Available Imatinib mesylate (Gleevec inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

  17. Enhanced viral replication and modulated innate immune responses in infant airway epithelium following H1N1 infection.

    Science.gov (United States)

    Clay, Candice C; Reader, J Rachel; Gerriets, Joan E; Wang, Theodore T; Harrod, Kevin S; Miller, Lisa A

    2014-07-01

    susceptibility of the host to respiratory virus infections. Despite the global burden of influenza, there are currently no vaccine formulations approved for children <6 months of age. Given the challenges of conducting experimental studies involving pediatric patients, rhesus monkeys are an ideal laboratory animal model to investigate the maturation of pulmonary mucosal immune mechanisms during early life because they are most similar to those of humans with regard to postnatal maturation of the lung structure and the immune system. Thus, our findings are highly relevant to translational medicine, and these data may ultimately lead to novel approaches that enhance airway immunity in very young children. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  18. Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis

    DEFF Research Database (Denmark)

    Pedersen, Morten Løbner; Walsted, Anette; Larsen, Rune

    2008-01-01

    The effect of consumption of Immulina, a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis, on adaptive immune responses was investigated by evaluation of changes in leukocyte responsiveness to two foreign recall antigens, Candida albicans (CA) and tetanus......beta, and IL-6 responses, indicating that it acts by inducing a pro-inflammatory state. Taken together, the data suggest that Immulina causes an age-dependent, temporary enhancement of adaptive immune responses....

  19. Enhanced iodine supplementation alters the immune process in a transgenic mouse model for autoimmune thyroiditis.

    Science.gov (United States)

    Ehlers, Margret; Thiel, Annette; Papewalis, Claudia; Domröse, Andreas; Stenzel, Wiebke; Bernecker, Christian; Haase, Matthias; Allelein, Stephanie; Schinner, Sven; Willenberg, Holger S; Feldkamp, Joachim; Schott, Matthias

    2014-05-01

    The impact of excessive iodine intake on the development of autoimmune thyroiditis (AIT) is still under debate. Transgenic, antibody-devoid TAZ10 mice spontaneously develop AIT due to autoreactive thyroperoxidase-specific T cells. In this model, development of AIT is determined by a T cell infiltration of the thyroid gland leading to an elevation of serum thyrotropin (TSH) levels and significant weight gain. In the present study we investigated the impact of moderate and high iodine supplementation on the course of disease in these mice, which are immunologically prone to AIT. In addition to normal nutrition, mice were supplemented for 20 weeks with 2.5 μg versus 5 μg iodine per milliliter drinking water, which corresponds to a human daily iodine supplementation of 150 μg, 315 μg, and 615 μg iodine. AIT-defining parameters (weight gain, elevation of serum TSH levels, cellular infiltration of the thyroid) and immunologic effects were analyzed. No significant differences were displayed when comparing weight and serum TSH levels in the iodine-supplemented versus control groups. Increased thyroid infiltrates with CD8⁺ T cells were detected by fluorescein-activated cell sorter (FACS) and immunofluorescence staining in mice supplemented with elevated iodine amounts (315 μg and 615 μg iodine per day, respectively). Immunologic monitoring revealed selective changes in immune cell frequencies (CD8⁺ and regulatory T cells, natural killer [NK] cells) and cytokine production (interferon-γ, interleukin-1α, and interleukin-17), however, without affecting the overall immune balance. Our results demonstrate that elevated iodine supplementation has no physical impact on the course of disease in transgenic, antibody-devoid TAZ10 mice, which are immunologically prone to AIT.

  20. Systemic administration of a novel immune-stimulatory pseudovirion suppresses lung metastatic melanoma by regionally enhancing IFN-γ production.

    Science.gov (United States)

    Saga, Kotaro; Tamai, Katsuto; Yamazaki, Takehiko; Kaneda, Yasufumi

    2013-02-01

    Cancer immunotherapy has encountered many difficulties in the face of the expectation to eradicate cancer, and new breakthroughs are required. We have previously shown that UV-inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) induce immunity against multiple tumor types. In this study, a novel pseudovirion that stimulates more robust antitumor immunity was designed for cancer treatment. First, we found that culturing murine splenocytes with HVJ-E in combination with interleukin (IL)-12 resulted in a remarkable increase in IFN-γ production compared with that observed in splenocytes cultured with IL-12 alone. The synergistic effects of HVJ-E and IL-12 on IFN-γ production were caused by viral F proteins independently of HVJ-E fusion activity and not by hemagglutination from hemagglutinin-neuraminidase (HN) proteins. We next constructed HN-depleted HVJ-E expressing the Fc region of immunoglobulin G (IgG) on the envelope and single-chain IL-12 containing the ZZ domain of protein A to produce an IL-12-conjugated HVJ-E particle without hemagglutinating activity. IL-12-conjugated HVJ-E dramatically enhanced the amount of IFN-γ produced by immune cells. Intratumoral injection of IL-12-conjugated HVJ-E eradicated murine melanomas more effectively than injection of wild-type HVJ-E through increased production of melanoma-specific CTLs. IL-12-conjugated HVJ-E preferentially accumulated in the lungs after systemic administration. When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12-conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs. IL-12-conjugated HVJ-E is a promising tool for the treatment of cancers, including lung metastasis.

  1. Enhancements of non-specific immune response in Mugil cephlus by seaweed extract against Vibrio alginolyticus (BRTR07

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    Rajasekar Thirunavukkarasu

    2015-10-01

    Full Text Available Objective: To focus on the growth rate and feed utilization of fish by using trash fish feeds supplement with marine seaweeds. Methods: Selected seaweed was extracted using hot-water and its extract was mixed with trash fish feed at different concentrations (0.5%, 1% and 2% for 1-30 days and the nonspecific immune response in fish was studied and challenged with Vibrio alginolyticus at 1 × 106 CFU/fish. The hot-water extract of seaweeds was analysed by gas chromatography-mass spectrometry. Results: The average body weight (5.320 ± 0.018, percent weight gain (227.66 ± 0.28, specific growth rate (2.080 ± 0.015, hepatosomatic index (1.197 ± 0.00 and viscerosomatic index (4.421 ± 0.150 were significantly increased in the fish feed with seaweed containing 5% of Sargassum wightii (S. wightii when compared with other seaweeds and control diet. Hotwater extract of S. wightii (1% was significantly enhanced the immune response in fish when compared with other diets (0.5% and 2%. S. wightii showed good immunostimulation properties. Gas chromatography-mass spectrometry result showed that the hot-water extract of S. wightii seaweed contained fatty acids. Conclusions: Trash fish feed will reduce the production cost and also provide evidence that aqueous leaf extract of S. wightii (1% was added to a formulated fish diet which could activate the non-specific immune response and disease resistance against Vibrio alginolyticus in Mugil cephalus.

  2. Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells.

    Science.gov (United States)

    Kim, Ki-Hye; Lee, Young-Tae; Hwang, Hye Suk; Kwon, Young-Man; Jung, Yu-Jin; Lee, Youri; Lee, Jong Seok; Lee, Yu-Na; Park, Soojin; Kang, Sang-Moo

    2015-01-01

    Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

  3. The design of propolis flavone microemulsion and its effect on enhancing the immunity and antioxidant activity in mice.

    Science.gov (United States)

    Fan, Yunpeng; Ma, Lin; Zhang, Weimin; Wang, Junmin; Chen, Ying; Gao, Yuanyuan; Feng, Wei; Zhong, Liuqing; Song, Xiaoping

    2014-04-01

    The objective of the present study was to formulate a microemulsion system for improving the activity of propolis flavone (PF). Pseudo-ternary phase diagrams were constructed to evaluate the existence area of PF microemulsion (PFM). The formulation was characterized by particle size, zeta potential, morphology and stability. The results showed that the optimal PFM formulation consists of 5.3% ethyl acetate, 14% RH-40, 7% ethanol and 73.7% water (w/w), with a solubility of PF up to 3.0 mg mL(-1). The immune-enhancing and antioxidant activity of PFM in vitro and in vivo were performed. The results showed that PFM could significantly promote the splenocyte proliferation and the secretion of IL-2 and IFN-γ in vitro. In vivo, PFM at high and medium doses was able to significantly increase the thymus and spleen indices, enhance splenocyte activity and improve the contents of IgG and IgM in serum, it could also improve the antioxidant activity, significantly increase the levels of superoxidase dismutase and glutathione peroxidase, and decrease the malondialdehyde levels compared with PF. These results indicated that microemulsion could be used as an effective formulation for enhancing the activity of PF. Therefore, microemulsion would be expected to exploit into a new-type preparation of PF. Copyright © 2014. Published by Elsevier B.V.

  4. Mycobacterium indicus pranii as a booster vaccine enhances BCG induced immunity and confers higher protection in animal models of tuberculosis.

    Science.gov (United States)

    Saqib, Mohd; Khatri, Rahul; Singh, Bindu; Gupta, Ananya; Kumar, Arvind; Bhaskar, Sangeeta

    2016-12-01

    BCG, the only approved vaccine protects against severe form of childhood tuberculosis but its protective efficacy wanes in adolescence. BCG has reduced the incidence of infant TB considerably in endemic areas; therefore prime-boost strategy is the most realistic measure for control of tuberculosis in near future. Mycobacterium indicus pranii (MIP) shares significant antigenic repertoire with Mtb and BCG and has been shown to impart significant protection in animal models of tuberculosis. In this study, MIP was given as a booster to BCG vaccine which enhanced the BCG mediated immune response, resulting in higher protection. MIP booster via aerosol route was found to be more effective in protection than subcutaneous route of booster immunization. Pro-inflammatory cytokines like IFN-γ, IL-12 and IL-17 were induced at higher level in infected lungs of 'BCG-MIP' group both at mRNA expression level and in secretory form when compared with 'only BCG' group. BCG-MIP groups had increased frequency of multifunctional T cells with high MFI for IFN-γ and TNF-α in Mtb infected mice. Our data demonstrate for the first time, potential application of MIP as a booster to BCG vaccine for efficient protection against tuberculosis. This could be very cost effective strategy for efficient control of tuberculosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Cell Based Autologous Immune Enhancement Therapy (AIET after Radiotherapy in a Locally Advanced Carcinoma of the Cervix

    Directory of Open Access Journals (Sweden)

    Sumana Premkumar

    2013-01-01

    Full Text Available Radiotherapy is the primary form of treatment in patients with locally advanced cervical carcinoma. However for residual disease in the form of the persistent lymph nodes, surgery or chemotherapy is recommended. As surgery is not acceptable by every patient and chemotherapy has associated side effects, we hereby report the positive outcome of in vitro expanded natural killer cell and activated T lymphocyte based autologous immune enhancement therapy (AIET for the residual lymphadenopathy in a patient with locally advanced cervical cancer after radiation. After six transfusions of AIET, there was complete resolution of residual lymph nodes and there was no evidence of local lesion. The patient also reported improvement in quality of life. As AIET has been reported as the least toxic among the available therapies for cancer, combining AIET with conventional forms of therapy in similar patients might not only improve the outcome but may also help the patients achieve a good quality of life.

  6. Early infections by myxoma virus of young rabbits (Oryctolagus cuniculus) protected by maternal antibodies activate their immune system and enhance herd immunity in wild populations.

    Science.gov (United States)

    Marchandeau, Stéphane; Pontier, Dominique; Guitton, Jean-Sébastien; Letty, Jérôme; Fouchet, David; Aubineau, Jacky; Berger, Francis; Léonard, Yves; Roobrouck, Alain; Gelfi, Jacqueline; Peralta, Brigitte; Bertagnoli, Stéphane

    2014-03-04

    The role of maternal antibodies is to protect newborns against acute early infection by pathogens. This can be achieved either by preventing any infection or by allowing attenuated infections associated with activation of the immune system, the two strategies being based on different cost/benefit ratios. We carried out an epidemiological survey of myxomatosis, which is a highly lethal infectious disease, in two distant wild populations of rabbits to describe the epidemiological pattern of the disease. Detection of specific IgM and IgG enabled us to describe the pattern of immunity. We show that maternal immunity attenuates early infection of juveniles and enables activation of their immune system. This mechanism associated with steady circulation of the myxoma virus in both populations, which induces frequent reinfections of immune rabbits, leads to the maintenance of high immunity levels within populations. Thus, myxomatosis has a low impact, with most infections being asymptomatic. This work shows that infection of young rabbits protected by maternal antibodies induces attenuated disease and activates their immune system. This may play a major role in reducing the impact of a highly lethal disease when ecological conditions enable permanent circulation of the pathogen.

  7. Evaluation of in Vivo Antioxidant and Immunity Enhancing Activities of Sodium Aescinate Injection Liquid

    Directory of Open Access Journals (Sweden)

    Hui Zhang

    2012-08-01

    Full Text Available Oxidative stress is involved in the development and progression of disease. Because sodium aescinate has been reported to have immunity enhancing and antioxidative effects, we investigated its activity by employing a hepatocellular carcinoma (HCC mouse model. Sixty BALB/c mice were randomly divided into four groups, including a 1.4 mg/kg treated group (n = 15, a 2.8 mg/kg treated group (n = 15, an untreated hepatocellular carcinoma control group (n = 15 and a normal control group (n = 15. After H22 cells were cultured for one week, we collected 2 × 106 cells and injected them subcutaneously as 0.2 mL cell suspensions in sterile saline into the right shoulder region of every mouse. The animals were monitored for changes in activity, physical condition and body weight during the experiment. The next day after injection of H22 cells, animals in these test groups received one intraperitoneal injection of drug or physiological saline for 13 days. Results showed that in the sodium aescinate injection liquid (SAIL-treated HCC mice, serum interleukin-1 beta (IL-1β, interleukin-6 (IL-6, tumor necrosis factor-alpha (TNF-α, interferon-gamma (IFN-γ, Gamma-glutamyltransferase (γ-GT, alanine transaminase (ALT, aspartate transaminase (AST and alkaline phosphatase (ALP levels were significantly decreased compared with normal control mice. In addition, treatment with sodium aescinate injection liquid significantly decreased blood and liver malondialdehyde (MDA levels, increased glutathione (GSH levels, and antioxidant enzyme [superoxide dismutase (SOD, catalase (CAT and glutathione peroxidase (GSH-Px] activities in a dose-dependent manner. We conclude that sodium aescinate injection liquid can decrease oxidative injury and enhance immunity functions in HCC mice.

  8. Enhancing whole-tumor cell vaccination by engaging innate immune system through NY-ESO-1/dendritic cell interactions.

    Science.gov (United States)

    Xu, Le; Zheng, Junying; Nguyen, David H; Luong, Quang T; Zeng, Gang

    2013-10-01

    NY-ESO-1 is a cancer/germline antigen (Ag) with distinctively strong immunogenicity. We have previously demonstrated that NY-ESO-1 serves as an endogenous adjuvant by engaging dendritic cell (DC)-surface receptors of calreticulin (CRT) and toll-like receptor (TLR) 4. In the present study, NY-ESO-1 was investigated for its immunomodulatory roles as a molecular adjuvant in whole-tumor cell vaccines using the Renca kidney cancer model. Renca cells were genetically engineered to express NY-ESO-1 on the cell surface to enhance direct interactions with DC. The effect of ectopic cell-surface expression of NY-ESO-1 was investigated on tumor immunogenicity, DC activation, cytotoxic T lymphocytes against model tumor-associated Ags, and the effectiveness of the modified tumor cells as a therapeutic whole-cell vaccine. Cell-surface expression of NY-ESO-1 was able to reduce the tumor growth of Renca cells in BALB/c mice, although the modification did not alter cell proliferation rate in vitro. Directly engaging the innate immune system through NY-ESO-1 facilitated the interaction of tumor cells with DC, leading to enhanced DC activation and subsequent tumor-specific T-cell priming. When used as a therapeutic whole-cell vaccine, Renca cells with NY-ESO-1 on the surface mediated stronger inhibitory effects on tumor growth and metastasis compared with parental Renca or Renca cells expressing a control protein GFP on the surface. Augmented antitumor efficacy correlated with increased CD8 T-cell infiltration into tumors and decreased myeloid-derived suppressor cells and regulatory T cells in the spleen. As a cancer/germline Ag and as an immunomodulatory adjuvant through engaging innate immune receptors, NY-ESO-1 offers a unique opportunity for improved whole-tumor cell vaccinations upon the classic GM-CSF-engineered cell vaccines.

  9. CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFNγ with Dependency on Natural Killer Cells

    Directory of Open Access Journals (Sweden)

    Frederick Allen

    2017-10-01

    Full Text Available Lymph node (LN plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2. Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell—antigen-presenting cell (APC encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3–5. In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs of a CCL3-secreting CT26 colon tumor (L3TU as compared to wild-type tumor (WTTU during the priming phase of an antitumor response (≤10 days. In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3 secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103+ dendritic cells (DCs, and CD49b+ natural killer (NK cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNγ-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNγ in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNγ production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.

  10. CCL3 Enhances Antitumor Immune Priming in the Lymph NodeviaIFNγ with Dependency on Natural Killer Cells.

    Science.gov (United States)

    Allen, Frederick; Rauhe, Peter; Askew, David; Tong, Alexander A; Nthale, Joseph; Eid, Saada; Myers, Jay T; Tong, Caryn; Huang, Alex Y

    2017-01-01

    Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell-antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3-5). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (≤10 days). In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3) secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103 + dendritic cells (DCs), and CD49b + natural killer (NK) cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNγ)-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNγ in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNγ production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.

  11. Hericium caput-medusae (Bull.:Fr.) Pers. polysaccharide enhance innate immune response, immune-related genes expression and disease resistance against Aeromonas hydrophila in grass carp (Ctenopharyngodon idella).

    Science.gov (United States)

    Gou, Changlong; Wang, Jiazhen; Wang, Yuqiong; Dong, Wenlong; Shan, Xiaofeng; Lou, Yujie; Gao, Yunhang

    2018-01-01

    The objective was to add 0, 400, 800 or 1200 mg/kg of Hericium caput-medusae polysaccharide (HCMP) to the basal diet of grass carp (Ctenopharyngodon idella) and determine effects on humoral innate immunity, expression of immune-related genes and disease resistance. Adding HCMP enhanced (P < 0.05) bactericidal activity at 1, 2 and 3 weeks and also lysozyme activity, complement C3, and SOD activity at 2 and 3 weeks. Supplementing 800 or 1200 mg/kg of HCMP for 2 or 3 weeks increased (P < 0.05) serum concentrations of total protein, albumin and globulin. Two immune-related genes (IL-1β and TNF-α) were up-regulated (P < 0.05) in HCMP supplemented groups given 800 or 1200 mg/kg HCMP after 2 and 3 weeks of feeding. Expression of anti-inflammatory cytokine IL-10 was down-regulated (P < 0.05) after receiving 800 or 1200 mg/kg HCMP for 2 or 3 weeks. Fish fed 800 mg/kg HCMP had maximal disease resistance against Aeromonas hydrophila (65.4%). In conclusion, HCMP enhanced immune response and expression of immune-related genes and increased disease resistance against Aeromonas hydrophila in grass carp, with greatest effects in fish given 800 mg/kg HCMP for 3 weeks. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Ex Vivo Innate Immune Cytokine Signature of Enhanced Risk of Relapsing Brucellosis

    Science.gov (United States)

    Feldman, Kristyn E.; Loriaux, Paul M.; Saito, Mayuko; Tuero, Iskra; Villaverde, Homarh; Siva, Tenaya; Gotuzzo, Eduardo; Gilman, Robert H.; Hoffmann, Alexander; Vinetz, Joseph M.

    2013-01-01

    Background Brucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5–40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis. Methodology/Principal Findings Blood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM. Conclusions/Significance This work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may

  13. Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety

    Directory of Open Access Journals (Sweden)

    Voils Stacy A

    2009-05-01

    Full Text Available Abstract Topical hemostats, fibrin sealants, and surgical adhesives are regularly used in a variety of surgical procedures involving multiple disciplines. Generally, these adjuncts to surgical hemostasis are valuable means for improving wound visualization, reducing blood loss or adding tissue adherence; however, some of these agents are responsible for under-recognized adverse reactions and outcomes. Bovine thrombin, for example, is a topical hemostat with a long history of clinical application that is widely used alone or in combination with other hemostatic agents. Hematologists and coagulation experts are aware that these agents can lead to development of an immune-mediated coagulopathy (IMC. A paucity of data on the incidence of IMC contributes to under-recognition and leaves many surgeons unaware that this clinical entity, originating from normal immune responses to foreign antigen exposure, requires enhanced post-operative vigilance and judicious clinical judgment to achieve best outcomes. Postoperative bleeding may result from issues such as loosened ties or clips or the occurrence of a coagulopathy due to hemodilution, vitamin K deficiency, disseminated intravascular coagulation (DIC or post-transfusion, post-shock coagulopathic states. Other causes, such as liver disease, may be ruled out by a careful patient history and common pre-operative liver function tests. Less common are coagulopathies secondary to pathologic immune responses. Such coagulopathies include those that may result from inherent patient problems such as patients with an immune dysfunction related to systemic lupus erythrematosus (SLE or lymphoma that can invoke antibodies against native coagulation factors. Medical interventions may also provoke antibody formation in the form of self-directed anti-coagulation factor antibodies, that result in problematic bleeding; it is these iatrogenic post-operative coagulopathies, including those associated with bovine thrombin

  14. Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity.

    Science.gov (United States)

    Hendricks, Matthew R; Lashua, Lauren P; Fischer, Douglas K; Flitter, Becca A; Eichinger, Katherine M; Durbin, Joan E; Sarkar, Saumendra N; Coyne, Carolyn B; Empey, Kerry M; Bomberger, Jennifer M

    2016-02-09

    Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation.

  15. BCG Δzmp1 vaccine induces enhanced antigen specific immune responses in cattle.

    Science.gov (United States)

    Khatri, Bhagwati; Whelan, Adam; Clifford, Derek; Petrera, Agnese; Sander, Peter; Vordermeier, H Martin

    2014-02-07

    Mycobacterium bovis (M. bovis) causes major economy and public health problem in numerous countries. In Great Britain, despite the use of a test-and-slaughter strategy, the incidence of bovine tuberculosis (bTB) in cattle has steadily risen in recent years. One strategy being considered to reduce the burden of bTB in cattle is the development of an efficient vaccine. The only current potentially available vaccine against tuberculosis, live attenuated M. bovis bacille Calmette-Guérin (BCG), has demonstrated variable efficacy in both humans and cattle and the development of improved vaccination strategies for cattle is a research priority. In this study we assessed the immunogenicity in cattle of two recombinant BCG strains, namely BCG Pasteur Δzmp1::aph and BCG Danish Δzmp1. By applying a recently defined predictive immune-correlate of protection (T cell memory responses measured by cultured ELISPOT), we have compared these two recombinant BCG with wild-type BCG Danish SSI. Our results demonstrated that both strains induced superior T cell memory responses compared to wild-type BCG. These data provide support for the prioritisation of testing BCG Danish Δzmp1 in vaccination/M. bovis challenge studies to determine its protective efficacy. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  16. Lactobacillus-derived extracellular vesicles enhance host immune responses against vancomycin-resistant enterococci.

    Science.gov (United States)

    Li, Ming; Lee, Kiho; Hsu, Min; Nau, Gerard; Mylonakis, Eleftherios; Ramratnam, Bharat

    2017-03-14

    Probiotic bacteria are known to modulate host immune responses against various pathogens. Recently, extracellular vesicles (EVs) have emerged as potentially important mediators of host-pathogen interactions. In this study, we explored the role of L. plantarum derived EVs in modulating host responses to vancomycin-resistant Enterococcus faecium (VRE) using both Caenorhabditis elegans and human cells. Our previous work has shown that probiotic conditioning C. elegans with L. acidophilus NCFM prolongs the survival of nematodes exposed to VRE. Similarly, L. plantarum WCFS1 derived extracellular vesicles (LDEVs) also significantly protected the worms against VRE infection. To dissect the molecular mechanisms of this EV-induced protection, we found that treatment of C. elegans with LDEVs significantly increased the transcription of host defense genes, cpr-1 and clec-60. Both cpr-1 and clec-60 have been previously reported to have protective roles against bacterial infections. Incubating human colon-derived Caco-2 cells with fluorescent dye-labeled LDEVs confirmed that LDEVs could be transported into the mammalian cells. Furthermore, LDEV uptake was associated with significant upregulation of CTSB, a human homologous gene of cpr-1, and REG3G, a human gene that has similar functions to clec-60. We have found that EVs produced from L. plantarum WCFS1 up-regulate the expression of host defense genes and provide protective effects on hosts. Using probiotic-derived EVs instead of probiotic bacteria themselves, this study provides a new direction to treat antimicrobial resistant pathogens, such as VRE.

  17. Pre-germinated brown rice could enhance maternal mental health and immunity during lactation.

    Science.gov (United States)

    Sakamoto, Shigeko; Hayashi, Takashi; Hayashi, Keiko; Murai, Fumie; Hori, Miyo; Kimoto, Koichi; Murakami, Kazuo

    2007-10-01

    Rice is a dietary staple worldwide, especially pre-germinated brown rice has recently been widely served in Japan because of its abundant nutrition. Relationship between lactation and pre-germinated brown rice has attracted interest in terms of mental health and immunity. To demonstrate that Japanese foods are beneficial for psychosomatic health, the effects of pre-germinated brown rice on the mental status and immunological features during lactation were investigated. Forty-one breast-feeding mothers were recruited, and randomly divided into two groups. One group took pre-germinated brown rice and the other white rice (control) as their staple diet for 2 weeks. The Profile of Mood States (POMS) and salivary amylase activity as psychological indices and secretory IgA (s-IgA) and lactoferrin (LTF) in breast milk as immunological indices were determined before and after dietary intervention, and changes were investigated. In the psychological assessment, the scores of depression, anger-hostility, and fatigue were decreased on POMS analysis in the pre-germinated brown rice diet group, resulting in a significant decrease in total mood disturbance (TMD). The salivary amylase activity measurement suggested that resistance to stress was increased in the pre-germinated brown rice diet group. On the immunological assessment, the s-IgA level was significantly increased in the pre-germinated brown rice diet group. We have shown that pre-germinated brown rice may have beneficial effects on psychosomatic health.

  18. Enhancing mucosal immunity in mice by recombinant adenovirus expressing major epitopes of porcine circovirus-2 capsid protein delivered with cytosine-phosphate-guanosine oligodeoxynucleotides.

    Science.gov (United States)

    Chang, Hong-Tao; He, Xiu-Yuan; Liu, Yu-Feng; Chen, Lu; Guo, Quan-Hai; Yu, Qiu-Ying; Zhao, Jun; Wang, Xin-Wei; Yang, Xia; Wang, Chuan-Qing

    2014-01-01

    A recombinant replication-defective adenovirus expressing the major epitopes of porcine circovirus-2 (PCV-2) capsid protein (rAd/Cap/518) was previously constructed and shown to induce mucosal immunity in mice following intranasal delivery. In the present study, immune responses induced by intranasal immunization with a combination of rAd/Cap/518 and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) were evaluated in mice. The levels of PCV-2-specific IgG in serum and IgA in saliva, lung, and intestinal fluids were significantly higher in the group immunized with rAd/Cap/518 and CpG ODN than animals immunized with rAd/Cap/518 alone. The frequencies of IL-2-secreting CD4⁺ T cells and IFN-γ-producing CD8⁺ T cells were significantly higher in the combined immunization group than mice immunized with rAd/Cap/518 alone. The frequencies of CD3⁺, CD3⁺CD4⁺CD8⁻, and CD3⁺CD4⁻CD8⁺ T cells in the combined immunization group were similar to that treated with CpG ODN alone, but significantly higher than mice that did not receive CpG ODN. PCV-2 load after challenge in the combined immunization group was significantly lower than that in the phosphate-buffered saline placebo group and approximately 7-fold lower in the group treated with CpG ODN alone. These results indicate that rAd/Cap/518 combined with CpG ODN can enhance systemic and local mucosal immunity in mice, and represent a promising synergetic mucosal vaccine against PCV-2.

  19. Enhancement of the Th1-phenotype immune system by the intake of Oyster mushroom (Tamogitake extract in a double-blind, placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Aiko Tanaka

    2016-10-01

    Full Text Available Pleurotus cornucopiae (Oyster mushroom, Tamogitake has long been eaten as a functional food for enhancement of the immune system, but its effectiveness has not been well confirmed in humans. To this end, we set up a double-blind placebo-controlled human clinical trial to investigate the potential of Oyster mushrooms with respect to the up-regulation of the immune system. The subjects ingested Oyster mushroom extract for 8 weeks. We measured the serum cytokine levels involved in regulation of the immune system, including interferon (IFN-γ, interleukin (IL-4, IL-5, IL-10, IL-12, IL-13, and tumor-necrosis factor (TNF-α. We found that intake of Oyster mushroom extract elevated IFN-γ (P = 0.013 and IL-12, whereas serum levels of IL-10 and IL-13 and other cytokines were minimally changed. We also measured natural killer (NK cell activity, the levels of which tended to increase, but not significantly. Taken together, these facts suggest that Oyster mushrooms have the potential to enhance the immune system, through Th1 phenotype potentiation as the macrophage-IL-12 – IFN-γ pathway. This results in activation of the cell-mediated immune system as exemplified by up-regulation of NK cell activity. Oyster mushroom extract may be beneficial for the prevention of various diseases, including infectious diseases and cancer, due to its stimulation of the immune system.

  20. A novel subunit vaccine co-expressing GM-CSF and PCV2b Cap protein enhances protective immunity against porcine circovirus type 2 in piglets.

    Science.gov (United States)

    Zhang, Huawei; Qian, Ping; Peng, Bo; Shi, Lin; Chen, Huanchun; Li, Xiangmin

    2015-05-15

    Porcine circovirus type 2 (PCV2) causes porcine circovirus-associated disease. Capsid (Cap) protein of PCV2 is the principal immunogenic protein that induces neutralizing antibodies and protective immunity. GM-CSF is an immune adjuvant that enhances responses to vaccines. In this study, recombinant baculoviruses Ac-Cap and Ac-Cap-GM-CSF expressing the Cap protein alone and co-expressing the Cap protein and porcine GM-CSF, respectively, were constructed successfully. The target proteins were analyzed by western blotting and IFA. Further, these proteins were confirmed by electron microscopy, which showed that Cap proteins could self-assemble into virus-like particles having diameters of 17-25nm. Animal experiments showed that pigs immunized with Cap-GM-CSF subunit vaccine showed significantly higher levels of PCV2-specific antibodies and neutralizing antibodies than pigs immunized with the Cap subunit vaccine and a commercial vaccine (Ingelvac CircoFLEX; PGM-CSF subunit vaccine showed significantly higher average daily weight gain after wild-type PCV2 challenge than pigs receiving the other three vaccines (PGM-CSF was a powerful immunoadjuvant for PCV2 subunit vaccines because it enhanced humoral immune response and improved immune protection against PCV2 infection in pigs. Thus, the novel Cap-GM-CSF subunit vaccine has the potential to be used as an effective and safe vaccine candidate against PCV2 infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. The Selenylation Modification of Epimedium Polysaccharide and Isatis Root Polysaccharide and the Immune-enhancing Activity Comparison of Their Modifiers.

    Science.gov (United States)

    Li, Xiuping; Hou, Ranran; Yue, Chanjuan; Liu, Jie; Gao, Zhenzhen; Chen, Jin; Lu, Yu; Wang, Deyun; Liu, Cui; Hu, Yuanliang

    2016-05-01

    Epimedium polysaccharide (EPS) and isatis root polysaccharide (IRPS) were extracted, purified, and selenizingly modified by nitric acid-sodium selenite method to obtain nine selenizing EPSs (sEPSs), sEPS1-sEPS9 and nine selenizing IRPSs (sIRPSs), sIRPS1-sIRPS9, respectively. Their effects on chicken peripheral lymphocyte proliferation in vitro were compared by MTT assay. The results showed that selenium polysaccharides at appropriate concentration could promote lymphocyte proliferation more significantly than unmodified polysaccharides, sEPS5 and sIRPS5 with stronger actions were picked out and injected into the chickens vaccinated with Newcastle disease vaccine in vivo tests. The peripheral lymphocyte proliferation and serum antibody titer were determined. The results showed that sEPS5 and sIRPS5 could elevate serum antibody titer and promote lymphocyte proliferation more significantly than unmodified polysaccharides, sEPS5 possessed the strongest efficacy. These results indicate that selenylation modification can significantly enhance the immune-enhancing activity of EPS and IRPS, and sEPS5 can be as a new-type immunopotentiator of chickens.

  2. Protein transfer-mediated surface engineering to adjuvantate virus-like nanoparticles for enhanced anti-viral immune responses.

    Science.gov (United States)

    Patel, Jaina M; Kim, Min-Chul; Vartabedian, Vincent F; Lee, Yu-Na; He, Sara; Song, Jae-Min; Choi, Hyo-Jick; Yamanaka, Satoshi; Amaram, Nikhil; Lukacher, Anna; Montemagno, Carlo D; Compans, Richard W; Kang, Sang-Moo; Selvaraj, Periasamy

    2015-07-01

    Recombinant virus-like nanoparticles (VLPs) are a promising nanoparticle platform to develop safe vaccines for many viruses. Herein, we describe a novel and rapid protein transfer process to enhance the potency of enveloped VLPs by decorating influenza VLPs with exogenously added glycosylphosphatidylinositol-anchored immunostimulatory molecules (GPI-ISMs). With protein transfer, the level of GPI-ISM incorporation onto VLPs is controllable by varying incubation time and concentration of GPI-ISMs added. ISM incorporation was dependent upon the presence of a GPI-anchor and incorporated proteins were stable and functional for at least 4weeks when stored at 4°C. Vaccinating mice with GPI-granulocyte macrophage colony-stimulating factor (GM-CSF)-incorporated-VLPs induced stronger antibody responses and better protection against a heterologous influenza virus challenge than unmodified VLPs. Thus, VLPs can be enriched with ISMs by protein transfer to increase the potency and breadth of the immune response, which has implications in developing effective nanoparticle-based vaccines against a broad spectrum of enveloped viruses. The inherent problem with current influenza vaccines is that they do not generate effective cross-protection against heterologous viral strains. In this article, the authors described the development of virus-like nanoparticles (VLPs) as influenza vaccines with enhanced efficacy for cross-protection, due to an easy protein transfer modification process. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Enhanced immune responses of foot-and-mouth disease vaccine using new oil/gel adjuvant mixtures in pigs and goats.

    Science.gov (United States)

    Park, Min-Eun; Lee, Seo-Yong; Kim, Rae-Hyung; Ko, Mi-Kyeong; Lee, Kwang-Nyeong; Kim, Su-Mi; Kim, Byoung-Kwan; Lee, Jong-Soo; Kim, Byounghan; Park, Jong-Hyeon

    2014-09-08

    The immunity and protective capability produced by vaccines can vary remarkably according to the kinds of adjuvants being used. In the case of foot-and-mouth disease (FMD) vaccines in pigs, only oil-adjuvant vaccines have been used, and these tend to show lower immunity in pigs than in cattle. New adjuvants for these vaccines are therefore needed. We made different experimental FMD vaccines using new adjuvants (ISA 201, Carbigen, Emulsigen-D) and well-known adjuvants (ISA 206, aluminum hydroxide gel) and then conducted tests to compare the enhancement in pig immunity. More effective immune responses and protection against challenge were observed with the new adjuvants Emulsigen-D and ISA 201 compared to existing adjuvants. In the case of dairy goats, a mixture of Emulsigen-D and aluminum hydroxide gel produced rapid neutralizing antibody responses that were similar to results from tests conducted with pigs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Evaluation of Antioxidant and Immunity-Enhancing Activities of Sargassum pallidum Aqueous Extract in Gastric Cancer Rats

    Directory of Open Access Journals (Sweden)

    Shen-Kang Zhou

    2012-07-01

    Full Text Available The effect of Sargassum pallidum (brown seaweed aqueous extract on the immunity function and antioxidant activities in was studied gastric cancer rats. Treatment with Sargassum pallidum aqueous extract at oral doses 400, 600 or 800 mg/kg body weight was found to provide a dose-dependent protection against N-methyl-N′-nitro-N-nitrosoguanidine (MNNG-induced immunity damage and oxidative injury by enhancing serum interleukin-2 (IL-2, interleukin-4 (IL-4, interleukin-10 (IL-10 levels, decreasing interleukin-6 (IL-6, interleukin-1β (IL-1β, tumor necrosis factor-alpha (TNF-α levels, preserving normal antioxidant enzymes activities, and by inhibiting lipid peroxidation in gastric mucosa. It can be concluded that Sargassum pallidum aqueous extract may enhance the immunity and antioxidant activities in gastric cancer rats.

  5. Characterization of a novel maitake (Grifola frondosa) protein that activates natural killer and dendritic cells and enhances antitumor immunity in mice.

    Science.gov (United States)

    Tsao, Yao-Wei; Kuan, Yen-Chou; Wang, Jia-Lin; Sheu, Fuu

    2013-10-16

    Grifola frondosa, also known as maitake, is a culinary mushroom with immune-enhancing and antitumor effects. Numerous studies have investigated the activity of maitake polysaccharide extracts, but studies of maitake proteins are scarce. In this study, we purified and characterized a new G. frondosa protein, GFP, from maitake fruiting bodies. GFP is a nonglucan heterodimeric 83 kDa protein that consists of two 41 kDa subunits. GFP induced interferon-γ secretion by murine splenocytes and natural killer cells and activated the maturation of bone marrow-derived dendritic cells (BMDCs) via a TLR4-dependent mechanism. GFP-treated BMDCs promoted a Th1 response and exhibited significant antitumor activity when transferred into tumor-bearing mice. In conclusion, we are the first to reveal the critical role of GFP in modulating the immune response and to link the immune-enhancing effects of maitake to its antitumor activities.

  6. Leukotriene B4 enhances innate immune defense against the puerperal sepsis agent Streptococcus pyogenes.

    Science.gov (United States)

    Soares, Elyara M; Mason, Katie L; Rogers, Lisa M; Serezani, Carlos H; Faccioli, Lucia H; Aronoff, David M

    2013-02-15

    Puerperal sepsis is a leading cause of maternal mortality worldwide. Streptococcus pyogenes [group A Streptococcus; (GAS)] is a major etiologic agent of severe postpartum sepsis, yet little is known regarding the pathogenesis of these infections. Tissue macrophages provide innate defense against GAS, and their actions are highly regulated. The intracellular second messenger cAMP can negatively regulate macrophage actions against GAS. Because leukotriene (LT) B(4) has been shown to suppress intracellular cAMP in macrophages, we hypothesized that it could enhance innate defenses against GAS. We assessed the capacity of LTB(4) to modulate antistreptococcal actions of human macrophages, including placental and decidual macrophages and used a novel intrauterine infection model of GAS in mice lacking the 5-lipoxygenase enzyme to determine the role of endogenous LTs in host defense against this pathogen. Animals lacking 5-lipoxygenase were significantly more vulnerable to intrauterine GAS infection than were wild-type mice and showed enhanced dissemination of bacteria out of the uterus and a more robust inflammatory response than did wild-type mice. In addition, LTB(4) reduced intracellular cAMP levels via the BLT1 receptor and was a potent stimulant of macrophage phagocytosis and NADPH oxidase-dependent intracellular killing of GAS. Importantly, interference was observed between the macrophage immunomodulatory actions of LTB(4) and the cAMP-inducing lipid PGE(2), suggesting that interplay between pro- and anti-inflammatory compounds may be important in vivo. This work underscores the potential for pharmacological targeting of lipid mediator signaling cascades in the treatment of invasive GAS infections.

  7. Alum Adjuvant Enhances Protection against Respiratory Syncytial Virus but Exacerbates Pulmonary Inflammation by Modulating Multiple Innate and Adaptive Immune Cells.

    Directory of Open Access Journals (Sweden)

    Ki-Hye Kim

    Full Text Available Respiratory syncytial virus (RSV is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.

  8. Enhanced CD8+ T cell immune responses and protection elicited against Plasmodium berghei malaria by prime boost immunization regimens using a novel attenuated fowlpox virus.

    Science.gov (United States)

    Anderson, Richard J; Hannan, Carolyn M; Gilbert, Sarah C; Laidlaw, Stephen M; Sheu, Eric G; Korten, Simone; Sinden, Robert; Butcher, Geoffrey A; Skinner, Michael A; Hill, Adrian V S

    2004-03-01

    Sterile immunity can be provided against the pre-erythrocytic stages of malaria by IFN-gamma-secreting CD8(+) T cells that recognize parasite-infected hepatocytes. In this study, we have investigated the use of attenuated fowlpox virus (FPV) strains as recombinant vaccine vectors for eliciting CD8(+) T cells against Plasmodium berghei. The gene encoding the P. berghei circumsporozoite (PbCS) protein was inserted into an FPV vaccine strain licensed for use in chickens, Webster's FPV, and the novel FPV vaccine strain FP9 by homologous recombination. The novel FP9 strain proved more potent as a vaccine for eliciting CD8(+) T cell responses against the PbCS Ag. Sequential immunization with rFP9 and recombinant modified vaccinia virus Anakara (MVA) encoding the PbCS protein, administered by clinically acceptable routes, elicited potent CD8(+) T cell responses against the PbCS protein. This immunization regimen elicited substantial protection against a stringent liver-stage challenge with P. berghei and was more immunogenic and protective than DNA/MVA prime/boost immunization. However, further improvement was not achieved by sequential (triple) immunization with a DNA vaccine, FP9, and MVA.

  9. Glycine does not add to the beneficial effects of perioperative oral immune-enhancing nutrition supplements in high-risk cardiac surgery patients.

    NARCIS (Netherlands)

    Tepaske, R.; Velthuis, H. te; Straaten, H.M. van der; Bossuyt, P.M.; Schultz, M.J.; Eijsman, L.; Vroom, M.

    2007-01-01

    BACKGROUND: Elderly patients and patients with a poor cardiac function have increased morbidity rates when undergoing cardiac surgery. The aim of this study was to determine whether addition of glycine to a standard preoperative oral immune-enhancing nutrition supplement (OIENS) improves outcome.

  10. Virus-stimulated neutrophils in the tumor microenvironment enhance T cell-mediated anti-tumor immunity.

    Science.gov (United States)

    Chang, Chin Yang; Tai, Jiayu A; Li, Sumin; Nishikawa, Tomoyuki; Kaneda, Yasufumi

    2016-07-05

    The tumor microenvironment (TME) fosters tumors by attenuating anti-tumor immunity, reinforcing tumor cell survival and increasing angiogenesis. Among the constituents of the TME, here, we focused on tumor-associated neutrophils (TANs). First, we found that the combination of poly I:C and inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) synergistically suppressed tumor growth in the B16-F10 melanoma mouse model. In this model, poly I:C contributed to the recruitment of CD11b+Ly6G+ neutrophils to the TME, and co-injection of poly I:C and HVJ-E increased CD11b+Ly6G+FAS+ TAN in the TME. Depletion of neutrophils abolished the synergistic anti-tumor effect of HVJ-E and poly I:C in B16-F10 tumors. We revealed that C-X-C motif chemokine ligand 2 (CXCL2) is produced in the TME by poly I:C, but HVJ-E enhanced neutrophil infiltration of the TME does not occur. An anti-CXCL2 antibody inhibited the tumor suppression by HVJ-E+poly I:C. HVJ-E in combination with recombinant CXCL2 protein or CXCL2 pDNA suppressed mouse melanoma by increasing cytotoxic T lymphocyte activity against B16-F10 melanoma, which was abolished by an anti-Ly6G antibody. HVJ-E directly and indirectly increased FAS and ICAM-1 expression in cultured bone marrow-derived naïve neutrophils. Thus, HVJ-E activates anti-tumor immunity via anti-tumorigenic neutrophils in the TME. An HVJ-E vector containing the CXCL2 gene may be applicable as a novel cancer gene therapy strategy.

  11. A live attenuated Salmonella Enteritidis secreting detoxified heat labile toxin enhances mucosal immunity and confers protection against wild-type challenge in chickens.

    Science.gov (United States)

    Lalsiamthara, Jonathan; Kamble, Nitin Machindra; Lee, John Hwa

    2016-06-04

    A live attenuated Salmonella Enteritidis (SE) capable of constitutively secreting detoxified double mutant Escherichia coli heat labile toxin (dmLT) was developed. The biologically adjuvanted strain was generated via transformation of a highly immunogenic SE JOL1087 with a plasmid encoding dmLT gene cassette; the resultant strain was designated JOL1641. A balanced-lethal host-vector system stably maintained the plasmid via auxotrophic host complementation with a plasmid encoded aspartate semialdehyde dehydrogenase (asd) gene. Characterization by western blot assay revealed the dmLT subunit proteins in culture supernatants of JOL1641. For the investigation of adjuvanticity and protective efficacy, chickens were immunized via oral or intramuscular routes with PBS, JOL1087 and JOL1641. Birds immunized with JOL1641 showed significant (P ≤ 0.05) increases in intestinal SIgA production at the 1(st) and 2(nd) weeks post-immunization via oral and intramuscular routes, respectively. Interestingly, while both strains showed significant splenic protection via intramuscular immunization, JOL1641 outperformed JOL1087 upon oral immunization. Oral immunization of birds with JOL1641 significantly reduced splenic bacterial counts. The reduction in bacterial counts may be correlated with an adjuvant effect of dmLT that increases SIgA secretion in the intestines of immunized birds. The inclusion of detoxified dmLT in the strain did not cause adverse reactions to birds, nor did it extend the period of bacterial fecal shedding. In conclusion, we report here that dmLT could be biologically incorporated in the secretion system of a live attenuated Salmonella-based vaccine, and that this construction is safe and could enhance mucosal immunity, and protect immunized birds against wild-type challenge.

  12. Intranasal Immunization with Influenza Virus-Like Particles Containing Membrane-Anchored Cholera Toxin B or Ricin Toxin B Enhances Adaptive Immune Responses and Protection against an Antigenically Distinct Virus

    Directory of Open Access Journals (Sweden)

    Xianliang Ji

    2016-04-01

    Full Text Available Vaccination is the most effective means to prevent influenza virus infection, although current approaches are associated with suboptimal efficacy. Here, we generated virus-like particles (VLPs composed of the hemagglutinin (HA, neuraminidase (NA and matrix protein (M1 of A/Changchun/01/2009 (H1N1 with or without either membrane-anchored cholera toxin B (CTB or ricin toxin B (RTB as molecular adjuvants. The intranasal immunization of mice with VLPs containing membrane-anchored CTB or RTB elicited stronger humoral and cellular immune responses when compared to mice immunized with VLPs alone. Administration of VLPs containing CTB or RTB significantly enhanced virus-specific systemic and mucosal antibody responses, hemagglutination inhibiting antibody titers, virus neutralizing antibody titers, and the frequency of virus-specific IFN-γ and IL-4 secreting splenocytes. VLPs with and without CTB or RTB conferred complete protection against lethal challenge with a mouse-adapted homologous virus. When challenged with an antigenically distinct H1N1 virus, all mice immunized with VLPs containing CTB or RTB survived whereas mice immunized with VLPs alone showed only partial protection (80% survival. Our results suggest that membrane-anchored CTB and RTB possess strong adjuvant properties when incorporated into an intranasally-delivered influenza VLP vaccine. Chimeric influenza VLPs containing CTB or RTB may represent promising vaccine candidates for improved immunological protection against homologous and antigenically distinct influenza viruses.

  13. Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation.

    Science.gov (United States)

    Lee, Yu-Hui; Shynlova, Oksana; Lye, Stephen J

    2015-03-01

    Spontaneous term labour is associated with amplified inflammatory events in the myometrium including cytokine production and leukocyte infiltration; however, potential mechanisms regulating such events are not fully understood. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte extravasation into the term myometrium through the release of various cytokines by uterine myocytes. Human myometrial cells (hTERT-HM) were subjected to static mechanical stretch; stretch-conditioned media was collected and analysed using 48-plex Luminex assay and ELISA. Effect of stretch-conditioned media on cell adhesion molecule expression of human uterine microvascular endothelial cells (UtMVEC-Myo) was detected by quantitative polymerase chain reaction (qPCR) and flow cytometry; functional assays testing leukocyte-endothelial interactions: adhesion of leukocytes to endothelial cells and transendothelial migration of calcein-labelled primary human neutrophils as well as migration of THP-1 monocytic cells were assessed by fluorometry. The current in vitro study demonstrated that mechanical stretch (i) directly induces secretion of multiple cytokines and chemokines by hTERT-HM cells (IL-6, CXCL8, CXCL1, migration inhibitory factor (MIF), VEGF, G-CSF, IL-12p70, bFGF and platelet-derived growth factor subunit B (PDGF-bb), Pcytokines (ii) enhance leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (iii) inducing the expression of endothelial cell adhesion molecules and (iv) directing the transendothelial migration of peripheral leukocytes. (vi) Chemokine-neutralizing antibodies and broad-spectrum chemokine inhibitor block leukocyte migration. Our data provide a proof of mechanical regulation for leukocyte recruitment from the uterine blood vessels to the myometrium, suggesting a putative mechanism for the leukocyte infiltrate into the uterus during labour and postpartum involution.

  14. Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

    Science.gov (United States)

    Lee, Yu-Hui; Shynlova, Oksana; Lye, Stephen J

    2015-01-01

    Spontaneous term labour is associated with amplified inflammatory events in the myometrium including cytokine production and leukocyte infiltration; however, potential mechanisms regulating such events are not fully understood. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte extravasation into the term myometrium through the release of various cytokines by uterine myocytes. Human myometrial cells (hTERT-HM) were subjected to static mechanical stretch; stretch-conditioned media was collected and analysed using 48-plex Luminex assay and ELISA. Effect of stretch-conditioned media on cell adhesion molecule expression of human uterine microvascular endothelial cells (UtMVEC-Myo) was detected by quantitative polymerase chain reaction (qPCR) and flow cytometry; functional assays testing leukocyte–endothelial interactions: adhesion of leukocytes to endothelial cells and transendothelial migration of calcein-labelled primary human neutrophils as well as migration of THP-1 monocytic cells were assessed by fluorometry. The current in vitro study demonstrated that mechanical stretch (i) directly induces secretion of multiple cytokines and chemokines by hTERT-HM cells (IL-6, CXCL8, CXCL1, migration inhibitory factor (MIF), VEGF, G-CSF, IL-12p70, bFGF and platelet-derived growth factor subunit B (PDGF-bb), Pstretch-induced cytokines (ii) enhance leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (iii) inducing the expression of endothelial cell adhesion molecules and (iv) directing the transendothelial migration of peripheral leukocytes. (vi) Chemokine-neutralizing antibodies and broad-spectrum chemokine inhibitor block leukocyte migration. Our data provide a proof of mechanical regulation for leukocyte recruitment from the uterine blood vessels to the myometrium, suggesting a putative mechanism for the leukocyte infiltrate into the uterus during labour and postpartum involution

  15. Enhancement of humoral and cellular immune responses by monophosphoryl lipid A (MPLA) as an adjuvant to the rabies vaccine in BALB/c mice.

    Science.gov (United States)

    Hu, Xiaobo; Liu, Rui; Zhu, Naishuo

    2013-12-01

    The development of effective vaccines against the rabies virus could prevent infection with this fatal virus. However, the current rabies vaccine fails to provide a full range of protection because of its limited ability to elicit a cellular immune response and the requirement for repeat vaccination. Monophosphoryl lipid A (MPLA) is well known as a potent adjuvant to enhance immune responses against virus infection. Here we investigated the efficacy of MPLA as an adjuvant to improve the humoral and cellular immune responses to the rabies vaccine in BALB/c mice. Supplementation of the rabies vaccine with MPLA significantly accelerated the production of specific antibodies by 10 days compared to the original vaccines. Furthermore, MPLA promoted the induction of stronger cellular immune responses by the rabies vaccine, including the production of IL-4, IFN-γ and the activation of CD4⁺/CD8⁺ T cells, than those elicited without MPLA. Collectively, our findings indicated that MPLA enhances humoral and cellular immunity and is a promising adjuvant for the development of more effective rabies vaccines. Copyright © 2013 Elsevier GmbH. All rights reserved.

  16. Optimization of Variable Ventilation for Physiology, Immune Response and Surfactant Enhancement in Preterm Lambs

    Directory of Open Access Journals (Sweden)

    Erzsébet Bartolák-Suki

    2017-06-01

    highest in CV. An overall combined index of performance that included physiological, biochemical and histological markers was the best in VV2 followed by VV1. Thus, VV2 outperformed VV1 by enhancing SP-B metabolism resulting in open alveolar airspaces, less leakage and inflammation and hence better respiratory mechanics.

  17. Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-viral immunity during chronic retroviral infection.

    Science.gov (United States)

    Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Sokolova, Viktoriya; Hansen, Wiebke; Sparwasser, Tim; Dittmer, Ulf; Epple, Matthias; Buer, Jan; Westendorf, Astrid M

    2016-04-14

    Regulatory T cells (Tregs) have been shown to limit anti-viral immunity during chronic retroviral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-viral immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8(+) or CD4(+) T cell epitope peptides (GagL85-93 or Env gp70123-141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4(+) and CD8(+) effector T cells was analysed and the viral loads were determined. Therapeutic vaccination of chronically FV-infected mice with functionalized CaP nanoparticles transiently reactivated cytotoxic CD8(+) T cells and significantly reduced the viral loads. Transient ablation of Tregs during nanoparticle-based therapeutic vaccination strongly enhanced anti-viral immunity and further decreased viral burden. Our data illustrate a crucial role for CD4(+) Foxp3(+) Tregs in the suppression of anti-viral T cell responses during therapeutic vaccination against chronic retroviral infection. Thus, the combination of transient Treg ablation and therapeutic nanoparticle-based vaccination confers robust and sustained anti-viral immunity.

  18. Enhanced immune response of red deer (Cervus elaphus) to live rb51 vaccine strain using composite microspheres.

    Science.gov (United States)

    Arenas-Gamboa, Angela M; Ficht, Thomas A; Davis, Donald S; Elzer, Philip H; Wong-Gonzalez, Alfredo; Rice-Ficht, Allison C

    2009-01-01

    Brucellosis is an important zoonotic disease of nearly worldwide distribution. The occurrence of the infection in humans is largely dependent on the prevalence of brucellosis in animal reservoirs, including wildlife. The current vaccine used for cattle Brucella abortus strain RB51, has proven ineffective in protecting bison (Bison bison) and elk (Cervus nelsoni) from infection and abortion. To test possible improvements in vaccine efficacy, a novel approach of immunization was examined from April 2004 to November 2006 using alginate composite microspheres containing a nonimmunogenic, eggshell-precursor protein of the parasite Fasciola hepatica (Vitelline protein B, VpB) to deliver live vaccine strain RB51. Red deer (Cervus elaphus), used as a model for elk, were vaccinated orally (PO) or subcutaneously (SC) with 1.5x10(10) viable organisms per animal. Humoral responses postvaccination (immunoglobulin G [IgG] levels), assessed at different time points, indicated that capsules containing live RB51 elicited an anti-Brucella specific IgG response. Furthermore, the encapsulated vaccine elicited a cell-mediated response that the nonencapsulated vaccinates failed to produce. Finally, red deer were challenged with B. abortus strain 19 by conjunctival exposure. Only animals that received encapsulated RB51 vaccine by either route exhibited a significant reduction in bacterial counts in their spleens. These data suggest that alginate-VpB microspheres provide a method to enhance the RB51 vaccine performance in elk.

  19. Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response.

    Science.gov (United States)

    Ye, Jun; Dong, Wujun; Yang, Yanfang; Hao, Huazhen; Liao, Hengfeng; Wang, Bangyuan; Han, Xue; Jin, Yiqun; Xia, Xuejun; Liu, Yuling

    2017-06-01

    To overcome the drawbacks of high dose regimen and improve the outcomes of chemotherapy at a low dose, an immunotherapeutic nanoemulsion based combination of chemotherapeutic agent (paclitaxel) with immunomodulatory agent (vitamin E) was developed and evaluated for their antitumor effect against breast cancer. A total of five nanoemulsions loaded with various content of vitamin E were prepared and characterized. The immunoregulatory effects of vitamin E along with the overall antitumor efficacy of vitamin E-rich nanoemulsion with a low dose of paclitaxel were investigated through in vitro and in vivo experiments. Vitamin E-rich nanoemulsion exhibited relatively narrow size distribution, high entrapment efficiency and controlled in vitro release profile. In RAW264.7 cells, vitamin E-rich nanoemulsion significantly enhanced the secretion of Th1 cytokines and down-regulated the secretion of Th2 cytokine. In a co-culture system, vitamin E-rich nanoemulsion induced a high apoptosis rate in MDA-MB-231 cells as compared with vitamin E-low nanoemulsion. Furthermore, vitamin E-rich nanoemulsion exhibited superior in vivo antitumor efficacy in comparison with Taxol and vitamin E-low nanoemulsion at a paclitaxel dose of 4 mg/kg. Vitamin E-rich nanoemulsion has great potential for the treatment of breast cancers with a low dose of paclitaxel via driving Th1 immune response.

  20. EGFR signaling enhances aerobic glycolysis in triple negative breast cancer cells to promote tumor growth and immune escape

    Science.gov (United States)

    Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya; Lee, Heng-Huan; Chang, Shih-Shin; Shen, Jia; Hsu, Jennifer L.; Raftery, Dan; Djukovic, Danijel; Gu, Haiwei; Chang, Wei-Chao; Wang, Hung-Ling; Chen, Mong-Liang; Huo, Longfei; Chen, Chung-Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M.; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. PMID:26759242

  1. EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.

    Science.gov (United States)

    Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya; Lee, Heng-Huan; Chang, Shih-Shin; Shen, Jia; Hsu, Jennifer L; Raftery, Daniel; Djukovic, Danijel; Gu, Haiwei; Chang, Wei-Chao; Wang, Hung-Ling; Chen, Mong-Liang; Huo, Longfei; Chen, Chung-Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2016-03-01

    Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. ©2016 American Association for Cancer Research.

  2. Combination of Protein and Viral Vaccines Induces Potent Cellular and Humoral Immune Responses and Enhanced Protection from Murine Malaria Challenge▿

    OpenAIRE

    Hutchings, Claire L.; Birkett, Ashley J.; Moore, Anne C.; Hill, Adrian V. S.

    2007-01-01

    The search for an efficacious vaccine against malaria is ongoing, and it is now widely believed that to confer protection a vaccine must induce very strong cellular and humoral immunity concurrently. We studied the immune response in mice immunized with the recombinant viral vaccines fowlpox strain FP9 and modified virus Ankara (MVA), a protein vaccine (CV-1866), or a combination of the two; all vaccines express parts of the same preerythrocytic malaria antigen, the Plasmodium berghei circums...

  3. Pilot Study on the Use of DNA Priming Immunization to Enhance Y. pestis LcrV-Specific B Cell Responses Elicited by a Recombinant LcrV Protein Vaccine

    Directory of Open Access Journals (Sweden)

    Wei Li

    2013-12-01

    Full Text Available Recent studies indicate that DNA immunization is powerful in eliciting antigen-specific antibody responses in both animal and human studies. However, there is limited information on the mechanism of this effect. In particular, it is not known whether DNA immunization can also enhance the development of antigen-specific B cell development. In this report, a pilot study was conducted using plague LcrV immunogen as a model system to determine whether DNA immunization is able to enhance LcrV-specific B cell development in mice. Plague is an acute and often fatal infectious disease caused by Yersinia pestis (Y. pestis. Humoral immune responses provide critical protective immunity against plague. Previously, we demonstrated that a DNA vaccine expressing LcrV antigen can protect mice from lethal mucosal challenge. In the current study, we further evaluated whether the use of a DNA priming immunization is able to enhance the immunogenicity of a recombinant LcrV protein vaccine, and in particular, the development of LcrV-specific B cells. Our data indicate that DNA immunization was able to elicit high-level LcrV antibody responses when used alone or as part of a prime-boost immunization approach. Most significantly, DNA immunization was also able to increase the levels of LcrV-specific B cell development. The finding that DNA immunization can enhance antigen-specific B cell responses is highly significant and will help guide similar studies in other model antigen systems.

  4. Combination of protein and viral vaccines induces potent cellular and humoral immune responses and enhanced protection from murine malaria challenge.

    Science.gov (United States)

    Hutchings, Claire L; Birkett, Ashley J; Moore, Anne C; Hill, Adrian V S

    2007-12-01

    The search for an efficacious vaccine against malaria is ongoing, and it is now widely believed that to confer protection a vaccine must induce very strong cellular and humoral immunity concurrently. We studied the immune response in mice immunized with the recombinant viral vaccines fowlpox strain FP9 and modified virus Ankara (MVA), a protein vaccine (CV-1866), or a combination of the two; all vaccines express parts of the same preerythrocytic malaria antigen, the Plasmodium berghei circumsporozoite protein (CSP). Mice were then challenged with P. berghei sporozoites to determine the protective efficacies of different vaccine regimens. Two immunizations with the protein vaccine CV-1866, based on the hepatitis B core antigen particle, induced strong humoral immunity to the repeat region of CSP that was weakly protective against sporozoite challenge. Prime-boost with the viral vector vaccines, FP9 followed by MVA, induced strong T-cell immunity to the CD8+ epitope Pb9 and partially protected animals from challenge. Physically mixing CV-1866 with FP9 or MVA and then immunizing with the resultant combinations in a prime-boost regimen induced both cellular and humoral immunity and afforded substantially higher levels of protection (combination, 90%) than either vaccine alone (CV-1866, 12%; FP9/MVA, 37%). For diseases such as malaria in which different potent immune responses are required to protect against different stages, using combinations of partially effective vaccines may offer a more rapid route to achieving deployable levels of efficacy than individual vaccine strategies.

  5. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack

    Directory of Open Access Journals (Sweden)

    Ercan Cacan

    2015-12-01

    Full Text Available Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.

  6. Immunization and chemical conjugation of Bm95 obtained from Pichia pastoris enhances the immune response against vaccinal protein and Neisseria meningitidis capsular polysaccharide

    Directory of Open Access Journals (Sweden)

    Rodriguez-Valle M

    2014-03-01

    Full Text Available Manuel Rodriguez-Valle,1 Leonardo Canan-Hadden,2 Olivia Niebla2 1Animal Biotechnology Division, 2Analytical Division, Centre for Genetic Engineering and Biotechnology, Havana, Cuba Abstract: The ectoparasite Rhipicephalus (Boophilus microplus causes severe economic losses to the cattle industry in tropical and subtropical regions, and transmits endoparasites, such as Babesia bovis. The glycoprotein Bm95 is homologous to Bm86, a surface membrane protein of gut epithelial cells in R. microplus, and has been shown to efficiently control this ectoparasite in regions of the Americas. The immunostimulant properties of Bm86 have already been demonstrated after its coinjection with hepatitis B surface antigen (HBsAg and the infectious bovine rhinotracheitis virus. This study evaluated the carrier and immunostimulant properties of Bm95 using low immunogenic Neisseria meningitidis capsular C polysaccharide (Men CpS and HBsAg. We produced two polysaccharide-Bm95 conjugates by carbodiimide (MenCpSBm-c and reductive amination (MenCpSBm-ra methods. These conjugates were characterized and evaluated in mice. Antibody titers against Men CpS were significantly higher in mice immunized with MenCpSBm-ra (2,350±250, P<0.01 than in those immunized with MenCpSBm-c (250±75 or Men CpS (570±104. The study data indicate effective immunological memory after booster inoculation in mice immunized with MenCpSBm-ra. Additionally, significant humoral immunity against HBsAg was documented in mice coimmunized via the intranasal route with recombinant Bm95 (11,400±345 and HBsAg (128,000±250 compared with mice immunized only with HBsAg (400±40 or Bm95 (5,461±150, P<0.01. In conclusion, the immunostimulatory properties of recombinant Bm95 make it a useful element for developing safer conjugated vaccines against bacterial pathogens and for evaluation against ticks and tick-borne diseases in the context of a polyvalent veterinary vaccine. Keywords: glycoconjugate, Bm86

  7. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2013-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)) and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12 and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing anti-tumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  8. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Yang, Xiao Yi; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R; Clay, Timothy M; Smith, Jonathan; Kim Lyerly, H

    2012-11-01

    We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.

  9. AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates.

    Science.gov (United States)

    Jeyanathan, Mangalakumari; Shao, Zhongqi; Yu, Xuefeng; Harkness, Robin; Jiang, Rong; Li, Junqiang; Xing, Zhou; Zhu, Tao

    2015-01-01

    Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen-specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.

  10. Addition of C3d-P28 adjuvant to a rabies DNA vaccine encoding the G5 linear epitope enhances the humoral immune response and confers protection.

    Science.gov (United States)

    Galvez-Romero, Guillermo; Salas-Rojas, Mónica; Pompa-Mera, Ericka N; Chávez-Rueda, Karina; Aguilar-Setién, Álvaro

    2017-11-27

    Rabies DNA vaccines based on full-length glycoprotein (G) induce virus neutralizing antibody (VNA) responses and protect against the virus challenge. Although conformational epitopes of G are the main target of VNAs, some studies have shown that a polypeptide linear epitope G5 is also able to induce VNAs. However, a G5 DNA vaccine has not been explored. While multiple doses of DNA vaccines are required in order to confer a protective immune response, this could be overcome by the inclusion of C3d-P28, a molecular adjuvant is know to improve the antibody response in several anti-viral vaccine models. To induce and enhance the immune response against rabies in mice, we evaluated two DNA vaccines based on the linear epitope G5 of Rabies Virus (RABV) glycoprotein (pVaxG5 vaccine) and another vaccine consisting of G5 fused to the molecular adjuvant C3d-P28 (pVaxF1 vaccine). VNA responses were measured in mice immunized with both vaccines. The VNA levels from the group immunized with pVaxG5 decreased gradually, while those from the group vaccinated with pVaxF1 remained high throughout the experimental study. After challenge with 22 LD50 of the Challenge Virus Strain (CVS), the survival rate of mice immunized with pVaxG5 and pVaxF1 was increased by 27% and 50% respectively, in comparison to the PBS group. Furthermore, the in vitro proliferation of anti-rabies specific spleen CD4+ and CD8+ T cells from mice immunized with pVaxF1 was observed. Collectively, these results suggest that the linear G5 epitope is a potential candidate vaccine. Furthermore, the addition of a C3d-P28 adjuvant contributed to enhanced protection, the sustained production of VNAs, and a specific T-cell proliferative response. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy.

    Science.gov (United States)

    Dammeijer, Floris; Lievense, Lysanne A; Kaijen-Lambers, Margaretha E; van Nimwegen, Menno; Bezemer, Koen; Hegmans, Joost P; van Hall, Thorbald; Hendriks, Rudi W; Aerts, Joachim G

    2017-07-01

    New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8(+) T-cell numbers and functionality. Total as well as tumor antigen-specific CD8(+) T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. Cancer Immunol Res; 5(7); 535-46. ©2017 AACR. ©2017 American Association for Cancer Research.

  12. Fucoidan can function as an adjuvant in vivo to enhance dendritic cell maturation and function and promote antigen-specific T cell immune responses.

    Directory of Open Access Journals (Sweden)

    Jun-O Jin

    Full Text Available Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-α in spleen cDCs. Fucoidan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA antigen, fucoidan promoted OVA-specific antibody production and primed IFN-γ production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development.

  13. Pleurocidin Peptide Enhances Grouper Anti-Vibrio harveyi Immunity Elicited by Poly(lactide-co-glycolide)-Encapsulated Recombinant Glyceraldehyde-3-phosphate Dehydrogenase.

    Science.gov (United States)

    Chuang, Shu-Chun; Huang, Wan-Ling; Kau, Sau-Wei; Yang, Yun-Pei; Yang, Chung-Da

    2014-05-14

    Outer membrane proteins, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are considered immunodominant antigens for eliciting protective immunity against Vibrio harveyi, the main etiological agent of vibriosis in fish. Cationic antimicrobial peptides (AMPs), such as pleurocidin (PLE), play important roles in activating and recruiting immune cells, thereby contributing to subsequent innate and adaptive immune responses. In the present study, we aimed to use PLE peptide as a potent adjuvant to improve the immunogenicity of V. harveyi recombinant GAPDH (rGAPDH). In order to prepare a controlled-release vaccine, PLE peptide and rGAPDH protein were simultaneously encapsulated into polymeric microparticles made from the biodegradable poly(lactide-co-glycolide) (PLG) polymer. The resulting PLG-encapsulated PLE plus rGAPDH (PLG-PLE/rGAPDH) microparticles, 3.21-6.27 μm in diameter, showed 72%-83% entrapment efficiency and durably released both PLE and rGAPDH for a long 30-day period. Following peritoneal immunization in grouper (Epinephelus coioides), PLG-PLE/rGAPDH microparticles resulted in significantly higher (p PLE/rGAPDH microparticles conferred a high survival rate (85%), which was significantly higher (p PLE peptide exhibits an efficacious adjuvant effect to elicit not only improved immunity, but also enhanced protection against V. harveyi in grouper induced by rGAPDH protein encapsulated in PLG microparticles.

  14. Enhanced immunogenicity of an anti-caries vaccine encoding a cell-surface protein antigen of Streptococcus mutans by intranasal DNA prime-protein boost immunization.

    Science.gov (United States)

    Li, Yuhong; Jin, Jie; Yang, Yaping; Bian, Zhuan; Chen, Zhi; Fan, Mingwen

    2009-11-01

    The present study aimed to enhance the specific anti-caries immunity induced by DNA prime-protein boost strategy for an A-P fragment of a cell-surface protein antigen of Streptococcus mutans (PAc). BALB/c mice were immunized with DNA prime-protein boost, DNA-DNA or protein-protein regimens by the intranasal route, using combinations of plasmid vector (pCIA-P) that express PAc protein and a pure secretec recombinant PAc protein (rPAc). Then, a gnotobiotic mouse model was constructed 2 weeks after the last immunization, and specific immune responses in vivo and their protection against dental caries were observed. The present study revealed stronger antibody responses in the DNA prime-protein boost group compared to those elicited by either DNA-DNA vaccination or protein-protein vaccination. In particular, PAc-specific antibody concentrations were improved significantly after boosting the pCIA-P DNA-primed mice with rPAc. Moreover, protection against S. mutans challenge was obtained in the mice treated with the DNA prime-protein boost vaccination, as demonstrated by a significant reduction in S. mutans colonization compared to control mice and animals immunized with the DNA-DNA vaccination or protein-protein vaccination. The results obtained in the present study suggest that the intranasal DNA prime-protein boost vaccination regimen is a novel strategy for the practical application of DNA vaccine against dental caries.

  15. Vitamin A supplementation in early life enhances the intestinal immune response of rats with gestational vitamin A deficiency by increasing the number of immune cells.

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    Xia Liu

    Full Text Available Vitamin A is a critical micronutrient for regulating immunity in many organisms. Our previous study demonstrated that gestational or early-life vitamin A deficiency decreases the number of immune cells in offspring. The present study aims to test whether vitamin A supplementation can restore lymphocyte pools in vitamin A-deficient rats and thereby improve the function of their intestinal mucosa; furthermore, the study aimed to identify the best time frame for vitamin A supplementation. Vitamin A-deficient pregnant rats or their offspring were administered a low-dose of vitamin A daily for 7 days starting on gestational day 14 or postnatal day 1, day 14 or day 28. Serum retinol concentrations increased significantly in all four groups that received vitamin A supplementation, as determined by high-performance liquid chromatography. The intestinal levels of secretory immunoglobulin A and polymeric immunoglobulin receptor increased significantly with lipopolysaccharide challenge in the rats that received vitamin A supplementation starting on postnatal day 1. The rats in this group had higher numbers of CD8+ intestinal intraepithelial lymphocytes, CD11C+ dendritic cells in the Peyer's patches and CD4+CD25+ T cells in the spleen compared with the vitamin A-deficient rats; flow cytometric analysis also demonstrated that vitamin A supplementation decreased the number of B cells in the mesenteric lymph nodes. Additionally, vitamin A supplementation during late gestation increased the numbers of CD8+ intestinal intraepithelial lymphocytes and decreased the numbers of B lymphocytes in the mesenteric lymph nodes. However, no significant differences in lymphocyte levels were found between the rats in the other two vitamin A supplement groups and the vitamin A-deficient group. In conclusion, the best recovery of a subset of lymphocytes in the offspring of gestational vitamin A-deficient rats and the greatest improvement in the intestinal mucosal immune

  16. Nutritional formula enhanced immune function and reduced days of symptoms of upper respiratory tract infection in seniors.

    Science.gov (United States)

    Langkamp-Henken, Bobbi; Bender, Bradley S; Gardner, Elizabeth M; Herrlinger-Garcia, Kelli A; Kelley, Michael J; Murasko, Donna M; Schaller, Joseph P; Stechmiller, Joyce K; Thomas, Debra J; Wood, Steven M

    2004-01-01

    To assess whether an experimental nutritional formula, given as a supplement, would reduce days of symptoms of upper respiratory tract infection (URTI) and affect antibody and lymphocyte proliferative responses to influenza vaccine. A prospective, randomized, double-blind, controlled trial was conducted between October 1999 and April 2000. Assisted- and independent-living facilities in North Central Florida. Sixty-six individuals, aged 65 and older. Subjects received 8 oz/d of an experimental formula containing antioxidants, zinc, selenium, fermentable oligosaccharides, and structured triacylglycerol or an isoenergetic, isonitrogenous control formula for 183 days. Subjects recorded daily symptoms of URTI. Antibody titers and lymphocyte proliferation to three influenza vaccine components were measured on Days 57 and 183. Eighteen subjects in the control group and 16 subjects in the experimental group consumed an average of 7 ounces of formula daily and completed the 183-day study. Median days of symptoms of URTI were 3 (range 0-69, total days=156) and 0 (range 0-49, total days=78) for the control and experimental groups, respectively (P=.049). On Day 57, seven of 17 (41%) subjects in the control group and 13 of 15 (87%) subjects in the experimental group achieved a fourfold or greater increase in serum antibody titer to A/Beijing (P=.012). Lymphocyte proliferation to influenza vaccine components was greater in the experimental (median=1,365 cpm, range=0-14,955 cpm) than the control group (median=136 cpm, range=0-4,270 cpm) (P=.013). Subjects consuming an experimental nutritional formula experienced enhanced immune function and fewer days of URTI symptoms.

  17. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    OpenAIRE

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2012-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associat...

  18. Induction of antigen-positive cell death by the expression of perforin, but not DTa, from a DNA vaccine enhances the immune response.

    Science.gov (United States)

    Gargett, Tessa; Grubor-Bauk, Branka; Garrod, Tamsin J; Yu, Wenbo; Miller, Darren; Major, Lee; Wesselingh, Steve; Suhrbier, Andreas; Gowans, Eric J

    2014-04-01

    The failure of traditional protein-based vaccines to prevent infection by viruses such as HIV or hepatitis C highlights the need for novel vaccine strategies. DNA vaccines have shown promise in small animal models, and are effective at generating anti-viral T cell-mediated immune responses; however, they have proved to be poorly immunogenic in clinical trials. We propose that the induction of necrosis will enhance the immune response to vaccine antigens encoded by DNA vaccines, as necrotic cells are known to release a range of intracellular factors that lead to dendritic cell (DC) activation and enhanced cross-presentation of antigen. Here we provide evidence that induction of cell death in DNA vaccine-targeted cells provides an adjuvant effect following intradermal vaccination of mice; however, this enhancement of the immune response is dependent on both the mechanism and timing of cell death after antigen expression. We report that a DNA vaccine encoding the cytolytic protein, perforin, resulted in DC activation, enhanced broad and multifunctional CD8 T-cell responses to the HIV-1 antigen GAG and reduced viral load following challenge with a chimeric virus, EcoHIV, compared with the canonical GAG DNA vaccine. This effect was not observed for a DNA vaccine encoding an apoptosis-inducing toxin, DTa, or when the level of perforin expression was increased to induce cell death sooner after vaccination. Thus, inducing lytic cell death following a threshold level of expression of a viral antigen can improve the immunogenicity of DNA vaccines, whereas apoptotic cell death has an inhibitory effect on the immune response.

  19. The Positive Correlation of the Enhanced Immune Response to PCV2 Subunit Vaccine by Conjugation of Chitosan Oligosaccharide with the Deacetylation Degree

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    Guiqiang Zhang

    2017-07-01

    Full Text Available Chitosan oligosaccharides (COS, the degraded products of chitosan, have been demonstrated to have versatile biological functions. In primary studies, it has displayed significant adjuvant effects when mixed with other vaccines. In this study, chitosan oligosaccharides with different deacetylation degrees were prepared and conjugated to porcine circovirus type 2 (PCV2 subunit vaccine to enhance its immunogenicity. The vaccine conjugates were designed by the covalent linkage of COSs to PCV2 molecules and administered to BALB/c mice three times at two-week intervals. The results indicate that, as compared to the PCV2 group, COS–PCV2 conjugates remarkably enhanced both humoral and cellular immunity against PCV2 by promoting lymphocyte proliferation and initiating a mixed T-helper 1 (Th1/T-helper 2 (Th2 response, including raised levels of PCV2-specific antibodies and an increased production of inflammatory cytokines. Noticeably, with the increasing deacetylation degree, the stronger immune responses to PCV2 were observed in the groups with COS-PCV2 vaccination. In comparison with NACOS (chitin oligosaccharides–PCV2 and LCOS (chitosan oligosaccharides with low deacetylation degree–PCV2, HCOS (chitosan oligosaccharides with high deacetylation degree–PCV2 showed the highest adjuvant effect, even comparable to that of PCV2/ISA206 (a commercialized adjuvant group. In summary, COS conjugation might be a viable strategy to enhance the immune response to PCV2 subunit vaccine, and the adjuvant effect was positively correlated with the deacetylation degree of COS.

  20. An enhanced immune response of Mclk1⁺/⁻ mutant mice is associated with partial protection from fibrosis, cancer and the development of biomarkers of aging.

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    Dantong Wang

    Full Text Available The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1⁺/⁻ mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection by Salmonella serovars and found that Mclk1⁺/⁻ mutants mount a stronger immune response, control bacterial proliferation better, and are resistant to cell and tissue damage resulting from the response, including fibrosis and types of oxidative damage that are considered to be biomarkers of aging. Moreover, these same types of tissue damage were found to be low in untreated 23 months-old mutants. We also examined the initiation of tumour growth after transplantation of mouse LLC1 carcinoma cells into Mclk1⁺/⁻ mutants, as well as during spontaneous tumorigenesis in Mclk1⁺/⁻Trp53⁺/⁻ double mutants. Tumour latency was increased by the Mclk1⁺/⁻ genotype in both models. Furthermore, we used the transplantation model to show that splenic CD8⁺ T lymphocytes from Mclk1⁺/⁻ graft recipients show enhanced cytotoxicity against LLC1 cells in vitro. Mclk1⁺/⁻ mutants thus display an association of an enhanced immune response with partial protection from age-dependent processes and from pathologies similar to those that are found with increased frequency during the aging process. This suggests that the immune phenotype of these mutants might contribute to their longevity. We discuss how these findings suggest a broader view of how the immune response might impact the aging process.

  1. Epimedium polysaccharide and propolis flavone can synergistically stimulate lymphocyte proliferation in vitro and enhance the immune responses to ND vaccine in chickens.

    Science.gov (United States)

    Fan, Yunpeng; Hu, Yuanliang; Wang, Deyun; Guo, Zhenhuan; Zhao, Xiaona; Guo, Liwei; Zhao, Biao; Zhang, Jing; Wang, Yuanlei; Nguyen, The Luong

    2010-08-01

    Four prescriptions, epimedium flavone plus propolis flavone (EF-PF), epimedium flavone plus propolis extracts (EF-PE), epimedium polysaccharide plus propolis flavone (EP-PF) and epimedium polysaccharide plus propolis extracts (EP-PE), were prepared and their immune-enhancing effects were compared. In test in vitro, the effects of them on chicken peripheral lymphocyte proliferation were determined by MTT method. The results showed that EP-PF group presented the highest stimulating index at most concentrations. In immune test, 300 14-day-old chickens were randomly divided into six groups and vaccinated with ND vaccine except for blank control (BC) group, re-challenged at 28 days of age. At the same time of the first vaccination, the chickens in four experimental groups were injected, respectively, with four prescriptions. The changes of the lymphocyte proliferation and antibody titer were determined. On day 28 after the first vaccination, the chickens except for BC group were challenged with NDV, the immune protective effect was observed. The results displayed that in EP-PF group, the antibody titers, lymphocyte proliferation and protective rate were the highest, the morbidity and mortality were the lowest. In dose test, 14-day-old chickens were randomly divided into five groups. The treatment and determinations were the same as the immune test except that the chickens in experimental groups were injected, respectively, with high, medium and low doses of EP-PF. The results revealed that in medium dose group, the antibody titers, lymphocyte proliferation and protective rate were the highest, the morbidity and mortality were the lowest. These results indicated that EP and PF possessed synergistically immune enhancement, EP-PF had the best efficacy, especially at medium dose, and would be expected to exploit into a new-type immunopotentiator. Copyright 2010 Elsevier B.V. All rights reserved.

  2. Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy.

    Science.gov (United States)

    Jackson, Ronald J; Worley, Matthew; Trivedi, Shubhanshi; Ranasinghe, Charani

    2014-09-29

    We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B

  3. Pleurocidin Peptide Enhances Grouper Anti-Vibrio harveyi Immunity Elicited by Poly(lactide-co-glycolide-Encapsulated Recombinant Glyceraldehyde-3-phosphate Dehydrogenase

    Directory of Open Access Journals (Sweden)

    Shu-Chun Chuang

    2014-05-01

    Full Text Available Outer membrane proteins, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH, are considered immunodominant antigens for eliciting protective immunity against Vibrio harveyi, the main etiological agent of vibriosis in fish. Cationic antimicrobial peptides (AMPs, such as pleurocidin (PLE, play important roles in activating and recruiting immune cells, thereby contributing to subsequent innate and adaptive immune responses. In the present study, we aimed to use PLE peptide as a potent adjuvant to improve the immunogenicity of V. harveyi recombinant GAPDH (rGAPDH. In order to prepare a controlled-release vaccine, PLE peptide and rGAPDH protein were simultaneously encapsulated into polymeric microparticles made from the biodegradable poly(lactide-co-glycolide (PLG polymer. The resulting PLG-encapsulated PLE plus rGAPDH (PLG-PLE/rGAPDH microparticles, 3.21–6.27 μm in diameter, showed 72%–83% entrapment efficiency and durably released both PLE and rGAPDH for a long 30-day period. Following peritoneal immunization in grouper (Epinephelus coioides, PLG-PLE/rGAPDH microparticles resulted in significantly higher (p < 0.05, nested design long-lasting GAPDH-specific immunity (serum titers and lymphocyte proliferation than PLG-encapsulated rGAPDH (PLG-rGAPDH microparticles. After an experimental challenge of V. harveyi, PLG-PLE/rGAPDH microparticles conferred a high survival rate (85%, which was significantly higher (p < 0.05, chi-square test than that induced by PLG-rGAPDH microparticles (67%. In conclusion, PLE peptide exhibits an efficacious adjuvant effect to elicit not only improved immunity, but also enhanced protection against V. harveyi in grouper induced by rGAPDH protein encapsulated in PLG microparticles.

  4. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Science.gov (United States)

    Nice, Timothy J; Osborne, Lisa C; Tomov, Vesselin T; Artis, David; Wherry, E John; Virgin, Herbert W

    2016-06-01

    In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  5. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Timothy J Nice

    2016-06-01

    Full Text Available In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV replicates in dendritic cells (DCs and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  6. Mixture of polysaccharide and nucleic acid extracted from Bacillus Calmette-Guerin (BCG) enhances immune response of infectious bursal disease virus vaccine in chickens.

    Science.gov (United States)

    Wang, X B; Liu, Z J; Lv, Y J; Long, Y; Bao, E D

    2016-05-12

    In this study, the immune response induced by a mixture of polysaccharide and nucleic acid extracted from Bacillus Calmette-Guerin (BCG) was evaluated in chickens inoculated with infectious bursal disease virus (IBDV) vaccine. After the mixture was injected intramuscularly at a dose of 0.075, 0.15 or 0.3 mg·kg(-1)·day(-1) for 3 days, the 14-day-old chickens were inoculated with the attenuated IBDV vaccine via intranasal and ocular routes. The relative weight of bursa of Fabricius (BF) and thymus, the serum IBD antibody titer, the CD4+/CD8+ ratio, and the concentrations of IFN-γ, IL-2 and IL-6 in peripheral blood were investigated on days 5, 15 and 25. The IBD antibody titer in BCG-treated groups was higher than in the negative control and only IBD-vaccinated chickens, indicating that the mixture of BCG can significantly enhance chicken humoral response. CD4+/CD8+ and the secretions of IFN-γ, IL-2 and IL-6 were also clearly increased compared with that in the negative control and IBD-vaccinated chickens, indicating that the mixture can also enhance the cell-mediated immune response. The results also showed that the relative weights of BF and thymus increased after chickens were inoculated with BCG, indicating that the BCG mixture can clearly enhance the immunity of IBD-vaccine and can be expected to be viewed as a candidate for a new type of immune adjuvant.

  7. Prophylactic Sublingual Immunization with Mycobacterium tuberculosis Subunit Vaccine Incorporating the Natural Killer T Cell Agonist Alpha-Galactosylceramide Enhances Protective Immunity to Limit Pulmonary and Extra-Pulmonary Bacterial Burden in Mice

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    Arshad Khan

    2017-12-01

    Full Text Available Infection by Mycobacterium tuberculosis (Mtb remains a major global concern and the available Bacillus Calmette-Guerin (BCG vaccine is poorly efficacious in adults. Therefore, alternative vaccines and delivery strategies focusing on Mtb antigens and appropriate immune stimulating adjuvants are needed to induce protective immunity targeted to the lungs, the primary sites of infections and pathology. We present here evidence in support of mucosal vaccination by the sublingual route in mice using the subunit Mtb antigens Ag85B and ESAT-6 adjuvanted with the glycolipid alpha-galactosylceramide (α-GalCer, a potent natural killer T (NKT cell agonist. Vaccinated animals exhibited strong antigen-specific CD4 and CD8 T cells responses in the spleen, cervical lymph nodes and lungs. In general, inclusion of the α-GalCer adjuvant significantly enhanced these responses that persisted over 50 days. Furthermore, aerosolized Mtb infection of vaccinated mice resulted in a significant reduction of bacterial load of the lungs and spleens as compared to levels seen in naïve controls or those vaccinated with subunit proteins, adjuvant , or BCG alone. The protection induced by the Mtb antigens and-GalCer vaccine through sublingual route correlated with a TH1-type immunity mediated by antigen-specific IFN-γ and IL-2 producing T cells.

  8. Photodynamic therapy-mediated cancer vaccination enhances stem-like phenotype and immune escape, which can be blocked by thrombospondin-1 signaling through CD47 receptor protein.

    Science.gov (United States)

    Zheng, Yuanhong; Zou, Fangyuan; Wang, Jingjing; Yin, Guifang; Le, Vanminh; Fei, Zhewei; Liu, Jianwen

    2015-04-03

    Like most of the strategies for cancer immunotherapy, photodynamic therapy-mediated vaccination has shown poor clinical outcomes in application. The aim of this study is to offer a glimpse at the mechanisms that are responsible for the failure based on cancer immuno-editing theory and to search for a positive solution. In this study we found that tumor cells were able to adapt themselves to the immune pressure exerted by vaccination. The survived tumor cells exhibited enhanced tumorigenic and stem-like phenotypes as well as undermined immunogenicity. Viewed as a whole, immune-selected tumor cells showed more malignant characteristics and the ability of immune escape, which might contribute to the eventual relapse. Thrombospondin-1 signaling via CD47 helped prevent tumor cells from becoming stem-like and rendered them vulnerable to immune attack. These findings prove that the TSP-1/CD47/SIRP-α signal axis is important to the evolution of tumor cells in the microenvironment of immunotherapy and identify thrombospondin-1 as a key signal with therapeutic benefits in overcoming long term relapse, providing new evidence for the clinical promise of cancer vaccination. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Bifidobacterium bifidum OLB6378 Simultaneously Enhances Systemic and Mucosal Humoral Immunity in Low Birth Weight Infants: A Non-Randomized Study

    Directory of Open Access Journals (Sweden)

    Katsunori Tanaka

    2017-02-01

    Full Text Available Probiotic supplementation has been part of the discussion on methods to enhance humoral immunity. Administration of Bifidobacterium bifidum OLB6378 (OLB6378 reduced the incidence of late-onset sepsis in infants. In this non-randomized study, we aimed to determine the effect of administration of live OLB6378 on infants’ humoral immunity. Secondly, we tried to elucidate whether similar effects would be observed with administration of non-live OLB6378. Low birth weight (LBW infants weighing 1500–2500 g were divided into three groups: Group N (no intervention, Group L (administered live OLB6378 concentrate, and Group H (administered non-live OLB6378 concentrate. The interventions were started within 48 h after birth and continued until six months of age. Serum immunoglobulin G (IgG levels (IgG at one month/IgG at birth were significantly higher in Group L than in Group N (p < 0.01. Group H exhibited significantly higher serum IgG levels (p < 0.01 at one month of age and significantly higher intestinal secretory immunoglobulin A (SIgA levels (p < 0.05 at one and two months of age than Group N. No difference was observed in the mortality or morbidity between groups. Thus, OLB6378 administration in LBW infants enhanced humoral immunity, and non-live OLB6378, which is more useful as a food ingredient, showed a more marked effect than the viable bacteria.

  10. Additive effects of enhanced ambient ultraviolet B radiation and increased temperature on immune function, growth and physiological condition of juvenile (parr) Atlantic Salmon, Salmo salar.

    Science.gov (United States)

    Jokinen, Ilmari E; Salo, Harri M; Markkula, Eveliina; Rikalainen, Kaisa; Arts, Michael T; Browman, Howard I

    2011-01-01

    Climate change models predict increased ultraviolet B (UVB) radiation levels due to stratospheric ozone depletion and global warming. In order to study the impact of these two environmental stressors acting simultaneously on the physiology of fish, Atlantic salmon parr were exposed, for 8 weeks in outdoor tanks, to different combinations of UVB radiation (depleted and enhanced) and temperature (standard rearing temperature of 14 °C or 19 °C). The immune function (plasma IgM, lysozyme activity and complement bacteriolytic activity), growth (body weight) and physiological condition (haematocrit and plasma protein concentration) of the fish were determined. Increased UVB level, regardless of water temperature, had a negative effect on immune function parameters, growth and physiological condition. Higher temperature increased plasma IgM concentration but had a negative effect on complement bacteriolytic activity under both spectral treatments. Increased temperature, irrespective of UVB level, increased fish growth but negatively affected haematocrit and plasma protein. Exposing the fish to enhanced UVB at elevated temperature increased plasma IgM concentration and slightly improved growth. However, complement activity and physiological condition parameters decreased more than when the fish were exposed to each stressor separately. The changes were mainly additive; no interactive or synergistic effects were observed. The negative impact of multiple stressors on immune function, together with predicted increases in pathogen load in warmer waters resulting from global climate change, suggest an increased risk to diseases in fishes. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Co-transfection of dendritic cells with AFP and IL-2 genes enhances the induction of tumor antigen-specific antitumor immunity.

    Science.gov (United States)

    Yang, Jing-Yue; Li, Xiao; Gao, Li; Teng, Zeng-Hui; Liu, Wen-Chao

    2012-10-01

    Dendritic cells (DCs) are highly efficient, specialized antigen-presenting cells and DCs transfected with tumor-related antigens are regarded as promising vaccines in cancer immunotherapy. The aim of the present study was to investigate whether DCs co-transfected with the α-fetoprotein (AFP) and human interleukin-2 (IL-2) genes were able to induce stronger therapeutic antitumor immunity in transfected DCs. In this study, DCs from hepatocellular carcinoma (HCC) patients were co-transfected with the IL-2 gene and/or the AFP gene. The reverse transcription-PCR (RT-PCR) data revealed that the DCs transfected with the adenovirus AdAFP/IL-2 expressed AFP and IL-2. The DCs co-transfected with IL-2 and AFP (AFP/IL-2-DCs) enhanced the cytotoxicities of cytotoxic T lymphocytes (CTLs) and increased the production of IL-2 and interferon-γ significantly compared with their AFP-DC, green fluorescent protein (GFP)-DC, DC or phosphate-buffered saline (PBS) counterparts. In vivo data suggested that immunization with AFP-DCs enhances antigen-specific antitumor efficacy more potently than immunization with IL-2-DCs or AFP-DCs. These findings provide a potential strategy to improve the efficacy of DC-based tumor vaccines.

  12. Antigen transfer from exosomes to dendritic cells as an explanation for the immune enhancement seen by IgE immune complexes.

    Directory of Open Access Journals (Sweden)

    Rebecca K Martin

    Full Text Available IgE antigen complexes induce increased specific T cell proliferation and increased specific IgG production. Immediately after immunization, CD23(+ B cells capture IgE antigen complexes, transport them to the spleen where, via unknown mechanisms, dendritic cells capture the antigen and present it to T cells. CD23, the low affinity IgE receptor, binds IgE antigen complexes and internalizes them. In this study, we show that these complexes are processed onto B-cell derived exosomes (bexosomes in a CD23 dependent manner. The bexosomes carry CD23, IgE and MHC II and stimulate antigen specific T-cell proliferation in vitro. When IgE antigen complex stimulated bexosomes are incubated with dendritic cells, dendritic cells induce specific T-cell proliferation in vivo, similar to IgE antigen complexes. This suggests that bexosomes can provide the essential transfer mechanism for IgE antigen complexes from B cells to dendritic cells.

  13. Abnormal CD161+ immune cells and retinoic acid receptor-related orphan receptor γt-mediate enhanced IL-17F expression in the setting of genetic hypertension.

    Science.gov (United States)

    Singh, Madhu V; Cicha, Michael Z; Kumar, Santosh; Meyerholz, David K; Irani, Kaikobad; Chapleau, Mark W; Abboud, François M

    2017-09-01

    Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor γt (RORγt) and a nicotinic proinflammatory innate immune response. We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs. SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38 weeks. The SHR splenocytes constitutively expressed more RORγt than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of RORγt by digoxin decreased systolic blood pressure in SHRs. SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. Mucosal immunization with the Moraxella catarrhalis porin m35 induces enhanced bacterial clearance from the lung: a possible role for opsonophagocytosis

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    Donna eEaston

    2011-05-01

    Full Text Available Moraxella catarrhalis is a significant cause of respiratory tract infection against which a vaccine is sought. Several outer membrane proteins are currently under investigation as potential vaccine antigens, including the porin M35. We have previously shown that the third external loop of M35 was immunodominant over the remainder of the protein for antibody produced in mice against the refolded recombinant protein. However, as this loop is predicted to fold inside the porin channel we also predicted that it would not be accessible to these antibodies when M35 is expressed on the surface of the bacteria in its native conformation. This study investigated the functional activity of antibodies against M35 and those specific for the loop 3 region of M35 in vitro and in vivo. Antisera from mice immunized with M35 or the loop 3-deletion, M35loop3–, recombinant proteins were not bactericidal but did have enhanced opsonic activity, whereas antibodies raised against the loop 3 peptide were not opsonising indicating that the immunodominant loop 3 of M35 was not accessible to antibody as we had previously predicted. Mucosal immunization with M35, M35 that had an antigenically altered loop 3 (M35(ID78 and M35loop3– enhanced the clearance of M. catarrhalis from the lungs of mice challenged with live M. catarrhalis. The in vivo clearance of bacteria in the mice with the M35-derived protein constructs correlated significantly (p<0.001 with the opsonic activity assessed an in vitro opsonophagocytosis assay. This study has demonstrated that the immunodominat B-cell epitope to loop 3 of the M. catarrhalis outer membrane protein M35 is not associated with immune protection and that M35-specific antibodies are not bactericidal but are opsonising. The opsonising activity correlated with in vivo clearance of the bacteria suggesting that opsonising antibody may be a good correlate of immune protection.

  15. Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity

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    Devon J. Shedlock

    2014-03-01

    Full Text Available DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent or non-pathogen (i.e., cancer antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a RelA, a subunit of the NF-κB transcription complex or (b T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP, a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

  16. Chicken IgY Fc linked to Bordetella avium ompA and Taishan Pinus massoniana pollen polysaccharide adjuvant enhances macrophage function and specific immune responses

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    Zhu Ruiliang

    2016-11-01

    Full Text Available Fc-fusion technologies, in which immunoglobulin Fc is genetically fused to an antigenic protein, have been developed to confer antibody-like properties to proteins and peptides. Mammalian IgG Fc fusion exhibits improved antigen-induced immune responses by providing aggregates with high avidity for the IgG Fc receptor and salvaging the antigenic portion from endosomal degradation. However, whether the linked chicken IgY Fc fragment shares similar characteristics to mammalian IgG Fc remains unclear. In this study, we linked the chicken IgY Fc gene to the outer membrane protein A (ompA of Borderella avium through overlapping PCR. The fusion gene was cloned into the pPIC9 plasmid to construct the recombinant Pichia pastoris transformant expressing the ompA–Fc fusion protein. The effects of the linked Fc on macrophage vitality, activity, efficiency of antigen processing, and immune responses induced by the fused ompA were investigated. Furthermore, the effect of Taishan Pinus massoniana pollen polysaccharide (TPPPS, an immunomodulator, on chicken macrophage activation was evaluated. TPPPS was also used as an adjuvant to investigate its immunomodulatory effect on immunoresponses induced by the fused ompA–Fc in chickens. The pinocytosis, phagocytosis, secretion of nitric oxide and TNF-α, and MHC-II molecular expression of the macrophages treated with the fused ompA–Fc were significantly higher than those of the macrophages treated with ompA alone. The addition of TPPPS to the fused ompA–Fc further enhanced macrophage functions. The fused ompA–Fc elicited higher antigen-specific immune responses and protective efficacy compared with ompA alone. Moreover, the fused ompA–Fc conferred higher serum antibody titers, serum IL-2 and IL-4 concentrations, CD4+ and CD8+ T-lymphocyte counts, lymphocyte transformation rate, and protection rate compared with ompA alone. Notably, the prepared TPPPS adjuvant ompA–Fc vaccines induced high immune

  17. A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

    Science.gov (United States)

    Daftarian, Pirouz M; Stone, Geoffrey W; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna; Alberola, Jordi; Perez, Victor L; Daunert, Sylvia; Ager, Arba L

    2013-12-01

    Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host. We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB. PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice. PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

  18. Multiple vaccinations with UV- attenuated cercariae in pig enhance protective immunity against Schistosoma japonicum infection as compared to single vaccination.

    Science.gov (United States)

    Lin, Dandan; Tian, Fang; Wu, Haiwei; Gao, Yanan; Wu, Jingjiao; Zhang, Donghui; Ji, Minjun; McManus, Donald P; Driguez, Patrick; Wu, Guanling

    2011-06-10

    Schistosomiasis japonica is a major public health problem in the endemic areas of China, the Philippines, and Indonesia. To date, a vaccine has not been developed against this disease but immunization with UV-attenuated cercariae can induce a high level of protective immunity in Landrace/Yorkshire/Duroc crossbred pigs. To compare the efficacy of a single vaccination and multiple vaccinations with UV-attenuated Schistosoma japonicum cercariae, two groups of pigs received either one or three exposures to 10,000 cercariae attenuated with 400 μw UV. Pigs with a single immunization had a 59.33% reduction in adult worm burden, a 89.87% reduction in hepatic eggs and a 86.27% reduction in fecal eggs at eight weeks post-challenge (P vaccinated groups were higher than in the infection-control group. Triple vaccinations resulted in higher levels of antibodies, especially IgG2, compared with a single vaccination and IFN-γ levels increased with repeated immunization with UV-irradiated cercariae. The high levels of protection against S. japonicum infection can be achieved with a UV-attenuated vaccine in pigs, and that three vaccinations were possibly more effective than a single vaccination. Moreover, triple vaccinations evoked a more vigorous IFN-γ response and a stronger antibody-mediated response, especially an increase in the levels of IgG2 antibodies.

  19. Enhancement of immune response induced by DNA vaccine cocktail expressing complete LACK and TSA genes against Leishmania major.

    Science.gov (United States)

    Ghaffarifar, Fatemeh; Jorjani, Ogholniaz; Sharifi, Zohreh; Dalimi, Abdolhossein; Hassan, Zuhair M; Tabatabaie, Fatemeh; Khoshzaban, Fariba; Hezarjaribi, Hajar Ziaei

    2013-04-01

    Leishmaniasis is an important disease in humans. Leishmania homologue of receptor for Activated C Kinase (LACK) and thiol specific antioxidant (TSA) as immuno-dominant antigens of Leishmania major are considered the most promising molecules for a DNA vaccine. We constructed a DNA cocktail, containing plasmids encoding LACK and TSA genes of Leishmania major and evaluated the immune response and survival rate in BALB/c mice. IgG and Interferon gamma values were noticeably increased in the immunized group with DNA cocktail vaccine, which were significantly higher than those in the single-gene vaccinated and control groups (p 0.05). The immunized mice with the cocktail DNA vaccine presented a considerable reduction in diameter of lesion compared to other groups and a significant difference was observed (p < 0.05) in this regard. The survival time of the immunized mice with the cocktail DNA vaccine was significantly higher than that in the other groups (p < 0.05) after their being challenged with Leishmania major. The findings of this study indicated that the cocktail DNA vaccine increased the cellular response and survival rate and induced protection against infection with Leishmania in the mice. © 2012 The Authors © 2012 APMIS.

  20. Immune response deviation and enhanced expression of chemokine receptor CCR4 in TBI patients due to unknown serum factors.

    Science.gov (United States)

    Cadosch, Dieter; Al-Mushaiqri, Mohamed S; Gautschi, Oliver P; Chan, Erwin; Jung, Florian J; Skirving, Allan P; Filgueira, Luis

    2010-06-01

    Severe brain trauma leads to an activation of the immune system. To this date, neither the exact perturbation of the specific immune reaction induced by the traumatic brain injury (TBI), nor the interactions leading to the infiltration of peripheral immune cells into the brain are fully understood. Serum was collected from 17 patients with TBI and a long bone fracture, 24 patients with an isolated long bone fracture and from healthy individuals. The effect of the serum on normal human monocytes and T-lymphocytes was tested in vitro by assessing proliferation and expression of surface markers, chemokine receptors and cytokines. Serum collected from patients with a TBI and a long bone fracture increased the expression of the chemokine receptor CCR4 in monocytes when compared to patients with an isolated long bone fracture. Extending this comparison to T-lymphocytes, the serum from TBI patients induced lower proliferation rates and decreased expression of the pro-inflammatory cytokine TNF-alpha, while simultaneously increasing the secretion of immune-modulatory cytokines (IL-4, IL-10 and TGF-beta) (p<0.05). Patients with a TBI release currently unknown soluble factors into the circulating blood that up regulate expression of chemokine receptor CCR4 in peripheral blood monocytes whilst concurrently inducing expression of immunosuppressive cytokines by activated T-lymphocytes. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. Enhanced mucosal immune responses induced by a combined candidate mucosal vaccine based on Hepatitis A virus and Hepatitis E virus structural proteins linked to tuftsin.

    Science.gov (United States)

    Gao, Yan; Su, Qiudong; Yi, Yao; Jia, Zhiyuan; Wang, Hao; Lu, Xuexin; Qiu, Feng; Bi, Shengli

    2015-01-01

    Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are the most common causes of infectious hepatitis. These viruses are spread largely by the fecal-oral route and lead to clinically important disease in developing countries. To evaluate the potential of targeting hepatitis A and E infection simultaneously, a combined mucosal candidate vaccine was developed with the partial open reading frame 2 (ORF2) sequence (aa 368-607) of HEV (HE-ORF2) and partial virus protein 1 (VP1) sequence (aa 1-198) of HAV (HA-VP1), which included the viral neutralization epitopes. Tuftsin is an immunostimulatory peptide which can enhance the immunogenicity of a protein by targeting it to macrophages and dendritic cells. Here, we developed a novel combined protein vaccine by conjugating tuftsin to HE-ORF2 and HA-VP1 and used synthetic CpG oligodeoxynucleotides (ODNs) as the adjuvant. Subsequent experiments in BALB/c mice demonstrated that tuftsin enhanced the serum-specific IgG and IgA antibodies against HEV and HAV at the intestinal, vaginal and pulmonary interface when delivered intranasally. Moreover, mice from the intranasally immunized tuftsin group (HE-ORF2-tuftsin + HA-VP1-tuftsin + CpG) showed higher levels of IFN-γ-secreting splenocytes (Th1 response) and ratio of CD4+/CD8+ T cells than those of the no-tuftsin group (HE-ORF2 + HA-VP1 + CpG). Thus, the tuftsin group generated stronger humoral and cellular immune responses compared with the no-tuftsin group. Moreover, enhanced responses to the combined protein vaccine were obtained by intranasal immunization compared with intramuscular injection. By integrating HE-ORF2, HA-VP1 and tuftsin in a vaccine, this study validated an important concept for further development of a combined mucosal vaccine against hepatitis A and E infection.

  2. Nanoparticle formulation enhanced protective immunity provoked by PYGPI8p-transamidase related protein (PyTAM) DNA vaccine in Plasmodium yoelii malaria model.

    Science.gov (United States)

    Cherif, Mahamoud Sama; Shuaibu, Mohammed Nasir; Kodama, Yukinobu; Kurosaki, Tomoaki; Helegbe, Gideon Kofi; Kikuchi, Mihoko; Ichinose, Akitoyo; Yanagi, Tetsuo; Sasaki, Hitoshi; Yui, Katsuyuki; Tien, Nguyen Huy; Karbwang, Juntra; Hirayama, Kenji

    2014-04-07

    We have previously reported the new formulation of polyethylimine (PEI) with gamma polyglutamic acid (γ-PGA) nanoparticle (NP) to have provided Plasmodium yoelii merozoite surface protein-1 (PyMSP-1) plasmid DNA vaccine with enhanced protective cellular and humoral immunity in the lethal mouse malaria model. PyGPI8p-transamidase-related protein (PyTAM) was selected as a possible candidate vaccine antigen by using DNA vaccination screening from 29 GPI anchor and signal sequence motif positive genes picked up using web-based bioinformatics tools; though the observed protection was not complete. Here, we observed augmented protective effect of PyTAM DNA vaccine by using PEI and γ-PGA complex as delivery system. NP-coated PyTAM plasmid DNA immunized mice showed a significant survival rate from lethal P. yoelii challenge infection compared with naked PyTAM plasmid or with NP-coated empty plasmid DNA group. Antigen-specific IgG1 and IgG2b subclass antibody levels, proportion of CD4 and CD8T cells producing IFN-γ in the splenocytes and IL-4, IFN-γ, IL-12 and TNF-α levels in the sera and in the supernatants from ex vivo splenocytes culture were all enhanced by the NP-coated PyTAM DNA vaccine. These data indicates that NP augments PyTAM protective immune response, and this enhancement was associated with increased DC activation and concomitant IL-12 production. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Repeated social stress enhances the innate immune response to a primary HSV-1 infection in the cornea and trigeminal ganglia of Balb/c mice.

    Science.gov (United States)

    Dong-Newsom, P; Powell, N D; Bailey, M T; Padgett, D A; Sheridan, J F

    2010-02-01

    Three to 5 days after a primary HSV-1 infection, macrophages infiltrate into the trigeminal ganglia (TG) and produce anti-viral cytokines to reduce viral replication. Previous research demonstrated that social disruption stress (SDR) enhances the trafficking of monocytes/macrophages from the bone marrow to the spleen and increases pro-inflammatory cytokine production in vitro and in vivo. The impact of SDR on the trafficking of these cells to loci of herpes simplex virus type 1 (HSV-1) infection and subsequent function has not been examined. The following studies were designed to determine whether SDR would enhance the innate immune response during a primary HSV-1 infection by increasing the number of macrophages in the cornea and TG, thus increasing anti-viral cytokine production and reducing viral replication. BALB/c mice were exposed to six cycles of SDR prior to ocular infection with HSV-1 McKrae virus. Flow cytometric analysis of cells from the TG revealed an increase in the percentage of CD11b+ macrophages in SDR mice compared to controls. Immune cell infiltration into the cornea, however, could not be determined due to low cell numbers. Although gene expression of IFN-beta was decreased, SDR increased gene expression of IFN-alpha, and TNF-alpha, in the cornea and TG. Examination of viral proteins showed decreased expression of infected cell protein 0 (ICP0), glycoprotein B (gB), glycoprotein H (gH) and latency-associated transcript (LAT) in the TG, however, expression of ICP0 and gB were elevated in the cornea of SDR mice. These results indicate that the innate immune response to HSV-1 was altered and enhanced by the experience of repeated social defeat. Copyright 2009 Elsevier Inc. All rights reserved.

  4. Peptides from Colochirus robustus Enhance Immune Function via Activating CD3ζ- and ZAP-70-Mediated Signaling in C57BL/6 Mice

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    Xiaogang Du

    2017-10-01

    Full Text Available Colochirus robustus, a species of sea cucumber, has long been used in East and Southeast Asia as nutritious food as well as for certain medicinal purpose. Studies have shown a number of biological functions associated with consumption of sea cucumber, many of which are attributed to its major component, sea cucumber peptides (SCP. However, how SCP impacts immune system, which is critical for host defense, has not been defined. To address this issue, in the present study, we conducted comprehensive analysis of immune function after oral administration of SCP (0, 25, 50, and 75 mg/kg body weigh for eight weeks in C57BL/6 mice. We found that SCP treatment significantly enhanced lymphocyte proliferation, serum albumin (ALB levels, and the natural killer (NK cell activity. Moreover, SCP promoted functions of helper T cells (Th as indicated by increased production of Th1 type cytokines of Interleukin (IL-1β, IL-2, Interferon (IFN-γ and TNF-α and Th2 type cytokines (IL-4, IL-6, and IL-10. To determine the effective components, SCP was hydrolyzed into 16 types of constituent amino acids in simulated gastrointestinal digestion and these hydrolytic amino acids (HAA were used for the mechanistic studies in the in vitro models. Results showed that HAA enhanced lymphocyte proliferation and production of IL-2, IL-10 and IFN-γ. Furthermore, CD3ζ (CD3ζ and ζ-chain-associated protein kinase 70 (ZAP-70, the signaling molecules essential for activating T lymphocytes, were significantly up-regulated after HAA treatment. In summary, our results suggest that SCP is effective in enhancing immune function by activating T cells via impacting CD3ζ- and ZAP-70-mediated signaling pathway.

  5. Adjuvant Immune Enhancement of Subunit Vaccine Encoding pSCPI of Streptococcus iniae in Channel Catfish (Ictalurus punctatus

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    Jie Jiang

    2015-11-01

    Full Text Available Channel catfish (Ictalurus punctatus is an important agricultural fish that has been plagued by Streptococcus iniae (S. iniae infections in recent years, some of them severe. C5a peptidase is an important virulent factor of S. iniae. In this study, the subunit vaccine containing the truncated part of C5a peptidase (pSCPI was mixed with aluminum hydroxide gel (AH, propolis adjuvant (PA, and Freund’s Incomplete Adjuvant (FIA. The immunogenicity of the pSCPI was detected by Western-blot in vitro. The relative percent survival (RPS, lysozyme activity, antibody titers, and the expression of the related immune genes were monitored in vivo to evaluate the immune effects of the three different adjuvants. The results showed that pSCPI exerted moderate immune protection (RPS = 46.43%, whereas each of the three adjuvants improved the immune protection of pSCPI. The immunoprotection of pSCPI + AH, pSCPI + PA, and pSCPI + FIA was characterized by RPS values of 67.86%, 75.00% and, 85.71%, respectively. Further, each of the three different adjuvanted pSCPIs stimulated higher levels of lysozyme activity and antibody titers than the unadjuvanted pSCPI and/or PBS buffer. In addition, pSCPI + FIA and pSCPI + PA induced expression of the related immune genes under investigation, which was substantially higher than the levels stimulated by PBS. pSCPI + AH significantly stimulated the induction of MHC II β, CD4-L2, and IFN-γ, while it induced slightly higher production of TNF-α and even led to a decrease in the levels of IL-1β, MHC I α, and CD8 α. Therefore, we conclude that compared with the other two adjuvants, FIA combined with pSCPI is a more promising candidate adjuvant against S. iniae in channel catfish.

  6. PLGA, PLGA-TMC and TMC-TPP nanoparticles differentially modulate the outcome of nasal vaccination by inducing tolerance or enhancing humoral immunity.

    Science.gov (United States)

    Keijzer, Chantal; Slütter, Bram; van der Zee, Ruurd; Jiskoot, Wim; van Eden, Willem; Broere, Femke

    2011-01-01

    Development of vaccines in autoimmune diseases has received wide attention over the last decade. However, many vaccines showed limited clinical efficacy. To enhance vaccine efficacy in infectious diseases, biocompatible and biodegradable polymeric nanoparticles have gained interest as antigen delivery systems. We investigated in mice whether antigen-encapsulated PLGA (poly-lactic-co-glycolic acid), PLGA-TMC (N-trimethyl chitosan) or TMC-TPP (tri-polyphosphate) nanoparticles can also be used to modulate the immunological outcome after nasal vaccination. These three nanoparticles enhanced the antigen presentation by dendritic cells, as shown by increased in vitro and in vivo CD4(+) T-cell proliferation. However, only nasal PLGA nanoparticles were found to induce an immunoregulatory response as shown by enhanced Foxp3 expression in the nasopharynx associated lymphoid tissue and cervical lymph nodes. Nasal administration of OVA-containing PLGA particle resulted in functional suppression of an OVA-specific Th-1 mediated delayed-type hypersensitivity reaction, while TMC-TPP nanoparticles induced humoral immunity, which coincided with the enhanced generation of OVA-specific B-cells in the cervical lymph nodes. Intranasal treatment with Hsp70-mB29a peptide-loaded PLGA nanoparticles suppressed proteoglycan-induced arthritis, leading to a significant reduction of disease. We have uncovered a role for PLGA nanoparticles to enhance CD4(+) T-cell mediated immunomodulation after nasal application. The exploitation of this differential regulation of nanoparticles to modulate nasal immune responses can lead to innovative vaccine development for prophylactic or therapeutic vaccination in infectious or autoimmune diseases.

  7. A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells.

    Science.gov (United States)

    Wang, Zhao; Li, Mingming; Zhou, Ming; Zhang, Yajing; Yang, Jie; Cao, Yandi; Wang, Kunlun; Cui, Min; Chen, Huanchun; Fu, Zhen F; Zhao, Ling

    2017-02-01

    Rabies remains a public health threat in most parts of the world, and approximately 99% of the cases are transmitted by dogs. There is an urgent need to develop an efficacious and affordable vaccine to control canine-transmitted rabies in developing countries. Our previous studies demonstrate that overexpression of chemokines/cytokines such as CCL-3 (MIP-1α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the immunogenicity of rabies vaccines. In the present study, the chemokine CXCL13 was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, and the effect of the chemokine CXCL13 on the immunogenicity of RABV was investigated. It was found that LBNSE-CXCL13 recruited follicular helper T (Tfh) and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice. Further studies showed that mice immunized with LBNSE-CXCL13 produced more rabies virus-neutralizing antibodies (VNAs) and developed better protection than those immunized with the parent virus LBNSE or the GM-CSF-expressing RABV (LBNSE-GM-CSF). Collectively, these findings provide a better understanding of the role of CXCL13 expression in the immunogenicity of the RABV, which may help in designing more-efficacious rabies vaccines. Rabies is endemic in most parts of the world, and more effort is needed to develop affordable and effective vaccines to control or eliminate this disease. The chemokine CXCL13 recruits both Tfh and B cells, which is essential for the homing of Tfh cells and the development of B cell follicles. In this study, the effect of the overexpression of CXCL13 on the immunogenicity of the RABV was evaluated in a mouse model. We found that CXCL13 expression promoted humoral immunity by recruiting Tfh and GC B cells, facilitating the formation of GCs, and increasing the number of plasma cells. As expected, the overexpression of CXCL13 resulted in enhanced virus-neutralizing antibody

  8. Enhanced antitumoral efficacy and immune response following conditionally replicative adenovirus containing constitutive HSF1 delivery to rodent tumors

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    Fan Rong

    2012-05-01

    Full Text Available Abstract Background Oncolytic adenoviruses are promising as anticancer agents but have limited clinical responses. Our previous study showed that heat shock transcription factor 1 (HSF1 overexpression could increase the anti-tumor efficacy of E1B55kD deleted oncolytic adenovirus through increasing the viral burst. Due to the important roles of heat shock proteins (HSPs in eliciting innate and adaptive immunity, we reasoned that besides increasing the viral burst, HSF1 may also play a role in increasing tumor specific immune response. Methods In the present study, intra-dermal murine models of melanoma (B16 and colorectal carcinoma (CT26 were treated with E1B55kD deleted oncolytic adenovirus Adel55 or Adel55 incorporated with cHSF1, HSF1i, HSP70, or HSP90 by intra-tumoral injection. Tumors were surgically excised 72 h post injection and animals were analyzed for tumor resistance and survival rate. Results Approximately 95% of animals in the Adel55-cHSF1 treated group showed sustained resistance upon re-challenge with autologous tumor cells, but not in PBS, Adel55, or Adel55-HSF1i treated groups. Only 50–65% animals in the Adel55-HSP70 and Adel55-HSP90 treated group showed tumor resistance. Tumor resistance was associated with development of tumor type specific cellular immune responses. Adel55-cHSF1 treatment also showed higher efficacy in diminishing progression of the secondary tumor focus than Adel55-HSP70 or Adel55-HSP90 treatment. Conclusions Besides by increasing its burst in tumor cells, cHSF1 could also augment the potential of E1B55kD deleted oncolytic adenovirus by increasing the tumor-specific immune response, which is beneficial to prevent tumor recurrence. cHSF1 is a better gene for neoadjuvant immunotherapy than other heat shock protein genes.

  9. Targeting Peripheral-Derived Regulatory T Cells as a Means of Enhancing Immune Responses Directed against Prostate Cancer

    Science.gov (United States)

    2017-08-01

    that mice that lack pTregs are insensitive to tumor- mediated immune suppression. Therefore, major aims of this research project are to: 1) determine...not succumb to lethal cancer (Figure 2). Considering that TRAMP; Lck-cre; Klf2fl/fl mice continue to express transformed cells throughout their...and has agreed to complete this study. Importantly, work in Year 2 fully supports the hypothesis that pTregs are crucial for transformed cells to

  10. The colitis-associated transcriptional profile of commensal Bacteroides thetaiotaomicron enhances adaptive immune responses to a bacterial antigen.

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    Jonathan J Hansen

    Full Text Available Inflammatory bowel diseases (IBD may be caused in part by aberrant immune responses to commensal intestinal microbes including the well-characterized anaerobic gut commensal Bacteroides thetaiotaomicron (B. theta. Healthy, germ-free HLA-B27 transgenic (Tg rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg rats remain disease-free. However, the role of B. theta in causing disease in Tg rats is unknown nor is much known about how gut microbes respond to host inflammation.Tg and nTg rats were monoassociated with a human isolate of B. theta. Colonic inflammation was assessed by histologic scoring and tissue pro-inflammatory cytokine measurement. Whole genome transcriptional profiling of B. theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA software. Western Blots were used to determine adaptive immune responses to a differentially expressed B. theta gene.B. theta monoassociated Tg rats, but not nTg or germ-free controls, developed chronic colitis. Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats. GSEA revealed that genes in KEGG canonical pathways involved in bacterial growth and metabolism were downregulated in B. theta from Tg rats with colitis though luminal bacterial concentrations were unaffected. Bacterial genes in the Gene Ontology molecular function "receptor activity", most of which encode nutrient binding proteins, were significantly upregulated in B. theta from Tg rats and include a SusC homolog that induces adaptive immune responses in Tg rats.B. theta induces colitis in HLA-B27 Tg rats, which is associated with regulation of bacterial genes in metabolic and nutrient binding pathways that may affect host immune responses. These studies of the host-microbial dialogue may lead to the identification of novel microbial targets

  11. The colitis-associated transcriptional profile of commensal Bacteroides thetaiotaomicron enhances adaptive immune responses to a bacterial antigen.

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    Hansen, Jonathan J; Huang, Yong; Peterson, Daniel A; Goeser, Laura; Fan, Ting-Jia; Chang, Eugene B; Sartor, R Balfour

    2012-01-01

    Inflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including the well-characterized anaerobic gut commensal Bacteroides thetaiotaomicron (B. theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg) rats remain disease-free. However, the role of B. theta in causing disease in Tg rats is unknown nor is much known about how gut microbes respond to host inflammation. Tg and nTg rats were monoassociated with a human isolate of B. theta. Colonic inflammation was assessed by histologic scoring and tissue pro-inflammatory cytokine measurement. Whole genome transcriptional profiling of B. theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Western Blots were used to determine adaptive immune responses to a differentially expressed B. theta gene. B. theta monoassociated Tg rats, but not nTg or germ-free controls, developed chronic colitis. Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats. GSEA revealed that genes in KEGG canonical pathways involved in bacterial growth and metabolism were downregulated in B. theta from Tg rats with colitis though luminal bacterial concentrations were unaffected. Bacterial genes in the Gene Ontology molecular function "receptor activity", most of which encode nutrient binding proteins, were significantly upregulated in B. theta from Tg rats and include a SusC homolog that induces adaptive immune responses in Tg rats. B. theta induces colitis in HLA-B27 Tg rats, which is associated with regulation of bacterial genes in metabolic and nutrient binding pathways that may affect host immune responses. These studies of the host-microbial dialogue may lead to the identification of novel microbial targets for IBD

  12. Immune System

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    ... Counselors Kidney Stones Brain and Nervous System Immune System KidsHealth > For Teens > Immune System Print A A ... put us out of commission. What the Immune System Does The immune (pronounced: ih-MYOON) system, which ...

  13. Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM

    Science.gov (United States)

    Mathios, Dimitrios; Kim, Jennifer E.; Mangraviti, Antonella; Phallen, Jillian; Park, Chul-Kee; Jackson, Christopher M.; Garzon-Muvdi, Tomas; Kim, Eileen; Theodros, Debebe; Polanczyk, Magdalena; Martin, Allison M.; Suk, Ian; Ye, Xiaobu; Tyler, Betty; Bettegowda, Chetan; Brem, Henry; Pardoll, Drew M.; Lim, Michael

    2017-01-01

    The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti–programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti–PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti–PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types. PMID:28003545

  14. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM.

    Science.gov (United States)

    Mathios, Dimitrios; Kim, Jennifer E; Mangraviti, Antonella; Phallen, Jillian; Park, Chul-Kee; Jackson, Christopher M; Garzon-Muvdi, Tomas; Kim, Eileen; Theodros, Debebe; Polanczyk, Magdalena; Martin, Allison M; Suk, Ian; Ye, Xiaobu; Tyler, Betty; Bettegowda, Chetan; Brem, Henry; Pardoll, Drew M; Lim, Michael

    2016-12-21

    The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types. Copyright © 2016, American Association for the Advancement of Science.

  15. Innate Immune Dysfunction is Associated with Enhanced Disease Severity In Infants with Severe Respiratory Syncytial Virus Bronchiolitis

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    Mella, Cesar; Suarez-Arrabal, M. Carmen; Lopez, Santiago; Stephens, Julie; Fernandez, Soledad; Hall, Mark W.; Ramilo, Octavio; Mejias, Asuncion

    2013-01-01

    Background. Most patients with respiratory syncytial virus (RSV) bronchiolitis requiring admission to the pediatric intensive care unit (PICU) have no risk factors for severe disease. We sought to investigate the relationship between serum cytokine concentrations, innate immune responsiveness, and RSV disease severity. Methods. Previously healthy infants (median age, 2.6 months) with RSV bronchiolitis (PICU, n = 20; floor, n = 46) and healthy matched controls (n = 14) were enrolled, and blood samples were obtained within 24 hours of admission to measure plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10) concentrations and, whole blood lipopolysaccharide-stimulated cytokine production capacity. Results. Plasma IL-6, IL-8, and IL-10 concentrations were comparable between PICU and floor patients, but higher than in healthy controls (P bronchiolitis had increased plasma cytokine concentrations and yet impaired innate immunity cytokine production capacity, which predicted worse disease outcomes. Immune monitoring of otherwise healthy infants with RSV lower respiratory tract infection could help identify patients at risk for severe disease at the time of hospitalization. PMID:23204162

  16. Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity.

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    Chen, Jing; Wang, Yacheng; Mei, Zijie; Zhang, Shimin; Yang, Jie; Li, Xin; Yao, Ye; Xie, Conghua

    2016-03-01

    Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  17. Innate immune dysfunction is associated with enhanced disease severity in infants with severe respiratory syncytial virus bronchiolitis.

    Science.gov (United States)

    Mella, Cesar; Suarez-Arrabal, M Carmen; Lopez, Santiago; Stephens, Julie; Fernandez, Soledad; Hall, Mark W; Ramilo, Octavio; Mejias, Asuncion

    2013-02-15

    Most patients with respiratory syncytial virus (RSV) bronchiolitis requiring admission to the pediatric intensive care unit (PICU) have no risk factors for severe disease. We sought to investigate the relationship between serum cytokine concentrations, innate immune responsiveness, and RSV disease severity. Previously healthy infants (median age, 2.6 months) with RSV bronchiolitis (PICU, n = 20; floor, n = 46) and healthy matched controls (n = 14) were enrolled, and blood samples were obtained within 24 hours of admission to measure plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10) concentrations and, whole blood lipopolysaccharide-stimulated cytokine production capacity. Plasma IL-6, IL-8, and IL-10 concentrations were comparable between PICU and floor patients, but higher than in healthy controls (P disease severity scores (P = .001). Infants with severe RSV bronchiolitis had increased plasma cytokine concentrations and yet impaired innate immunity cytokine production capacity, which predicted worse disease outcomes. Immune monitoring of otherwise healthy infants with RSV lower respiratory tract infection could help identify patients at risk for severe disease at the time of hospitalization.

  18. Garlic and alpha lipoic supplementation enhance the immune system of albino rats and alleviate implications of pesticides mixtures.

    Science.gov (United States)

    Elhalwagy, Manal Ea; Darwish, Nevine S; Shokry, Dina A; El-Aal, Aly Ge Abd; Abd-Alrahman, Sherif H; Nahas, Abd-Alhamed; Ziada, Reem M

    2015-01-01

    This study aimed to investigate age dependent immune-system response versus exposure to different doses of mixture of (chlorpyrifos, profenofose, and fenitrothion) and/or combined with 60 and 250 mg kg(-1) alpha lipoic acid and garlic, respectively. 120 males of albino rats were divided to two groups according to age; weaning group (2 months age and 60-80 gm.), adult (6 months and 180-200 gm). Each age was divided into 6 subgroups treated orally for 3 months , G1 (control), G2 high dose (HDPM) CPF10 mg kg(-1), PRO 3 mg kg(-1), FEN 6 mg kg(-1), G3 low dose (LDPM) CPF 1 mg kg(-1), PFN 0.3 mg kg(-1) and FEN 0.6 mg kg(-1), G4 AOX (alpha lipoic + Garlic), G5 HDPM + AOX and G6 LDPM + AOX. Results showed significant inhibition in serum acetylcholinesterase (AChE), elevation in malondialdehyde (MDA) concurrent with reduction in total reduced glutathione (GSH) in both ages was recorded as well as, decrease in IGG, IGM, Lymphocyte transformation and Phagocytosis humeral and cellular immunity confirmed by alteration in lymph nodes architecture. This study was concluded that the supplementation with alpha lipoic acid and garlic improved previous alternations slightly to be more or less near the control level in both adult and weaning rats. It seems that, immune-responses of both adult and weaning rats were slightly similar.

  19. IgE/FcεRI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses

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    Barbara Platzer

    2015-03-01

    Full Text Available Epidemiologic studies discovered an inverse association between immunoglobulin E (IgE-mediated allergies and cancer, implying tumor-protective properties of IgE. However, the underlying immunologic mechanisms remain poorly understood. Antigen cross-presentation by dendritic cells (DCs is of key importance for anti-tumor immunity because it induces the generation of cytotoxic CD8+ T lymphocytes (CTLs with specificity for tumor antigens. We demonstrate that DCs use IgE and FcεRI, the high-affinity IgE receptor, for cross-presentation and priming of CTLs in response to free soluble antigen at low doses. Importantly, IgE/FcεRI-mediated cross-presentation is a distinct receptor-mediated pathway because it does not require MyD88 signals or IL-12 induction in DCs. Using passive immunization with tumor antigen-specific IgE and DC-based vaccination experiments, we demonstrate that IgE-mediated cross-presentation significantly improves anti-tumor immunity and induces memory responses in vivo. Our findings suggest a cellular mechanism for the tumor-protective features of IgE and expand the known physiological functions of this immunoglobulin.

  20. Norovirus (NoV) specific protective immune responses induced by recombinant P dimer vaccine are enhanced by the mucosal adjuvant FlaB.

    Science.gov (United States)

    Verma, Vivek; Tan, Wenzhi; Puth, Sao; Cho, Kyoung-Oh; Lee, Shee Eun; Rhee, Joon Haeng

    2016-05-17

    Noroviruses (NoVs) are a major cause of childhood gastroenteritis and foodborne diseases worldwide. Lack of appropriate animal models or cell-based culture systems makes the development and evaluation of NoV-specific vaccines a daunting task. VP1 is the major capsid protein of the NoVs that acts as a binding motif to human histo-blood group antigens (HBGAs) through its protruding 2 (P2) domain and can serve as a protective antigen candidate for vaccine development. Recombinantly produced NoV specific P domain (Pd) vaccine was inoculated into groups of mice either alone or in conjugation with mucosal adjuvant FlaB, the flagellar protein from Vibrio vulnificus. Antigen specific humoral and cell mediated immune responses were assessed by enzyme linked immunosorbent assay (ELISA) or fluorescent activated cell sorting (FACS). A comparative analysis of various routes of vaccination viz. intranasal, sublingual and subcutaneous, was also done. In this study, we show that a recombinant Pd-vaccine administered through intranasal route induced a robust TH2-dependent humoral immune response and that the combination of vaccine with FlaB significantly enhanced the antibody response. Interestingly, FlaB induced a mixed TH1/TH2 type of immune response with a significant induction of IgG1 as well as IgG2a antibodies. FlaB also induced strong IgA responses in serum and feces. FlaB mediated antibody responses were toll like receptor 5 (TLR5) dependent, since the FlaB adjuvanticity was lost in TLR5(-/-) mice. Further, though the Pd-vaccine by itself failed to induce a cell mediated immune response, the Pd-FlaB combination stimulated a robust CD4(+)IFNγ(+) and CD8(+)IFNγ(+) T cell response in spleen and mesenteric lymph nodes. We also compared the adjuvant effects of FlaB with that of alum and complete Freund's adjuvant (CFA). We found that subcutaneously inoculated FlaB induced more significant levels of IgG and IgA in both serum and feces compared to alum or CFA in respective

  1. AFCo1, a meningococcal B-derived cochleate adjuvant, strongly enhances antibody and T-cell immunity against Plasmodium falciparum merozoite surface protein 4 and 5

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    Pérez Oliver

    2009-02-01

    Full Text Available Abstract Background Whilst a large number of malaria antigens are being tested as candidate malaria vaccines, a major barrier to the development of an effective vaccine is the lack of a suitable human adjuvant capable of inducing a strong and long lasting immune response. In this study, the ability of AFCo1, a potent T and B cell adjuvant based on cochleate structures derived from meningococcal B outer membrane proteoliposomes (MBOMP, to boost the immune response against two Plasmodium falciparum antigens, merozoite surface protein 4 (MSP4 and 5 (MSP5, was evaluated. Methods Complete Freund's adjuvant (CFA, which is able to confer protection against malaria in animal MSP4/5 vaccine challenge models, was used as positive control adjuvant. MSP4 and 5-specific IgG, delayed-type hypersensitivity (DTH, T-cell proliferation, and cytokine production were evaluated in parallel in mice immunized three times intramuscularly with MSP4 or MSP5 incorporated into AFCo1, synthetic cochleate structures, CFA or phosphate buffered saline. Results AFCo1 significantly enhanced the IgG and T-cell response against MSP4 and MSP5, with a potency equivalent to CFA, with the response being characterized by both IgG1 and IgG2a isotypes, increased interferon gamma production and a strong DTH response, consistent with the ability of AFCo1 to induce Th1-like immune responses. Conclusion Given the proven safety of MBOMP, which is already in use in a licensed human vaccine, AFCo1 could assist the development of human malaria vaccines that require a potent and safe adjuvant.

  2. Enrichment of sialylated IgG by lectin fractionation does not enhance the efficacy of immunoglobulin G in a murine model of immune thrombocytopenia.

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    Theresa Guhr

    Full Text Available Intravenous immunoglobulin G (IVIg is widely used against a range of clinical symptoms. For its use in immune modulating therapies such as treatment of immune thrombocytopenic purpura high doses of IVIg are required. It has been suggested that only a fraction of IVIg causes this anti immune modulating effect. Recent studies indicated that this fraction is the Fc-sialylated IgG fraction. The aim of our study was to determine the efficacy of IVIg enriched for sialylated IgG (IVIg-SA⁺ in a murine model of passive immune thrombocytopenia (PIT. We enriched IVIg for sialylated IgG by Sambucus nigra agglutinin (SNA lectin fractionation and determined the degree of sialylation. Analysis of IVIg-SA⁺ using a lectin-based ELISA revealed that we enriched predominantly for Fab-sialylated IgG, whereas we did not find an increase in Fc-sialylated IgG. Mass spectrometric analysis confirmed that Fc sialylation did not change after SNA lectin fractionation. The efficacy of sialylated IgG was measured by administering IVIg or IVIg-SA⁺ 24 hours prior to an injection of a rat anti-mouse platelet mAb. We found an 85% decrease in platelet count after injection of an anti-platelet mAb, which was reduced to a 70% decrease by injecting IVIg (p<0.01. In contrast, IVIg-SA⁺ had no effect on the platelet count. Serum levels of IVIg and IVIg-SA⁺ were similar, ruling out enhanced IgG clearance as a possible explanation. Our results indicate that SNA lectin fractionation is not a suitable method to enrich IVIg for Fc-sialylated IgG. The use of IVIg enriched for Fab-sialylated IgG abolishes the efficacy of IVIg in the murine PIT model.

  3. Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination.

    Science.gov (United States)

    Bagri, Puja; Anipindi, Varun C; Nguyen, Philip V; Vitali, Danielle; Stämpfli, Martin R; Kaushic, Charu

    2017-12-01

    It is well established that interferon gamma (IFN-γ) production by CD4 + T cells is critical for antiviral immunity against herpes simplex virus 2 (HSV-2) genital infection. However, the role of interleukin-17A (IL-17A) production by CD4 + T cells in HSV-2 antiviral immunity is yet to be elucidated. Here we demonstrate that IL-17A plays an important role in enhancing antiviral T helper type 1 (T h 1) responses in the female genital tract (FGT) and is essential for effective protection conferred by HSV-2 vaccination. While IL-17A did not play a critical role during primary genital HSV-2 infection, seen by lack of differences in susceptibility between IL-17A-deficient ( IL-17A -/- ) and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, IL-17A -/- mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated IL-17A -/- mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, IL-17A -/- mice had impaired T h 1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ + CD4 + T cells. The impaired T h 1 cell responses in IL-17A -/- mice coincided with smaller populations of IFN-γ + CD4 + tissue resident memory T (T RM ) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ + T h 1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination. IMPORTANCE T helper type 1 (T h 1) immunity, specifically interferon gamma (IFN-γ) production by CD4 + T cells, is critical for protection against genital herpesvirus (HSV-2) infection, and

  4. Monitoring of immune cell response to B cell depletion therapy and nerve root injury using SPIO enhanced MRI

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    Thorek, Daniel L.

    2009-12-01

    Magnetic resonance (MR) is a robust platform for non-invasive, high-resolution anatomical imaging. However, MR imaging lacks the requisite sensitivity and contrast for imaging at the cellular level. This represents a clinical impediment to greater diagnostic accuracy. Recent advances have allowed for the in vivo visualization of populations and even of individual cells using superparamagnetic iron oxide (SPIO) MR contrast agents. These nanoparticles, commonly manifested as a core of a single iron oxide crystal or cluster of crystals coated in a biocompatible shell, function to shorten proton relaxation times. In MR imaging these constructs locally dephase protons, resulting in a decrease in signal (hypointensity) localized to the region of accumulation of SPIO. In the context of immune cell imaging, SPIO can provide insight into the cellular migration patterns, trafficking, temporal dynamics and progression of diseases and their related pathological states. Furthermore, by visualizing the presence and activity of immune cells, SPIO-enabled cellular imaging can help evaluate the efficacy of therapy in immune disorders. This thesis examines the production, modification and application of SPIO in a range of in vitro and in vivo immune-response-relevant cellular systems. The role of different nanoparticle characteristics including diameter, surface charge and concentration are investigated in the labeling of T cells in culture. Following optimization of SPIO loading conditions for lymphocytes, the effect these particles have on the activation of primary B cells are elucidated. B cells are tracked using a variety of modalities, with and without the application of B cell depleting therapy. This is to evaluate the efficacy of SPIO as in vivo marker for B cell distribution. Unmodified SPIO were applied to monitor macrophage infiltration in a transient nerve root compression model, with implications for neck pain diagnosis and treatment. Nanoparticle accumulation and MR

  5. Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

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    Masanori Matsui

    2014-01-01

    Full Text Available We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide-specific cytotoxic T lymphocyte (CTL recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT in which three components involving a peptide, β2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP-derived peptide, β2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors.

  6. A Built-In CpG Adjuvant in RSV F Protein DNA Vaccine Drives a Th1 Polarized and Enhanced Protective Immune Response

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    Yao Ma

    2018-01-01

    Full Text Available Human respiratory syncytial virus (RSV is the most significant cause of acute lower respiratory infection in children. However, there is no licensed vaccine available. Here, we investigated the effect of five or 20 copies of C-Class of CpG ODN (CpG-C motif incorporated into a plasmid DNA vaccine encoding RSV fusion (F glycoprotein on the vaccine-induced immune response. The addition of CpG-C motif enhanced serum binding and virus-neutralizing antibody responses in BALB/c mice immunized with the DNA vaccines. Moreover, mice vaccinated with CpG-modified vaccines, especially with the higher 20 copies, resulted in an enhanced shift toward a Th1-biased antibody and T-cell response, a decrease in pulmonary pathology and virus replication, and a decrease in weight loss after RSV challenge. This study suggests that CpG-C motif, cloned into the backbone of DNA vaccine encoding RSV F glycoprotein, functions as a built-in adjuvant capable of improving the efficacy of DNA vaccine against RSV infection.

  7. Structure-based stabilization of HIV-1 gp120 enhances humoral immune responses to the induced co-receptor binding site.

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    Barna Dey

    2009-05-01

    Full Text Available The human immunodeficiency virus type 1 (HIV-1 exterior envelope glycoprotein, gp120, possesses conserved binding sites for interaction with the primary virus receptor, CD4, and also for the co-receptor, generally CCR5. Although gp120 is a major target for virus-specific neutralizing antibodies, the gp120 variable elements and its malleable nature contribute to evasion of effective host-neutralizing antibodies. To understand the conformational character and immunogenicity of the gp120 receptor binding sites as potential vaccine targets, we introduced structure-based modifications to stabilize gp120 core proteins (deleted of the gp120 major variable regions into the conformation recognized by both receptors. Thermodynamic analysis of the re-engineered core with selected ligands revealed significant stabilization of the receptor-binding regions. Stabilization of the co-receptor-binding region was associated with a marked increase in on-rate of ligand binding to this site as determined by surface plasmon resonance. Rabbit immunization studies showed that the conformational stabilization of core proteins, along with increased ligand affinity, was associated with strikingly enhanced humoral immune responses against the co-receptor-binding site. These results demonstrate that structure-based approaches can be exploited to stabilize a conformational site in a large functional protein to enhance immunogenic responses specific for that region.

  8. Live Yeast and Yeast Cell Wall Supplements Enhance Immune Function and Performance in Food-Producing Livestock: A Review †,‡

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    Paul R. Broadway

    2015-08-01

    Full Text Available More livestock producers are seeking natural alternatives to antibiotics and antimicrobials, and searching for supplements to enhance growth performance, and general animal health and well-being. Some of the compounds currently being utilized and studied are live yeast and yeast-based products derived from the strain Saccharomyces cerevisiae. These products have been reported to have positive effects both directly and indirectly on the immune system and its subsequent biomarkers, thereby mitigating negative effects associated with stress and disease. These yeast-based products have also been reported to simultaneously enhance growth and performance by enhancing dry matter intake (DMI and average daily gain (ADG perhaps through the establishment of a healthy gastrointestinal tract. These products may be especially useful in times of potential stress such as during birth, weaning, early lactation, and during the receiving period at the feedlot. Overall, yeast supplements appear to possess the ability to improve animal health and metabolism while decreasing morbidity, thereby enhancing profitability of these animals.

  9. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract

    OpenAIRE

    Bowman, L. M.; Holt, P. G.

    2001-01-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM...

  10. Enhancements of non-specific immune response in Mugil cephlus by seaweed extract against Vibrio alginolyticus (BRTR07)

    OpenAIRE

    Rajasekar Thirunavukkarasu; Priyadharshini Pandiyan; Deivasigamani Balaraman; Ilamathi Jayaraman; Kumaran Subaramaniyan; Edward Gnana Jothi George

    2015-01-01

    Objective: To focus on the growth rate and feed utilization of fish by using trash fish feeds supplement with marine seaweeds. Methods: Selected seaweed was extracted using hot-water and its extract was mixed with trash fish feed at different concentrations (0.5%, 1% and 2% for 1-30 days) and the nonspecific immune response in fish was studied and challenged with Vibrio alginolyticus at 1 × 106 CFU/fish. The hot-water extract of seaweeds was analysed by gas chromatography-mass ...

  11. Elevated Expression of CD160 and 2B4 Defines a Cytolytic HIV-Specific CD8+ T-Cell Population in Elite Controllers.

    Science.gov (United States)

    Pombo, Carolina; Wherry, E John; Gostick, Emma; Price, David A; Betts, Michael R

    2015-11-01

    During chronic human immunodeficiency virus (HIV) infection, virus-specific CD8(+) T cells become functionally exhausted. Unlike most chronically infected individuals, elite controllers of HIV retain CD8(+) T-cell polyfunctionality and cytolytic capacity. It remains unclear whether elite controllers manifest T-cell exhaustion similar to subjects with chronic progression of HIV infection. Here we assessed coexpression of PD-1, Lag-3, CD160, and 2B4 as a measure of T-cell exhaustion in a cohort of elite controllers and in chronic progressors. We found that elite controllers have a high proportion of potentially exhausted (PD1(+)CD160(+)2B4(+)) HIV-specific CD8(+) T cells that is comparable to the proportion in chronic progressors. However, elite controllers also harbor a population of HIV-specific CD160(+)2B4(+) CD8(+) T cells that correlates with cytolytic capacity, as measured by perforin expression, a population not commonly present in chronic progressors. We therefore propose that coexpression of CD160 and 2B4 delineates a population of cytolytic CD8(+) T cells important for the control of HIV. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Dengue-1 envelope protein domain III along with PELC and CpG oligodeoxynucleotides synergistically enhances immune responses.

    Directory of Open Access Journals (Sweden)

    Chen-Yi Chiang

    Full Text Available The major weaknesses of subunit vaccines are their low immunogenicity and poor efficacy. Adjuvants can help to overcome some of these inherent defects with subunit vaccines. Here, we evaluated the efficacy of the newly developed water-in-oil-in-water multiphase emulsion system, termed PELC, in potentiating the protective capacity of dengue-1 envelope protein domain III. Unlike aluminum phosphate, dengue-1 envelope protein domain III formulated with PELC plus CpG oligodeoxynucleotides induced neutralizing antibodies against dengue-1 virus and increased the splenocyte secretion of IFN-γ after in vitro re-stimulation. The induced antibodies contained both the IgG1 and IgG2a subclasses. A rapid anamnestic neutralizing antibody response against a live dengue virus challenge was elicited at week 26 after the first immunization. These results demonstrate that PELC plus CpG oligodeoxynucleotides broaden the dengue-1 envelope protein domain III-specific immune responses. PELC plus CpG oligodeoxynucleotides is a promising adjuvant for recombinant protein based vaccination against dengue virus.

  13. Fast, continuous recirculation of germinal center B cell populations enhances robustness of immune response towards varying pathogens

    Science.gov (United States)

    Or-Guil, Michal

    2009-03-01

    Germinal centers (GCs) are dynamic microstructures that form in lymphatic tissues during immune responses. There, B cells undergo rapid proliferation and mutation of their B cell receptors (BCRs). Selection of B cells bearing BCRs that bind to the pathogen causing the immune response ultimately leads to BCRs that, when secreted as antibodies, form a new, effective, and pathogen specific antibody repertoire. However, the details of this evolutionary process are poorly understood, since currently available experimental techniques do not allow for direct observation of the prevailing mechanisms [Or-Guil et al., Imm.Rev. 2007]. Based on optimality considerations, we put forward the assumption that GCs are not isolated entities where evolutionary processes occur independently, but interconnected structures which allow for continuous exchange of B cells. We show that this architecture leads to a system whose response is much more robust towards different antigen variants than a set of independently working GCs could ever be. We test this hypothesis by generating our own experimental data (time course of 3-D volume distribution of GCs, analysis of high-throughput BCR sequences), and show that available data is consistent with the outlined hypothesis.

  14. The enhanced immune responses induced by Salmonella enteritidis ghosts loaded with Neisseria gonorrhoeae porB against Salmonella in mice.

    Science.gov (United States)

    Jiao, Hongmei; Yang, Hui; Zhao, Dan; He, Li; Chen, Jin; Li, Guocai

    2016-11-01

    Human health has been seriously endangered by highly prevalent salmonellosis and multidrug-resistant Salmonella strains. Current vaccines suffer from variable immune-protective effects, so more effective ones are needed to control Salmonella infection : Bacterial ghosts have been produced by the expression of lysis gene E from bacteriophage PhiX174 and can be filled with considerable exogenous substances such as DNA or drugs as a novel platform. In this study, Salmonella enteritidis (SE) ghosts were developed and loaded with Neisseria gonorrhoeae porin B (porB) to construct a novel inactive vaccine. Our new studies show that SE ghosts loaded with porB displayed increased production of pro-inflammatory cytokines (IL-1β, IL-6, IL-10 and IL-12p70) in bone marrow-derived dendritic cells (BMDCs), and elicited significantly higher specific systemic and mucosal immune responses to Salmonella than SE ghosts alone. In addition, the novel porB-loaded ghosts conferred higher protective effects on virulent Salmonella challenge. For the first time, we demonstrate that N. gonorrhoeae porB, as a novel adjuvant, can increase the immunogenicity of SE ghosts. Our studies suggested that Salmonella enteritidis ghosts loaded with Neisseria gonorrhoeae porin B might be a useful mucosal Salmonella vaccine candidate for practical use in the future. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Tasco®: A Product of Ascophyllum nodosum Enhances Immune Response of Caenorhabditis elegans Against Pseudomonas aeruginosa Infection

    Directory of Open Access Journals (Sweden)

    Franklin Evans

    2012-01-01

    Full Text Available The effects of Tasco®, a product made from the brown seaweed (Ascophyllum nodosum were tested for the ability to protect Caenorhabditis elegans against Pseudomonas aeruginosa infection. A water extract of Tasco® (TWE reduced P. aeruginosa inflicted mortality in the nematode. The TWE, at a concentration of 300 µg/mL, offered the maximum protection and induced the expression of innate immune response genes viz.; zk6.7 (Lypases, lys-1 (Lysozyme, spp-1 (Saponin like protein, f28d1.3 (Thaumatin like protein, t20g5.7 (Matridin SK domain protein, abf-1 (Antibacterial protein and f38a1.5 (Lectin family protein. Further, TWE treatment also affected a number of virulence components of the P. aeuroginosa and reduced its secreted virulence factors such as lipase, proteases and toxic metabolites; hydrogen cyanide and pyocyanin. Decreased virulence factors were associated with a significant reduction in expression of regulatory genes involved in quorum sensing, lasI, lasR, rhlI and rhlR. In conclusion, the TWE-treatment protected the C. elegans against P. aeruginosa infection by a combination of effects on the innate immunity of the worms and direct effects on the bacterial quorum sensing and virulence factors.

  16. Coinjection of IL2 DNA enhances E7-specific antitumor immunity elicited by intravaginal therapeutic HPV DNA vaccination with electroporation.

    Science.gov (United States)

    Sun, Y; Peng, S; Yang, A; Farmer, E; Wu, T-C; Hung, C-F

    2017-07-01

    The generation and use of therapeutic human papillomavirus (HPV) DNA vaccines represent an appealing treatment method against HPV-associated cervical cancer owing to their safety and durability. Previously, we created a therapeutic HPV DNA vaccine candidate by linking the HPV16-E7 DNA sequence to calreticulin (CRT/E7), which we showed could generate significant E7-specific cytotoxic T lymphocyte (CTL)-mediated antitumor immune responses against HPV16 oncogenes expressing murine tumor model TC-1. Here we assess the therapeutic efficacy of intravaginal immunization with pcDNA3-CRT/E7 followed by electroporation. In addition, we examined whether coadministration of DNA-encoding interleukin 2 (IL2) with the pcDNA3-CRT/E7 could improve the T-cell responses elicited by pcDNA3-CRT/E7. TC-1 tumor-bearing mice vaccinated intravaginally with both pcDNA3-CRT/E7 and IL2 DNA followed by electroporation induced stronger local antitumor CTL response in comparison to mice that received other treatment regimens. Additionally, we found that coadministration of IL2 DNA with pcDNA3-CRT/E7 modified the tumor microenvironment by decreasing the population of regulatory T cells and myeloid-derived suppressor cells relative to that of CTLs. Our data demonstrate the translational potential of local administration of IL2 and pcDNA3-CRT/E7 followed by electroporation in treating cervicovaginal tumors.

  17. HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

    Science.gov (United States)

    Kanagavelu, Saravana; Termini, James M; Gupta, Sachin; Raffa, Francesca N; Fuller, Katherine A; Rivas, Yaelis; Philip, Sakhi; Kornbluth, Richard S; Stone, Geoffrey W

    2014-01-01

    Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D) as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag) which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from vaccinia

  18. Enhanced inhibition of murine prostatic carcinoma growth by immunization with or administration of viable human umbilical vein endothelial cells and CRM197

    Directory of Open Access Journals (Sweden)

    Zhang Huiyong

    2011-02-01

    Full Text Available Vaccination with xenogeneic and syngeneic endothelial cells is effective for inhibiting tumor growth. Nontoxic diphtheria toxin (CRM197, as an immunogen or as a specific inhibitor of heparin-binding EGF-like growth factor, has shown promising antitumor activity. Therefore, immunization with or administration of viable human umbilical vein endothelial cells (HUVECs combined with CRM197 could have an enhanced antitumor effect. Six-week-old C57BL/6J male mice were vaccinated with viable HUVECs, 1 x 10(6 viable HUVECs combined with 100 μg CRM197, or 100 μg CRM197 alone by ip injections once a week for 4 consecutive weeks. RM-1 cells (5 x 10(5 were inoculated by sc injection as a preventive procedure. During the therapeutic procedure, 6-week-old male C57BL/6J mice were challenged with 1 x 10(5 RM-1 cells, then injected sc with 1 x 10(6 viable HUVECs, 1 x 10(6 viable HUVECs + 100 μg CRM197, and 100 μg CRM197 alone twice a week for 4 consecutive weeks. Tumor volume and life span were monitored. We also investigated the effects of immunization with HUVECs on the aortic arch wall and on wound healing. Vaccination with or administration of viable HUVECs+CRM197 enhanced the inhibition of RM-1 prostatic carcinoma by 24 and 29%, respectively, and prolonged the life span for 3 and 4 days, respectively, compared with those of only vaccination or administration with viable HUVECs of tumor-bearing C57BL/6J mice. Furthermore, HUVEC immunization caused some damage to the aortic arch wall but did not have remarkable effects on the rate of wound healing; the wounds healed in approximately 13 days. Treatment with CRM197 in combination with viable HUVECs resulted in a marked enhancement of the antitumor effect in the preventive or therapeutic treatment for prostatic carcinoma in vivo, suggesting a novel combination for anti-cancer therapy.

  19. Chimeric rabies virus-like particles containing membrane-anchored GM-CSF enhances the immune response against rabies virus.

    Science.gov (United States)

    Kang, Hongtao; Qi, Yinglin; Wang, Hualei; Zheng, Xuexing; Gao, Yuwei; Li, Nan; Yang, Songtao; Xia, Xianzhu

    2015-03-11

    Rabies remains an important public health threat in most developing countries. To develop a more effective and safe vaccine against rabies, we have constructed a chimeric rabies virus-like particle (VLP), which containing glycoprotein (G) and matrix protein (M) of rabies virus (RABV) Evelyn-Rokitnicki-Abelseth (ERA) strain, and membrane-anchored granulocyte-macrophage colony-stimulating factor (GM-CSF), and it was named of EVLP-G. The immunogenicity and protective efficacy of EVLP-G against RABV were evaluated by intramuscular administration in a mouse model. The EVLP-G was successfully produced in insect cells by coinfection with three recombinant baculoviruses expressing G, M, and GM-CSF, respectively. The membrane-anchored GM-CSF possesses a strong adjuvant activity. More B cells and dendritic cells (DCs) were recruited and/or activated in inguinal lymph nodes in mice immunized with EVLP-G. EVLP-G was found to induce a significantly increased RABV-specific virus-neutralizing antibody and elicit a larger and broader antibody subclass responses compared with the standard rabies VLP (sRVLP, consisting of G and M). The EVLP-G also elicited significantly more IFN-γ- or IL-4-secreting CD4+ and CD8+ T cells than the sRVLP. Moreover, the immune responses induced by EVLP-G protect all vaccinated mice from lethal challenge with RABV. These results suggest that EVLP-G has the potential to be developed as a novel vaccine candidate for the prevention and control of animal rabies.

  20. Chimeric Rabies Virus-Like Particles Containing Membrane-Anchored GM-CSF Enhances the Immune Response against Rabies Virus

    Directory of Open Access Journals (Sweden)

    Hongtao Kang

    2015-03-01

    Full Text Available Rabies remains an important public health threat in most developing countries. To develop a more effective and safe vaccine against rabies, we have constructed a chimeric rabies virus-like particle (VLP, which containing glycoprotein (G and matrix protein (M of rabies virus (RABV Evelyn-Rokitnicki-Abelseth (ERA strain, and membrane-anchored granulocyte-macrophage colony-stimulating factor (GM-CSF, and it was named of EVLP-G. The immunogenicity and protective efficacy of EVLP-G against RABV were evaluated by intramuscular administration in a mouse model. The EVLP-G was successfully produced in insect cells by coinfection with three recombinant baculoviruses expressing G, M, and GM-CSF, respectively. The membrane-anchored GM-CSF possesses a strong adjuvant activity. More B cells and dendritic cells (DCs were recruited and/or activated in inguinal lymph nodes in mice immunized with EVLP-G. EVLP-G was found to induce a significantly increased RABV-specific virus-neutralizing antibody and elicit a larger and broader antibody subclass responses compared with the standard rabies VLP (sRVLP, consisting of G and M. The EVLP-G also elicited significantly more IFN-γ- or IL-4-secreting CD4+ and CD8+ T cells than the sRVLP. Moreover, the immune responses induced by EVLP-G protect all vaccinated mice from lethal challenge with RABV. These results suggest that EVLP-G has the potential to be developed as a novel vaccine candidate for the prevention and control of animal rabies.

  1. Immune-enhancing effects of Taishan Pinus massoniana pollen polysaccharides on DNA vaccine expressing Bordetella avium ompA

    Directory of Open Access Journals (Sweden)

    Fujie eZhu

    2016-02-01

    Full Text Available Bordetella avium is the causative agent of bordetellosis, which remains to be the cause of severe losses in the turkey industry. Given the lack of vaccines that can provide good protection, developing a novel vaccine against B. avium infection is crucial. In this study, we constructed a eukaryotic expression plasmid, which expressed the outer membrane protein A (ompA of B. avium, to prepare a B. avium recombinant ompA-DNA vaccine. Three concentrations (low, middle, and high of Taishan Pinus massoniana pollen polysaccharides (TPPPS, a known immunomodulator, were used as adjuvants, and their immune conditioning effects on the developed DNA vaccine were examined. The pure ompA-DNA vaccine, Freund's incomplete adjuvant ompA-DNA vaccine, and the empty plasmid served as the controls. The chickens in each group were separately inoculated with these vaccines three times at 1, 7 and 14 days old. Dynamic changes in antibody production, cytokine secretion, and lymphocyte count were then determined from 7 days to 49 days after the first inoculation. Protective rates of the vaccines were also determined after the third inoculation. Results showed that the pure DNA vaccine obviously induced the production of antibodies, the secretion of cytokines, and the increase in CD4+ and CD8+ T lymphocyte counts in peripheral blood, as well as provided a protective rate of 50% to the B. avium-challenged chickens. The chickens inoculated with the TPPPS adjuvant ompA-DNA vaccine and Freund’s adjuvant ompA-DNA vaccine demonstrated higher levels of immune responses than those inoculated with pure ompA-DNA vaccine, whereas only the ompA-DNA vaccine with 200 mg/mL TPPPS completely protected the chickens against B. avium infection. These findings indicate that the B. avium ompA-DNA vaccine combined with TPPPS is a potentially effective B. avium vaccine.

  2. Dietary administration of Bacillus subtilis HAINUP40 enhances growth, digestive enzyme activities, innate immune responses and disease resistance of tilapia, Oreochromis niloticus.

    Science.gov (United States)

    Liu, Haitian; Wang, Shifeng; Cai, Yan; Guo, Xiaohui; Cao, Zhenjie; Zhang, Yongzheng; Liu, Shubin; Yuan, Wei; Zhu, Weiwei; Zheng, Yu; Xie, Zhenyu; Guo, Weiliang; Zhou, Yongcan

    2017-01-01

    The probiotic properties of Bacillus subtilis HAINUP40 isolated from the aquatic environment, and the effects of dietary administration of B. subtilis HAINUP40 on the growth performance, intestinal probiotic recovery, digestive enzyme activities, innate immunity and disease resistance of tilapia (Oreochromis niloticus) were evaluated. The probiotic properties investigated include tolerance to simulated gastrointestinal stress, auto-aggregation, cell surface hydrophobicity and extracellular enzyme production. The cell number of B. subtilis changed little after 4 h in simulated gastric fluid at pH = 2.0, 3.0, 4.0 and simulated intestinal fluid at pH = 6.8.B.subtilis HAINUP40 revealed strong auto-aggregation property (34.6-87.0%) after 24 h incubation period. It exhibited significant cell surface hydrophobicity in xylene (28.8%) and chloroform (41.3%) and produced extracellular proteases and amylase. After tilapia (mean weight = 95 ± 8 g) were fed with a diet containing 10 8  cfu/g B. subtilis HAINUP40, their final body weight, percent weight gain (PWG), specific growth rate (SGR), total antioxidant capacity (T-AOC) and serum superoxide dismutase (SOD) increased significantly (p subtilis HAINUP40 can effectively enhances the growth performance, immune response, and disease resistance of Nile tilapia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Regulation of IgE antibody production by serum molecules. I. Serum from complete Freund's adjuvant-immune donors suppresses irradiation-enhanced IgE production in low responder mouse strains

    Energy Technology Data Exchange (ETDEWEB)

    Tung, A.S.; Chiorazzi, N.; Katz, D.H.

    1978-06-01

    Exposure of mice to low doses of x irradiation at or near the time of primary immunization with 2,4-dinitrophenyl (DNP)-Ascaris suum extract (ASC) results in substantial enhancement of IgE anti-DNP antibody responses; the IgG antibody responses of such mice do not increase after such manipulations. This selective enhancement of IgE antibody production occurs in mice of both high and low IgE responder phenotype, although the extent of enhancement compared to unmanipulated control animals is more striking in low IgE responder mice. The studies presented here demonstrate that the irradiation-enhanced IgE antibody responses of low responder SJL and C57BL/6 mice as well as of intermediate responder AKR mice can be effectively suppressed by passive transfer of CFA-immune serum obtained from isologous donor mice. Moreover, adoptive secondary IgE antibody responses in SJL recipients of primed syngeneic spleen cells can be totally abolished by passive transfer of CFA-immune serum or ascitic fluid from CFA-immune mice. The suppressive activity of CFA-immune serum can be diminished or eliminated by exposure of CFA-primed donor mice to low dose x irradiation at an appropriate point during the priming regimen, after a single inoculation of CFA, and before collection of serum. Low dose x irradiation was not effective in eliminating suppressive activity of CFA-induced ascites fluid obtained from donor mice inoculated repeatedly with CFA. In contrast to the capacity of CFA-immune serum from isologous donors to suppress irradiation-enhanced IgE responses of low responder mice, similar sera or ascites fluids were ineffective in suppressing irradiation-enhanced responses of high responder BALB/c or (SJL x BALB/c)F/sub 1/ hybrid mice.

  4. Induction of innate immunity by Apergillus fumigatus cell wall polysaccharides is enhanced by the composite presentation of chitin and beta-glucan

    DEFF Research Database (Denmark)

    Dubey, L. K.; Moeller, J. B.; Schlosser, A.

    2014-01-01

    Chitin and beta-glucan are conserved throughout evolution in the fungal cell wall and are the most common polysaccharides in fungal species. Together, these two polysaccharides form a structural scaffold that is essential for the survival of the fungus. In the present study, we demonstrated...... that Aspergillus fumigatus alkali-insoluble cell wall fragments (AIF), composed of chitin linked covalently to beta-glucan, induced enhanced immune responses when compared with individual cell wall polysaccharides. Intranasal administration of AIF induced eosinophil and neutrophil recruitment, chitinase activity......, TNF-alpha and TSLP production in mice lungs. Selective destruction of chitin or beta-glucan from AIF significantly reduced eosinophil and neutrophil recruitment as well as chitinase activity and cytokine expression by macrophages, indicating the synergistic effect of the cell wall polysaccharides when...

  5. Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

    Science.gov (United States)

    Kuramitsu, S; Ohno, M; Ohka, F; Shiina, S; Yamamichi, A; Kato, A; Tanahashi, K; Motomura, K; Kondo, G; Kurimoto, M; Senga, T; Wakabayashi, T; Natsume, A

    2015-10-01

    The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

  6. Immunological changes in human immunodeficiency virus (HIV)-infected individuals during HIV-specific protease inhibitor treatment

    DEFF Research Database (Denmark)

    Ullum, H; Katzenstein, T; Aladdin, H

    1999-01-01

    The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment...... Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed...... count increased mainly due to increases in numbers of CD4+ CD28+ and CD4+ CD45RO+ cells, whereas increases in numbers of CD4+ CD45RA+ cells contributed little to the increase in CD4+ cell count. The total cytotoxic T-cell (CTL) killing of autologous B cells infected with HIV-encoding recombinant...

  7. Immunological changes in human immunodeficiency virus (HIV)-infected individuals during HIV-specific protease inhibitor treatment

    DEFF Research Database (Denmark)

    Ullum, H; Katzenstein, T; Aladdin, H

    1999-01-01

    Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed......The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment...... including a protease inhibitor. Unstimulated and pokeweed mitogen (PWM)-, interleukin (IL)-2- and phytohaemagglutinin (PHA)-stimulated lymphocyte proliferative responses increased during follow-up reaching average levels from 1.3-fold (PHA) to 3.7-fold (PWM) above baseline values. The total CD4+ lymphocyte...

  8. Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection.

    Science.gov (United States)

    Vijayan, Madhuvanthi; Xia, Chuan; Song, Yul Eum; Ngo, Hanh; Studstill, Caleb J; Drews, Kelly; Fox, Todd E; Johnson, Marc C; Hiscott, John; Kester, Mark; Alexander, Stephen; Hahm, Bumsuk

    2017-07-15

    Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however, the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I IFN-mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to influenza A virus infection. In support of this, SPL-deficient cells were defective in mounting an effective IFN response when stimulated by influenza viral RNAs. SPL augmented the activation status of IKKε and enhanced the kinase-induced phosphorylation of IRF3 and the synthesis of type I IFNs. However, the S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL's pro-IFN function is independent of S1P. Biochemical analyses revealed that SPL, as well as the mutant form of SPL, interacts with IKKε. Importantly, when endogenous IKKε was downregulated using a small interfering RNA approach, SPL's anti-influenza viral activity was markedly suppressed. This indicates that IKKε is crucial for SPL-mediated inhibition of influenza virus replication. Thus, the results illustrate the functional significance of the SPL-IKKε-IFN axis during host innate immunity against viral infection. Copyright © 2017 by The American Association of Immunologists, Inc.

  9. Sequential Immune Responses: The Weapons of Immunity.

    Science.gov (United States)

    Mills, Charles D; Ley, Klaus; Buchmann, Kurt; Canton, Johnathan

    2015-01-01

    Sequential immune responses (SIR) is a new model that describes what 'immunity' means in higher animals. Existing models, such as self/nonself discrimination or danger, focus on how immune responses are initiated. However, initiation is not protection. SIR describes the actual immune responses that provide protection. SIR resulted from a comprehensive analysis of the evolution of immune systems that revealed that several very different types of host innate responses occur (and at different tempos) which together provide host protection. SIR1 uses rapidly activated enzymes like the NADPH oxidases and is present in all animal cells. SIR2 is mediated by the first 'immune' cells: macrophage-like cells. SIR3 evolved in animals like invertebrates and provides enhanced protection through advanced macrophage recognition and killing of pathogens and through other innate immune cells such as neutrophils. Finally, in vertebrates, macrophages developed SIR4: the ability to present antigens to T cells. Though much slower than SIR1-3, adaptive responses provide a unique new protection for higher vertebrates. Importantly, newer SIR responses were added on top of older, evolutionarily conserved functions to provide 'layers' of host protection. SIR transcends existing models by elucidating the different weapons of immunity that provide host protection in higher animals. © 2015 S. Karger AG, Basel.

  10. Carpobrotus edulis methanol extract inhibits the MDR efflux pumps, enhances killing of phagocytosed S. aureus and promotes immune modulation.

    Science.gov (United States)

    Ordway, Diane; Hohmann, Judit; Viveiros, Miguel; Viveiros, Antonio; Molnar, Joseph; Leandro, Clara; Arroz, Maria Jorge; Gracio, Maria Amelia; Amaral, Leonard

    2003-05-01

    Although alkaloids from the family Aizoaceae have anticancer activity, species of this family have received little attention. Because these alkaloids also exhibit properties normally associated with compounds that have activity at the level of the plasma membrane, a methanol extract of Carpobrotus edulis, a common plant found along the Portuguese coast, was studied for properties normally associated with plasma membrane active compounds. The results of this study show that the extract is non-toxic at concentrations that inhibit a verapamil sensitive efflux pump of L5178 mouse T cell lymphoma cell line thereby rendering these multi-drug resistant cells susceptible to anticancer drugs. These non-toxic concentrations also prime THP-1 human monocyte-derived macrophages to kill ingested Staphylococcus aureus and to promote the release of lymphokines associated with cellular immune functions. The extract also induces the proliferation of THP-1 cells within 1 day of exposure to quantities normally associated with phytohaemagglutinin. The potential role of the compound(s) isolated from this plant in cancer biology is intriguing and is currently under investigation. It is supposed that the resistance modifier and immunomodulatory effect of this plant extract can be exploited in the experimental chemotherapy of cancer and bacterial or viral infections. Copyright 2003 John Wiley & Sons, Ltd.

  11. A BCR/ABL-hIL-2 DNA Vaccine Enhances the Immune Responses in BALB/c Mice

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    Yanan Qin

    2013-01-01

    Full Text Available The use of a DNA vaccine encoding the BCR/ABL fusion gene is thought to be a promising approach for patients with chronic myeloid leukemia (CML to eradicate minimal residual disease after treatment with chemotherapy or targeted therapy. In this study, our strategy employs genetic technology to create a DNA vaccine encoding the BCR/ABL fusion and human interleukin-2 (hIL-2 genes. The successfully constructed plasmids BCR/ABL-pIRES-hIL-2, BCR/ABL-pIRES, and pIRES-hIL-2 were delivered intramuscularly to BALB/c mice at 14-day intervals for three cycles. The transcription and expression of the BCR/ABL and hIL-2 genes were found in the injected muscle tissues. The interferon-γ (IFN-γ serum levels were increased, and the splenic CD4+/CD8+ T cell ratio was significantly decreased in the BCR/ABL-pIRES-hIL-2-injected mice. Furthermore, specific antibodies against K562 cells could be detected by indirect immunofluorescence. These results indicate that a DNA vaccine containing BCR/ABL and hIL-2 together may elicit increased in vivo humoral and cellular immune responses in BALB/c mice.

  12. Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers.

    Science.gov (United States)

    Hua, Stéphane; Lécuroux, Camille; Sáez-Cirión, Asier; Pancino, Gianfranco; Girault, Isabelle; Versmisse, Pierre; Boufassa, Faroudy; Taulera, Olivier; Sinet, Martine; Lambotte, Olivier; Venet, Alain

    2014-01-01

    HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. We compared CD38-/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. Compared to CD38+/HLA-DR+ cells, CD38-/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134-462] vs 638 [307-747], P = 0.001), higher frequency of polyfunctional cells (15% [7%-33%] vs 21% [16%-43%], P = 0.0003), greater proliferative capacity (0-fold [0-2] vs 3-fold [2]-[11], P = 0.007), and higher cytotoxicity in vitro (7% [3%-11%] vs 13% [6%-22%], P = 0.02). The CD38-/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. These data highlight the role of CD38-/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.

  13. Potential Role for HIV-Specific CD38−/HLA-DR+ CD8+ T Cells in Viral Suppression and Cytotoxicity in HIV Controllers

    Science.gov (United States)

    Hua, Stéphane; Lécuroux, Camille; Sáez-Cirión, Asier; Pancino, Gianfranco; Girault, Isabelle; Versmisse, Pierre; Boufassa, Faroudy; Taulera, Olivier; Sinet, Martine; Lambotte, Olivier; Venet, Alain

    2014-01-01

    Background HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38−/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. Materials and Methods We compared CD38−/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. Results Compared to CD38+/HLA-DR+ cells, CD38−/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134–462] vs 638 [307–747], P = 0.001), higher frequency of polyfunctional cells (15% [7%–33%] vs 21% [16%–43%], P = 0.0003), greater proliferative capacity (0-fold [0–2] vs 3-fold [2]–[11], P = 0.007), and higher cytotoxicity in vitro (7% [3%–11%] vs 13% [6%–22%], P = 0.02). The CD38−/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. Conclusions These data highlight the role of CD38−/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies. PMID:25000587

  14. Enhancement of the immune response and protection against Vibrio parahaemolyticus by indigenous probiotic Bacillus strains in mud crab (Scylla paramamosain).

    Science.gov (United States)

    Wu, Hui-Juan; Sun, Ling-Bin; Li, Chuan-Biao; Li, Zhong-Zhen; Zhang, Zhao; Wen, Xiao-Bo; Hu, Zhong; Zhang, Yue-Ling; Li, Sheng-Kang

    2014-12-01

    In a previous study, bacterial communities of the intestine in three populations of crabs (wild crabs, pond-raised healthy crabs and diseased crabs) were probed by culture-independent methods. In this study, we examined the intestinal communities of the crabs by bacterial cultivation with a variety of media. A total of 135 bacterial strains were isolated from three populations of mud crabs. The strains were screened for antagonistic activity against Vibrio parahaemolyticus using an agar spot assay. Antagonistic strains were then identified by 16S rRNA gene sequence analysis. Three strains (Bacillus subtilis DCU, Bacillus pumilus BP, Bacillus cereus HL7) with the strongest antagonistic activity were further evaluated for their probiotic characteristics. The results showed that two (BP and DCU) of them were able to survive low pH and high bile concentrations, showed good adherence characteristics and a broad spectrum of antibiotic resistance. The probiotic effects were then tested by feeding juvenile mud crabs (Scylla paramamosain) with foods supplemented with 10(5) CFU/g of BP or DCU for 30 days before being subjected to an immersion challenge with V. parahaemolyticus for 48 h. The treated crabs showed significantly higher expression levels of immune related genes (CAT, proPO and SOD) and activities of respiratory burst than that in controlled groups. Crabs treated with BP and DCU supplemented diets exhibited survival rates of 76.67% and 78.33%, respectively, whereas survival rate was 54.88% in crabs not treated with the probiotics. The data showed that indigenous mud-associated microbiota, such as DCU and BP, have potential application in controlling pathogenic Vibriosis in mud crab aquaculture. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Benny J Chen

    Full Text Available Medications that can mitigate against radiation injury are limited. In this study, we investigated the ability of recombinant human growth hormone (rhGH to mitigate against radiation injury in mice and nonhuman primates. BALB/c mice were irradiated with 7.5 Gy and treated post-irradiation with rhGH intravenously at a once daily dose of 20 microg/dose for 35 days. rhGH protected 17 out of 28 mice (60.7% from lethal irradiation while only 3 out of 28 mice (10.7% survived in the saline control group. A shorter course of 5 days of rhGH post-irradiation produced similar results. Compared with the saline control group, treatment with rhGH on irradiated BALB/c mice significantly accelerated overall hematopoietic recovery. Specifically, the recovery of total white cells, CD4 and CD8 T cell subsets, B cells, NK cells and especially platelets post radiation exposure were significantly accelerated in the rhGH-treated mice. Moreover, treatment with rhGH increased the frequency of hematopoietic stem/progenitor cells as measured by flow cytometry and colony forming unit assays in bone marrow harvested at day 14 after irradiation, suggesting the effects of rhGH are at the hematopoietic stem/progenitor level. rhGH mediated the hematopoietic effects primarily through their niches. Similar data with rhGH were also observed following 2 Gy sublethal irradiation of nonhuman primates. Our data demonstrate that rhGH promotes hematopoietic engraftment and immune recovery post the exposure of ionizing radiation and mitigates against the mortality from lethal irradiation even when administered after exposure.

  16. Experimental food allergy to peanut enhances the immune response to house dust mite in the airways of mice.

    Science.gov (United States)

    Utsch, L; Logiantara, A; van Ree, R; van Rijt, L S

    2017-01-01

    Food allergy has been associated with an increased risk for the development of allergic asthma. Asthma is a risk factor for the development of an anaphylactic response to food allergens. An immunological interplay between sensitization to different allergens in different compartments of the body might be involved. To evaluate the immunological interplay between intragastrical peanut (PE) sensitization and respiratory sensitization to house dust mite (HDM) allergens. BALB/c mice were intragastrically sensitized to peanut or sham-sensitized and challenged systemically to PE. Between sensitization and challenge, mice were intranasally exposed to HDM extract or PBS, as a control. The response to HDM (eosinophil recruitment, cytokine response, HDM-specific immunoglobulins and airway hyper-reactivity) and to PE (cytokine response, mast cells in gut, mMCP-1 in serum and body temperature) was assessed. A preceding PE sensitization increased HDM-induced production of IL-4, IL-5, IL-13 and IFNγ in lung-draining lymph nodes and total IgE levels in HDM-sensitized mice. However, recruitment of inflammatory cells to the airways or airway hyper-reactivity was not aggravated in PE/HDM double-sensitized mice. Alternatively, HDM-induced airway inflammation did not significantly affect the immune response or the anaphylactic response to a systemic challenge with peanut. Our data show that a preceding peanut sensitization boosted IgE- and HDM-specific Th2 response in the airways in mice. It contributes to the understanding of the underlying immunological mechanism of polysensitization which often occurs in allergic individuals over time. © 2016 John Wiley & Sons Ltd.

  17. Modification of cytokine-induced killer cells with chimeric antigen receptors (CARs) enhances antitumor immunity to epidermal growth factor receptor (EGFR)-positive malignancies.

    Science.gov (United States)

    Ren, Xuequn; Ma, Wanli; Lu, Hong; Yuan, Lei; An, Lei; Wang, Xicai; Cheng, Guanchang; Zuo, Shuguang

    2015-12-01

    Epidermal growth factor receptor (EGFR, ErbB1, Her-1) is a cell surface molecule overexpressing in a variety of human malignancies and, thus, is an excellent target for immunotherapy. Immunotherapy targeting EGFR-overexpressing malignancies using genetically modified immune effector cells is a novel and promising approach. In the present study, we have developed an adoptive cellular immunotherapy strategy based on the chimeric antigen receptor (CAR)-modified cytokine-induced killer (CAR-CIK) cells specific for the tumor cells expressing EGFR. To generate CAR-CIK cells, a lentiviral vector coding the EGFR-specific CAR was constructed and transduced into the CIK cells. The CAR-CIK cells showed significantly enhanced cytotoxicity and increased production of cytokines IFN-γ and IL-2 when co-cultured with EGFR-positive cancer cells. In tumor xenografts, adoptive immunotherapy of CAR-CIK cells could inhibit tumor growth and prolong the survival of EGFR-overexpressing human tumor xenografts. Moreover, tumor growth inhibition and prolonged survival in mice with EGFR(+) human cancer were associated with the increased persistence of CAR-CIK cells in vivo. Our study indicates that modification with EGFR-specific CAR strongly enhances the antitumor activity of the CIK cells against EGFR-positive malignancies.

  18. Enhancement of antitumor immune response by targeted interleukin-12 electrogene transfer through antiHER2 single-chain antibody in a murine bladder tumor model.

    Science.gov (United States)

    Tsai, Yuh-Shyan; Shiau, Ai-Li; Chen, Yu-Fon; Tsai, Hsin-Tzu; Lee, Hwei-Ling; Tzai, Tzong-Shin; Wu, Chao-Liang

    2009-08-27

    Interleukin-12 (IL-12), despite exerting antitumor activity, has limited therapeutic uses due to its systemic toxicity. Since HER2 (also known as ErbB-2, neu, and HER2/neu) is frequently overexpressed on cancer cells, HER2-targeted delivery of IL-12 to tumors may be a promising strategy for enhancing antitumor immunity. Here we showed that intramuscular electrogene transfer of an expression vector encoding a fusion protein antiHER2scFv-IL12, which consists of antiHER2 single-chain variable fragment (scFv) and single-chain IL-12, significantly retarded tumor growth and prolonged the survival in a syngeneic bladder tumor model. Elevated IL-12 and interferon-gamma (IFN-gamma) levels, increased infiltration of CD4(+) and CD8(+) T cells, and reduced vascular endothelial growth factor (VEGF) expression in the tumors, as well as enhanced cytolytic activity of splenocytes were noted in the treated mice. Our results suggest that this approach may be effective for the treatment of HER2-overexpressing tumors.

  19. Using immunoadjuvant agent glycated chitosan to enhance anti-cancer stem like cell immunity induced by HIFU

    Science.gov (United States)

    Chen, Y.-L.; Chen, W.-R.; Liu, R.-S.; Yang, F.-Y.; Wang, C.-Y.; Lee, Y.-J.

    2013-02-01

    Thermal therapy is based on the observation that tumor cells are sensitive to increased temperature, which is important for tumor control. In this study, the high intensity focused ultrasound (HIFU) system was used to simulate thermal therapy on breast cancer control in the small animal model. Additionally, the immunoadjuvant agent, so called glycated chitosan (GC), was used to enhance the immunological effects on tumor control. The bioluminescent imaging showed that tumor metastasis was apparently suppressed by a combined treatment using HIFU and GC, but not in HIFU or GC alone. Using immunohistochemical (IHC) staining, lung metastasis of 4T1-3R tumor cells further agree the observations obtained from non-invasive in vivo imaging. We also found that plasma collected from mice treated with combined HIFU and GC could significantly suppress the viability of cultured 4T1 cells compared to untreated or single treated group. In summary, these results suggest that the HIFU therapy combined with GC can enhance the tumor immunogenicity and tumor control.

  20. Noise-immune cavity-enhanced analytical atomic spectrometry — NICE-AAS — A technique for detection of elements down to zeptogram amounts

    Energy Technology Data Exchange (ETDEWEB)

    Axner, Ove, E-mail: ove.axner@physics.umu.se; Ehlers, Patrick, E-mail: patrick.ehlers@physics.umu.se; Hausmaninger, Thomas, E-mail: thomas.hausmaninger@physics.umu.se; Silander, Isak, E-mail: isak.silander@physics.umu.se; Ma, Weiguang, E-mail: weiguang.ma@physics.umu.se

    2014-10-01

    Noise-immune cavity-enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) is a powerful technique for detection of molecular compounds in gas phase that is based on a combination of two important concepts: frequency modulation spectroscopy (FMS) for reduction of noise, and cavity enhancement, for prolongation of the interaction length between the light and the sample. Due to its unique properties, it has demonstrated unparalleled detection sensitivity when it comes to detection of molecular constituents in the gas phase. However, despite these, it has so far not been used for detection of atoms, i.e. for elemental analysis. The present work presents an assessment of the expected performance of Doppler-broadened (Db) NICE-OHMS for analytical atomic spectrometry, then referred to as noise-immune cavity-enhanced analytical atomic spectrometry (NICE-AAS). After a description of the basic principles of Db-NICE-OHMS, the modulation and detection conditions for optimum performance are identified. Based on a previous demonstrated detection sensitivity of Db-NICE-OHMS of 5 × 10{sup −12} cm{sup −1} Hz{sup −1∕2} (corresponding to a single-pass absorbance of 7 × 10{sup −11} over 10 s), the expected limits of detection (LODs) of Hg and Na by NICE-AAS are estimated. Hg is assumed to be detected in gas phase directly while Na is considered to be atomized in a graphite furnace (GF) prior to detection. It is shown that in the absence of spectral interferences, contaminated sample compartments, and optical saturation, it should be feasible to detect Hg down to 10 zg/cm{sup 3} (10 fg/m{sup 3} or 10{sup −5} ng/m{sup 3}), which corresponds to 25 atoms/cm{sup 3}, and Na down to 0.5 zg (zg = zeptogram = 10{sup −21} g), representing 50 zg/mL (parts-per-sextillion, pps, 1:10{sup 21}) in liquid solution (assuming a sample of 10 μL) or solely 15 atoms injected into the GF, respectively. These LODs are several orders of magnitude lower (better) than any previous

  1. Enhancement of Th1-biased protective immunity against avian influenza H9N2 virus via oral co-administration of attenuated Salmonella enterica serovar Typhimurium expressing chicken interferon-α and interleukin-18 along with an inactivated vaccine

    Directory of Open Access Journals (Sweden)

    Rahman Md

    2012-07-01

    Full Text Available Abstract Background Control of currently circulating re-assorted low-pathogenicity avian influenza (LPAI H9N2 is a major concern for both animal and human health. Thus, an improved LPAI H9N2 vaccination strategy is needed to induce complete immunity in chickens against LPAI H9N2 virus strains. Cytokines play a crucial role in mounting both the type and extent of an immune response generated following infection with a pathogen or after vaccination. To improve the efficacy of inactivated LPAI H9N2 vaccine, attenuated Salmonella enterica serovar Typhimurium was used for oral co-administration of chicken interferon-α (chIFN-α and chicken interleukin-18 (chIL-18 as natural immunomodulators. Results Oral co-administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18, prior to vaccination with inactivated AI H9N2 vaccine, modulated the immune response of chickens against the vaccine antigen through enhanced humoral and Th1-biased cell-mediated immunity, compared to chickens that received single administration of S. enterica serovar Typhimurium expressing either chIFN-α or chIL-18. To further test the protective efficacy of this improved vaccination regimen, immunized chickens were intra-tracheally challenged with a high dose of LPAI H9N2 virus. Combined administration of S. enterica serovar Typhimurium expressing chIFN-α and chIL-18 showed markedly enhanced protection compared to single administration of the construct, as determined by mortality, clinical severity, and feed and water intake. This enhancement of protective immunity was further confirmed by reduced rectal shedding and replication of AIV H9N2 in different tissues of challenged chickens. Conclusions Our results indicate the value of combined administration of chIFN-α and chIL-18 using a Salmonella vaccine strain to generate an effective immunization strategy in chickens against LPAI H9N2.

  2. Transient human anti-mouse antibody generated with immune enhancement in a carbohydrate antigen 19-9 immunoassay after surgical resection of recurrent cancer.

    Science.gov (United States)

    Nakano, Keiichi; Yasuda, Keiko; Shibuya, Hitoshi; Moriyama, Takanori; Kahata, Kaoru; Shimizu, Chikara

    2016-07-01

    We report a case of transient human anti-mouse antibody from a 64-year-old man in a carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser that generated immune enhancement after surgical resection of recurrent cancer. The carbohydrate antigen 19-9 concentration was measured using an AIA 1800 analyser and a UniCel Dxl 800. Size-exclusion high-performance liquid chromatography was carried out on a Superose 12 column to estimate the carbohydrate antigen 19-9 elution profile using an AIA 1800 analyser. To determine whether IgM in the patient contributed to the carbohydrate antigen 19-9 immunoassay, immunoprecipitation was performed. Furthermore, mouse immunoglobulins were added to the patient's serum to verify that the patient's IgM reacted with it. The carbohydrate antigen 19-9 concentration was >400 and 9.5 kU/L using an AIA 1800 analyser and using a UniCel Dxl 800, respectively. In the single carbohydrate antigen 19-9 peak, the molecular weight corresponded to IgM by size-exclusion high-performance liquid chromatography on a Superose 12 column. In the immunoprecipitation reaction and addition of mouse immunoglobulins, there was interference for anti-human IgM and mouse immunoglobulins whose recoveries were 3.2 and 14.2%, respectively. These results indicated that IgM in the patient's serum interfered with the carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser. A novel transient human anti-mouse antibody generated with immune activation in a carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser was identified in a patient with rectal cancer after surgical resection. These findings demonstrate the importance of monitoring tumour markers in patients after treatment with mouse monoclonal antibody. © The Author(s) 2016.

  3. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

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    Varun C Anipindi

    2016-05-01

    Full Text Available Clinical and experimental studies have shown that estradiol (E2 confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

  4. Heat-killed Lactobacillus gasseri can enhance immunity in the elderly in a double-blind, placebo-controlled clinical study.

    Science.gov (United States)

    Miyazawa, K; Kawase, M; Kubota, A; Yoda, K; Harata, G; Hosoda, M; He, F

    2015-01-01

    This double-blind, placebo-controlled clinical trial was conducted to test whether Lactobacillus gasseri TMC0356 (TMC0356) can modify the immune response in the elderly. Heat-killed TMC0356 or placebo was orally administered to 28 healthy subjects aged 50-70 years old for 4 weeks at a dosage of 1.0×10(9) cfu/day. Peripheral blood mononuclear cells (PBMCs) were collected from the subjects before and after the study completion, together with general health and blood examination records. Isolated PBMCs were examined for the number of T cells, CD8(+)CD28(+) cells, native T cells, B cells, natural killer (NK) cells and the ratios of CD4/CD8 T cells and native/memory T cells. NK cell activation and concanavalin A-induced lymphocyte transformation of the isolated PBMCs were also examined. The number of CD8(+) T cells significantly increased in the subjects after TMC0356 oral administration (P<0.05). Furthermore, the population of CD8(+)CD28(+) T cells and the amount of lymphocyte transformation both significantly decreased in PBMCs from the placebo group (P<0.05). However, such changes were not observed in the subjects exposed to TMC0356. These results suggest that TMC0356 can increase the number of CD8(+) T cells and reduce CD28 expression loss in CD8(+) T cells of the elderly. The effect of TMC0356 on immune responses in the elderly may enhance their natural defence mechanisms against pathogenic infections.

  5. Modulation of Trehalose Dimycolate and Immune System by Rv0774c Protein Enhanced the Intracellular Survival of Mycobacterium smegmatis in Human Macrophages Cell Line

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    Arbind Kumar

    2017-06-01

    Full Text Available Mycobacterium tuberculosis Rv0774c protein was reported previously to express under stress conditions. Therefore, Rv0774c gene was cloned and expressed in Mycobacterium smegmatis, a surrogate host, to determine its role in bacterial persistence and immune modulation in natural environment. The bacterial colonies expressing Rv0774c (Ms_rv0774c were larger, smoother, more moist, and flatter than the control ones (Ms_ve. Enhanced survival of Ms_rv0774c after treatment with streptomycin was observed when compared with control. The cell envelope of Ms_rv0774c was demonstrated to have more trehalose di-mycolate (TDM and lesser amount of mycolylmannosylphosphorylheptaprenol (Myc-PL in comparison to control. Higher intracellular survival rate was observed for Ms_rv0774c as compared to Ms_ve in the THP-1 cells. This could be correlated to the reduction in the levels of reactive NO and iNOS expression. Infection of macrophages with Ms_rv0774c resulted in significantly increased expression of TLR2 receptor and IL-10 cytokines. However, it lowered the production of pro-inflammatory cytokines such as IL-12, TNF-α, IFN-γ, and MCP-1 in Ms_rv0774c infected macrophages in comparison to the control and could be associated with decreased phosphorylation of p38 MAPK. Though, predicted with high antigenicity index bioinformatically, extracellular in nature and accessible to host milieu, Rv0774c was not able to generate humoral response in patient samples. Overall, the present findings indicated that Rv0774c altered the morphology and streptomycin sensitivity by altering the lipid composition of M. smegmatis as well as modulated the immune response in favor of bacterial persistence.

  6. ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia.

    Directory of Open Access Journals (Sweden)

    Benjamin Bondue

    2011-11-01

    Full Text Available Viral diseases of the respiratory tract, which include influenza pandemic, children acute bronchiolitis, and viral pneumonia of the elderly, represent major health problems. Plasmacytoid dendritic cells play an important role in anti-viral immunity, and these cells were recently shown to express ChemR23, the receptor for the chemoattractant protein chemerin, which is expressed by epithelial cells in the lung. Our aim was to determine the role played by the chemerin/ChemR23 system in the physiopathology of viral pneumonia, using the pneumonia virus of mice (PVM as a model. Wild-type and ChemR23 knock-out mice were infected by PVM and followed for functional and inflammatory parameters. ChemR23(-/- mice displayed higher mortality/morbidity, alteration of lung function, delayed viral clearance and increased neutrophilic infiltration. We demonstrated in these mice a lower recruitment of plasmacytoid dendritic cells and a reduction in type I interferon production. The role of plasmacytoid dendritic cells was further addressed by performing depletion and adoptive transfer experiments as well as by the generation of chimeric mice, demonstrating two opposite effects of the chemerin/ChemR23 system. First, the ChemR23-dependent recruitment of plasmacytoid dendritic cells contributes to adaptive immune responses and viral clearance, but also enhances the inflammatory response. Second, increased morbidity/mortality in ChemR23(-/- mice is not due to defective plasmacytoid dendritic cells recruitment, but rather to the loss of an anti-inflammatory pathway involving ChemR23 expressed by non-leukocytic cells. The chemerin/ChemR23 system plays important roles in the physiopathology of viral pneumonia, and might therefore be considered as a therapeutic target for anti-viral and anti-inflammatory therapies.

  7. Integrated Immune

    Science.gov (United States)

    Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarnece

    2010-01-01

    This slide presentation reviews the program to replace several recent studies about astronaut immune systems with one comprehensive study that will include in-flight sampling. The study will address lack of in-flight data to determine the inflight status of immune systems, physiological stress, viral immunity, to determine the clinical risk related to immune dysregulation for exploration class spaceflight, and to determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

  8. Enrichment of sialylated IgG by lectin fractionation does not enhance the efficacy of immunoglobulin G in a murine model of immune thrombocytopenia

    NARCIS (Netherlands)

    Guhr, T.; Bloem, J.; Derksen, N.I.L.; Wuhrer, M.; Koenderman, A.H.L.; Aalberse, R.C.; Rispens, T.

    2011-01-01

    Intravenous immunoglobulin G (IVIg) is widely used against a range of clinical symptoms. For its use in immune modulating therapies such as treatment of immune thrombocytopenic purpura high doses of IVIg are required. It has been suggested that only a fraction of IVIg causes this anti immune

  9. Immune enhancement by novel vaccine adjuvants in autoimmune-prone NZB/W F1 mice: relative efficacy and safety

    Directory of Open Access Journals (Sweden)

    Ghosh Swapan K

    2011-10-01

    Full Text Available Abstract Background Vaccines have profoundly impacted global health although concerns persist about their potential role in autoimmune or other adverse reactions. To address these concerns, vaccine components like immunogens and adjuvants require critical evaluation not only in healthy subjects but also in those genetically averse to vaccine constituents. Evaluation in autoimmune-prone animal models of adjuvants is therefore important in vaccine development. The objective here was to assess the effectiveness of experimental adjuvants: two phytol-derived immunostimulants PHIS-01 (phytanol and PHIS-03 (phytanyl mannose, and a new commercial adjuvant from porcine small intestinal submucosa (SIS-H, relative to a standard adjuvant alum. Phytol derivatives are hydrophobic, oil-in water diterpenoids, while alum is hydrophilic, and SIS is essentially a biodegradable and collagenous protein cocktail derived from extracellular matrices. Results We studied phthalate -specific and cross-reactive anti-DNA antibody responses, and parameters associated with the onset of autoimmune disorders. We determined antibody isotype and cytokine/chemokine milieu induced by the above experimental adjuvants relative to alum. Our results indicated that the phytol-derived adjuvant PHIS-01 exceeded alum in enhancing anti-phthalate antibody without much cross reactivity with ds-DNA. Relatively, SIS and PHIS-03 proved less robust, but they were also less inflammatory. Interestingly, these adjuvants facilitated isotype switching of anti-hapten, but not of anti-DNA response. The current study reaffirms our earlier reports on adjuvanticity of phytol compounds and SIS-H in non autoimmune-prone BALB/c and C57BL/6 mice. These adjuvants are as effective as alum also in autoimmune-prone NZB/WF1 mice, and they have little deleterious effects. Conclusion Although all adjuvants tested impacted cytokine/chemokine milieu in favor of Th1/Th2 balance, the phytol compounds fared better in

  10. Evolving meningococcal immunization strategies.

    Science.gov (United States)

    Sáfadi, Marco Aurélio; Bettinger, Julie A; Maturana, Gabriela Moreno; Enwere, Godwin; Borrow, Ray

    2015-04-01

    Meningococcal disease is a major public health problem and immunization is considered the best strategy for prevention. The introduction of meningococcal C conjugate immunization schedules that targeted adolescents, with catch-up programs in several European countries, Australia and Canada proved to be highly effective, with dramatic reduction in the incidence of serogroup C disease, not only in vaccinated, but also in unvaccinated individuals. Meningococcal quadrivalent (A, C, W, Y) conjugate vaccines are now licensed and are being used in adolescent programs in North America and to control serogroup W disease in South America. In the African meningitis belt, a mass immunization campaign against serogroup A disease using a meningococcal A conjugate vaccine is now controlling the devastating epidemics of meningococcal disease. After introducing new immunization programs, it is of importance to maintain enhanced surveillance for a better understanding of the changing nature of disease epidemiology. This information is crucial for identifying optimal immunization policies.

  11. Ubiquitin conjugation of open reading frame F DNA vaccine leads to enhanced cell-mediated immune response and induces protection against both antimony-susceptible and -resistant strains of Leishmania donovani.

    Science.gov (United States)

    Sharma, Ankur; Madhubala, Rentala

    2009-12-15

    Resistance of Leishmania donovani to sodium antimony gluconate has become a critical issue in the current, prolonged epidemic in India. Hence, there is an urgent need for a vaccine that is protective against both antimony-susceptible and -resistant strains of L. donovani. The multigene LD1 locus located on chromosome 35 of Leishmania is amplified in approximately 15% of the isolates examined. The open reading frame F (ORFF), a potential vaccine candidate against visceral leishmaniasis, is part of the multigene LD1 locus. ORFF was expressed as a chimeric conjugate of ubiquitin to elicit an Ag-specific cell-mediated immune response. Analysis of the cellular immune responses of ubiquitin-conjugated ORFF (UBQ-ORFF) DNA-immunized, uninfected BALB/c mice demonstrated that the vaccine induced enhanced IFN-gamma-producing CD4(+) and CD8(+) T cells compared with nonubiquitinated ORFF DNA vaccine. Higher levels of IL-12 and IFN-gamma and the low levels of IL-4 and IL-10 further indicated that the immune responses with UBQ-ORFF were mediated toward the Th1 rather than Th2 type. Infection of immunized mice with either the antimony-susceptible (AG83) or -resistant (GE1F8R) L. donovani strain showed that UBQ-ORFF DNA vaccine induced higher protection when compared with ORFF DNA. UBQ-ORFF DNA-immunized and -infected mice showed a significant increase in IL-12 and IFN-gamma and significant down-regulation of IL-10. High levels of production of nitrite and superoxide, two macrophage-derived oxidants that are critical in controlling Leishmania infection, were observed in protected mice. The feasibility of using ubiquitinated-conjugated ORFF DNA vaccine as a promising immune enhancer for vaccination against both antimony-susceptible and -resistant strains of L. donovani is reported.

  12. Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG microparticles in combination with Ulex Europaeus-I lectin as M cell target.

    Science.gov (United States)

    Manocha, Monika; Pal, Pramod Chandra; Chitralekha, K T; Thomas, Beena Elizabeth; Tripathi, Vinita; Gupta, Siddhartha Dutta; Paranjape, Ramesh; Kulkarni, Smita; Rao, D Nageswara

    2005-12-01

    The predominant route of HIV infection is through the sexual transmission via M cells. Most of the peptide and protein vaccines show poor transport across the epithelial barrier and are commonly administered by parenteral route. In the present study four HIV peptides from envelope (gp 41-LZ (leucine zipper), gp 41-FD (fusion domain) and gp120-C2) and regulatory (Nef) region in poly lactic-co-glycolide (PLG) micro-particle delivery were evaluated in mice of outbred and with different genetic background to compare immune response versus MHC restriction. Out of the combinational and single routes of immunization attempted, the single route maintained the IgG, IgA and sIgA in sera and washes for longer duration as compared to combinational routes in which the response was declined. The study demonstrated that single intranasal immunization offered significantly higher immune response (pPP>or=SP. The cytokine measurement profile of IL-2, IFN-gamma and IL-6 and low levels of IL-4 in the cultural supernatants of SP, PP and LP showed mixed CD4(+) Th1 and Th2 immune response. The p24 assay showed high percent inhibition of HIV-IIIB virus with sera and washes obtained from intranasal route. Thus, overall the study highlighted the combination of UEA-1 lectin with HIV peptides in micro-particles through intranasal immunization generated systemic as well as mucosal immune response.

  13. Lineshape and Sensitivity of Spectroscopic Signals of N_2^+ in a Positive Column Collected Using Noise Immune Cavity Enhanced Optical Heterodyne Velocity Modulation Spectroscopy

    Science.gov (United States)

    Mills, Rew; Siller, Brian; Porambo, Michael; McCall, Benjamin J.

    2011-06-01

    Challenges to studying gas phase ions include the dilute analyte, Doppler line broadening, and a lack of ion/neutral discrimination. Techniques which provide high sensitivity, sub-Doppler features, and some form of ion/neutral discrimination increase the ability to study gas phase ions. Recently our group has used noise immune cavity enhanced optical heterodyne velocity modulated spectroscopy (NICE-OHVMS) to help overcome each of these challenges. Using NICE-OHMS to probe a velocity modulated positive column produces a distinctive line shape. The high optical power from and geometry of the cavity saturates optical transitions and allows sub-Doppler Lamb dips to be observed. Depending on sideband frequency (1 or 9 times the free spectral range) the sub-Doppler features are closer together or further apart. The sub-Doppler features can then be used to measure the line-centers with high (˜1 MHz) precision and accuracy using an optical frequency comb. The Kramers-Kronig relations describe how the absorption and dispersion are related to one another and can be used to obtain the absorption from the dispersion (and vice-versa). Owing to the phase dependent absorption signal produced with heterodyne spectroscopy, both absorption and dispersion signals can be obtained simultaneously. Two RF mixers (one for absorption and one for dispersion), each driving its own lock-in amplifier, are used to obtain a signal for ions and excited neutrals. We will report a comparison of the sensitivities of several absorbance techniques to study a nitrogenic velocity modulated positive column including: direct absorption, cavity enhanced velocity modulation, heterodyne spectroscopy and NICE-OHMS, and show how the signal-to-noise ratio is increased by using NICE-OHMS. Future plans for this technique include using a high power cw-OPO in the mid-IR to perform high precision vibrational spectroscopy of ions such as CH_5^+.

  14. HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and are Commonly Detected in Plasma from HIV-infected Humans

    Directory of Open Access Journals (Sweden)

    Katherine L. Williams

    2015-10-01

    Full Text Available HIV-specific antibodies (Abs can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc–FcR interaction. This latter process, referred to as antibody-dependent cellular cytotoxicity (ADCC, has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP-based sorting strategy that led to identification of HIV-specific memory B cells encoding Abs that mediate ADCC from a subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs were isolated and three mediated potent ADCC activity when compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI, which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4-induced (CD4i epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcγRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18–78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6 months of infection and they can arise from unique B

  15. Different arms of the adaptive immune system induced by a combination vaccine work in concert to provide enhanced clearance of influenza.

    Science.gov (United States)

    Cobbin, Joanna C A; Zeng, Weiguang; Jackson, David C; Brown, Lorena E

    2014-01-01

    Current split influenza virus vaccines that induce strain-specific neutralising antibodies provide some degree of protection against influenza infection but there is a clear need to improve their effectiveness. The constant antigenic drift of influenza viruses means that vaccines are often not an exact match to the circulating strain and so levels of relevant antibodies may not be sufficiently high to afford protection. In the situation where the emergent influenza virus is completely novel, as is the case with pandemic strains, existing vaccines may provide no benefit. In this study we tested the concept of a combination vaccine consisting of sub-optimal doses of split influenza virus vaccine mixed with a cross-protective T-cell inducing lipopeptide containing the TLR2 ligand Pam2Cys. Mice immunised with combination vaccines showed superior levels of lung viral clearance after challenge compared to either split virus or lipopeptide alone, mediated through activation of enhanced humoral and/or additional cellular responses. The mechanism of action of these vaccines was dependent on the route of administration, with intranasal administration being superior to subcutaneous and intramuscular routes, potentially through the induction of memory CD8+ T cells in the lungs. This immunisation strategy not only provides a mechanism for minimising the dose of split virus antigen but also, through the induction of cross-protective CD8+ T cells, proves a breadth of immunity to provide potential benefit upon encounter with serologically diverse influenza isolates.

  16. PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

    Science.gov (United States)

    Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

    2016-11-20

    Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Different arms of the adaptive immune system induced by a combination vaccine work in concert to provide enhanced clearance of influenza.

    Directory of Open Access Journals (Sweden)

    Joanna C A Cobbin

    Full Text Available Current split influenza virus vaccines that induce strain-specific neutralising antibodies provide some degree of protection against influenza infection but there is a clear need to improve their effectiveness. The constant antigenic drift of influenza viruses means that vaccines are often not an exact match to the circulating strain and so levels of relevant antibodies may not be sufficiently high to afford protection. In the situation where the emergent influenza virus is completely novel, as is the case with pandemic strains, existing vaccines may provide no benefit. In this study we tested the concept of a combination vaccine consisting of sub-optimal doses of split influenza virus vaccine mixed with a cross-protective T-cell inducing lipopeptide containing the TLR2 ligand Pam2Cys. Mice immunised with combination vaccines showed superior levels of lung viral clearance after challenge compared to either split virus or lipopeptide alone, mediated through activation of enhanced humoral and/or additional cellular responses. The mechanism of action of these vaccines was dependent on the route of administration, with intranasal administration being superior to subcutaneous and intramuscular routes, potentially through the induction of memory CD8+ T cells in the lungs. This immunisation strategy not only provides a mechanism for minimising the dose of split virus antigen but also, through the induction of cross-protective CD8+ T cells, proves a breadth of immunity to provide potential benefit upon encounter with serologically diverse influenza isolates.

  18. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade.

    Science.gov (United States)

    Xue, Wei; Metheringham, Rachael L; Brentville, Victoria A; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M; Durrant, Lindy G

    2016-06-01

    Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.

  19. Exopolysaccharides Produced by Leuconostoc mesenteroides Strain NTM048 as an Immunostimulant To Enhance the Mucosal Barrier and Influence the Systemic Immune Response.

    Science.gov (United States)

    Matsuzaki, Chiaki; Hayakawa, Asuka; Matsumoto, Kenji; Katoh, Toshihiko; Yamamoto, Kenji; Hisa, Keiko

    2015-08-12

    Leuconostoc mesenteroides strain NTM048 has been shown to have intestinal IgA-inducing ability. In this study, we investigated the immunostimulant potency of an exopolysaccharide secreted from strain NTM048 (NTM048 EPS) in vitro and in vivo in a murine model. NTM048 EPS ranges in size from 10 to 40 kDa and is speculated to be mainly composed of glucose and fructose. The in vitro study revealed that NTM048 EPS induced total and antigen-specific IgA production by Peyer's patch cells and influenced Th1 and Th2 cell-mediated response in splenocytes. Oral administration of NTM048 EPS dose-dependently induced fecal IgA production accompanied by the up-regulation of retinoic acid synthase and transforming growth factor-β receptor genes in Peyer's patch cells. Flow cytometric analysis of the splenocytes revealed an increase of the CD3+ T-cell population and the ratio of CD4+ T-cells/CD8+ T-cells. These results indicate that NTM048 EPS could enhance the mucosal barrier and influence the systemic immune response.

  20. Post-chemotherapeutic administration of interleukin-12 retards tumor growth and enhances immune cell function: combination therapy using paclitaxel and IL-12.

    Science.gov (United States)

    Pressley, Jennifer S; Elgert, Klaus D

    2006-01-01

    The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division that also suppresses lymphocyte proliferative responses. Because chemotherapy-induced immunosuppression may limit the patient's antitumor responses, we investigated the possibility that the T cell stimulatory cytokine interleukin-12 (IL-12) could be used to reverse paclitaxel-mediated lymphocyte suppression. Recognizing that IL-12 treatment following paclitaxel exposure promotes T cell responses in vitro, we evaluated the antitumor efficacy of IL-12 administration concurrent and subsequent to paclitaxel treatment. Simultaneous administration of IL-12 and paclitaxel failed to limit tumor outgrowth or extend survival beyond chemotherapy alone, although IL-12 did not manifest negative effects. In contrast, post-chemotherapeutic IL-12 significantly delayed tumor outgrowth and extended survival in tumor-burdened BALB/c mice. Correlative enhancements in ex vivo immune cell effector function were also observed following paclitaxel and temporally delayed IL-12 therapy. Collectively, these data demonstrate an immunotherapeutic efficacy of IL-12 that augments the chemotherapeutic activities of paclitaxel when delivered in the appropriate temporal sequence.

  1. Innate immune memory in plants.

    Science.gov (United States)

    Reimer-Michalski, Eva-Maria; Conrath, Uwe

    2016-08-01

    The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Sequential Immune Responses: The Weapons of Immunity

    Science.gov (United States)

    Mills, Charles D.; Ley, Klaus; Buchmann, Kurt; Canton, Johnathan

    2016-01-01

    Sequential immune responses (SIR) is a new model that describes what ‘immunity’ means in higher animals. Existing models, such as self/nonself discrimination or danger, focus on how immune responses are initiated. However, initiation is not protection. SIR describes the actual immune responses that provide protection. SIR resulted from a comprehensive analysis of the evolution of immune systems that revealed that several very different types of host innate responses occur (and at different tempos) which together provide host protection. SIR1 uses rapidly activated enzymes like the NADPH oxidases and is present in all animal cells. SIR2 is mediated by the first ‘immune’ cells: macrophage-like cells. SIR3 evolved in animals like invertebrates and provides enhanced protection through advanced macrophage recognition and killing of pathogens and through other innate immune cells such as neutrophils. Finally, in vertebrates, macrophages developed SIR4: the ability to present antigens to T cells. Though much slower than SIR1–3, adaptive responses provide a unique new protection for higher vertebrates. Importantly, newer SIR responses were added on top of older, evolutionarily conserved functions to provide ‘layers’ of host protection. SIR transcends existing models by elucidating the different weapons of immunity that provide host protection in higher animals. PMID:25871013

  3. A Novel Prime and Boost Regimen of HIV Virus-Like Particles with TLR4 Adjuvant MPLA Induces Th1 Oriented Immune Responses against HIV.

    Directory of Open Access Journals (Sweden)

    Ethan Poteet

    Full Text Available HIV virus-like particles (VLPs present the HIV envelope protein in its native conformation, providing an ideal vaccine antigen. To enhance the immunogenicity of the VLP vaccine, we sought to improve upon two components; the route of administration and the additional adjuvant. Using HIV VLPs, we evaluated sub-cheek as a novel route of vaccine administration when combined with other conventional routes of immunization. Of five combinations of distinct prime and boost sequences, which included sub-cheek, intranasal, and intradermal routes of administration, intranasal prime and sub-cheek boost (IN+SC resulted in the highest HIV-specific IgG titers among the groups tested. Using the IN+SC regimen we tested the adjuvant VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV + monophosphoryl lipid A (MPLA at MPLA concentrations of 0, 7.5, 12.5, and 25 μg/dose in combination with our VLPs. Mice that received 12.5 or 25 μg/dose MPLA had the highest concentrations of Env-specific IgG2c (20.7 and 18.4 μg/ml respectively, which represents a Th1 type of immune response in C57BL/6 mice. This was in sharp contrast to mice which received 0 or 7.5 μg MPLA adjuvant (6.05 and 5.68 μg/ml of IgG2c respectively. In contrast to IgG2c, MPLA had minor effects on Env-specific IgG1; therefore, 12.5 and 25 μg/dose of MPLA induced the optimal IgG1/IgG2c ratio of 1.3. Additionally, the percentage of germinal center B cells increased significantly from 15.4% in the control group to 31.9% in the CALV + 25 μg MPLA group. These mice also had significantly more IL-2 and less IL-4 Env-specific CD8+ T cells than controls, correlating with an increased percentage of Env-specific central memory CD4+ and CD8+ T cells. Our study shows the strong potential of IN+SC as an efficacious route of administration and the effectiveness of VLPs combined with MPLA adjuvant to induce Env specific Th1-oriented HIV-specific immune responses.

  4. Immunizations - diabetes

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000331.htm Immunizations - diabetes To use the sharing features on this page, please enable JavaScript. Immunizations (vaccines or vaccinations) help protect you from some ...

  5. Childhood Immunization

    Science.gov (United States)

    ... lowest levels in history, thanks to years of immunization. Children must get at least some vaccines before ... child provide protection for many years, adults need immunizations too. Centers for Disease Control and Prevention

  6. HETEROLOGOUS IMMUNITY BETWEEN VIRUSES

    Science.gov (United States)

    Welsh, Raymond M.; Che, Jenny; Brehm, Michael A.; Selin, Liisa K.

    2010-01-01

    Summary Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as heterologous immunity. This response can lead to enhanced or diminished protective immunity and altered immunopathology. Here we discuss the nature of T-cell cross-reactivity and describe matrices of epitopes from different viruses eliciting cross-reactive CD8+ T-cell responses. We examine the parameters of heterologous immunity mediated by these cross-reactive T cells during viral infections in mice and humans. We show that heterologous immunity can disrupt T-cell memory pools, alter the complexity of the T-cell repertoire, change patterns of T-cell immunodominance, lead to the selection of viral epitope-escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T-cell repertoires within individuals, contribute to dramatic variations in viral disease. We propose that heterologous immunity is an important factor in resistance to and variations of human viral infections and that issues of heterologous immunity should be considered in the design of vaccines. PMID:20536568

  7. Epigenetics and Trained Immunity.

    Science.gov (United States)

    van der Heijden, Charlotte D C C; Noz, Marlies P; Joosten, Leo A B; Netea, Mihai G; Riksen, Niels P; Keating, Samuel T

    2017-11-21

    A growing body of clinical and experimental evidence has challenged the traditional understanding that only the adaptive immune system can mount immunological memory. Recent findings describe the adaptive characteristics of the innate immune system, underscored by its ability to remember antecedent foreign encounters and respond in a nonspecific sensitized manner to reinfection. This has been termed trained innate immunity. Although beneficial in the context of recurrent infections, this might actually contribute to chronic immune-mediated diseases, such as atherosclerosis. Recent Advances: In line with its proposed role in sustaining cellular memories, epigenetic reprogramming has emerged as a critical determinant of trained immunity. Recent technological and computational advances that improve unbiased acquisition of epigenomic profiles have significantly enhanced our appreciation for the complexities of chromatin architecture in the contexts of diverse immunological challenges. Key to resolving the distinct chromatin signatures of innate immune memory is a comprehensive understanding of the precise physiological targets of regulatory proteins that recognize, deposit, and remove chemical modifications from chromatin as well as other gene-regulating factors. Drawing from a rapidly expanding compendium of experimental and clinical studies, this review details a current perspective of the epigenetic pathways that support the adapted phenotypes of monocytes and macrophages. We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders. Antioxid. Redox Signal. 00, 000-000.

  8. Immunization Schedule

    Science.gov (United States)

    ... may be given as part of a combination vaccine so that a child gets fewer shots. Talk with your doctor about ... Kids Teens Frequently Asked Questions About Immunizations Your Child's Immunizations Is the Flu Vaccine a Good Idea for Your Family? Word! Immunizations ...

  9. Oral administration of Lactococcus lactis subsp. lactis JCM5805 enhances lung immune response resulting in protection from murine parainfluenza virus infection.

    Directory of Open Access Journals (Sweden)

    Kenta Jounai

    Full Text Available When activated by viral infection, plasmacytoid dendritic cells (pDCs play a primary role in the immune response through secretion of IFN-α. Lactococcus lactis subsp. lactis JCM5805 (JCM5805 is a strain of lactic acid bacteria (LAB that activates murine and human pDCs to express type I and type III interferons (IFNs. JCM5805 has also been shown to activate pDCs via a Toll-like receptor 9 (TLR9 dependent pathway. In this study, we investigated the anti-viral effects of oral administration of JCM5805 using a mouse model of murine parainfluenza virus (mPIV1 infection. JCM5805-fed mice showed a drastic improvement in survival rate, prevention of weight loss, and reduction in lung histopathology scores compared to control mice. We further examined the mechanism of anti-viral effects elicited by JCM5805 administration using naive mice. Microscopic observations showed that JCM5805 was incorporated into CD11c+ immune cells in Peyer's patches (PP and PP pDCs were significantly activated and the expression levels of IFNs were significantly increased. Interestingly, nevertheless resident pDCs at lung were not activated and expressions levels of IFNs at whole lung tissue were not influenced, the expressions of anti-viral factors induced by IFNs, such as Isg15, Oasl2, and Viperin, at lung were up-regulated in JCM5805-fed mice compared to control mice. Therefore expressed IFNs from intestine might be delivered to lung and IFN stimulated genes might be induced. Furthermore, elevated expressions of type I IFNs from lung lymphocytes were observed in response to mPIV1 ex vivo stimulation in JCM5805-fed mice compared to control. This might be due to increased ratio of pDCs located in lung were significantly increased in JCM5805 group. Taken together, a specific LAB strain might be able to affect anti-viral immunological profile in lung via activation of intestinal pDC leading to enhanced anti-viral phenotype in vivo.

  10. Immunizing Children

    Directory of Open Access Journals (Sweden)

    Geraldine Jody Macdonald

    2014-11-01

    Full Text Available This article addresses the complex contexts within which Canadian health professionals engage in immunizing children and focuses on the Canadian practice guidelines and current scientific evidence that direct Canadian health professional competencies. The article begins by presenting two current global vaccine initiatives and links these to immunization in Canada. A selected literature review identifies current best immunization practices. With the purpose of promoting quality improvement, three key Canadian immunization competencies for health professional are highlighted: communication with parents, including those who are experiencing vaccine hesitancy; administration of immunizing agents; and documentation of immunizations. Health professionals are encouraged to reflect on immunization competencies and ensure evidence-based practices underpin vaccine delivery in their primary care settings.

  11. Cross-fostering to prevent maternal cell transfer did not prevent vaccine-associated enhanced respiratory disease that occurred following heterologous influenza challenge of pigs vaccinated in the presence of maternal immunity.

    Science.gov (United States)

    Loving, Crystal L; Brockmeier, Susan L; Vincent, Amy L; Gauger, Phillip C; Zanella, Eraldo L; Lager, Kelly M; Kehrli, Marcus E

    2014-09-01

    Whole inactivated virus (WIV) vaccines for influenza A virus (IAV) provide limited cross-protection to diverse antigenic strains that are circulating or may emerge in a population. Maternal vaccination is used to protect neonatal animals from disease through passive transfer of immunity. It is desirable to vaccinate at a young age to induce active immunity that provides protection against infection before maternal immunity wanes. However, maternal-derived immunity (MDI; antibody or cells) can interfere with vaccine priming. Previous work indicates that vaccine-associated enhanced respiratory disease (VAERD) occurs in pigs following heterologous IAV challenge if pigs were previously vaccinated with WIV vaccine in the presence of matched MDI. However, the component of MDI (antibody or cells) that is required for the mispriming of piglet immunity has not been determined. While antibody from colostrum is absorbed into piglet circulation regardless of the sow from which it receives colostrum, transfer of maternal cells requires colostrum from the biological dam. We used cross-fostering (CF) as a tool to determine if maternal cells are required for the mispriming of piglet immunity upon WIV vaccination in the presence of MDI. Piglets vaccinated in the presence of MDI, regardless of CF, displayed characteristics of VAERD following heterologous challenge. MDI alone (no piglet vaccination) did not provide cross-protection against the antigenic variant. However, it did not induce VAERD. WIV vaccination provided complete protection against homologous challenge when delivered to piglets without MDI. Vaccination in the presence of MDI inhibited an increase in hemagglutination inhibiting (HI) antibody titers to vaccine antigen, but did not alter development of total immunoglobulin levels to vaccine virus. Taken together, the cellular component of MDI did not contribute to the mispriming of piglet immunity to WIV vaccine, but maternal-derived antibody (MDA) alone was sufficient

  12. Live Brucella abortus rough vaccine strain RB51 stimulates enhanced innate immune response in vitro compared to rough vaccine strain RB51SOD and virulent smooth strain 2308 in murine bone marrow-derived dendritic cells.

    Science.gov (United States)

    Surendran, Naveen; Hiltbold, Elizabeth M; Heid, Bettina; Sriranganathan, Nammalwar; Boyle, Stephen M; Zimmerman, Kurt L; Makris, Melissa R; Witonsky, Sharon G

    2011-01-10

    Brucella spp. are Gram-negative, coccobacillary, facultative intracellular pathogens. B. abortus strain 2308 is a pathogenic strain affecting cattle and humans. Rough B. abortus strain RB51, which lacks the O-side chain of lipopolysaccharide (LPS), is the live attenuated USDA approved vaccine for cattle in the United States. Strain RB51SOD, which overexpresses Cu-Zn superoxide dismutase (SOD), has been shown to confer better protection than strain RB51 in a murine model. Protection against brucellosis is mediated by a strong CD4+ Th(1) and CD8+ Tc(1) adaptive immune response. In order to stimulate a robust adaptive response, a solid innate immune response, including that mediated by dendritic cells, is essential. As dendritic cells (DCs) are highly susceptible to Brucella infection, it is possible that pathogenic strains could limit the innate and thereby adaptive immune response. By contrast, vaccine strains could limit or bolster the innate and subsequent adaptive immune response. Identifying how Brucella vaccines stimulate innate and adaptive immunity is critical for enhancing vaccine efficacy. The ability of rough vaccine strains RB51 and RB51SOD to stimulate DC function has not been characterized. We report that live rough vaccine strain RB51 induced significantly better (p ≤ 0.05) DC maturation and function compared to either strain RB51SOD or smooth virulent strain 2308, based on costimulatory marker expression and cytokine production. Copyright © 2010. Published by Elsevier B.V.

  13. Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response.

    Science.gov (United States)

    Laborde, Rady J; Sanchez-Ferras, Oraly; Luzardo, María C; Cruz-Leal, Yoelys; Fernández, Audry; Mesa, Circe; Oliver, Liliana; Canet, Liem; Abreu-Butin, Liane; Nogueira, Catarina V; Tejuca, Mayra; Pazos, Fabiola; Álvarez, Carlos; Alonso, María E; Longo-Maugéri, Ieda M; Starnbach, Michael N; Higgins, Darren E; Fernández, Luis E; Lanio, María E

    2017-04-01

    Vaccine strategies to enhance CD8 + CTL responses remain a current challenge because they should overcome the plasmatic and endosomal membranes for favoring exogenous Ag access to the cytosol of APCs. As a way to avoid this hurdle, sticholysin (St) II, a pore-forming protein from the Caribbean Sea anemone Stichodactyla helianthus , was encapsulated with OVA into liposomes (Lp/OVA/StII) to assess their efficacy to induce a CTL response. OVA-specific CD8 + T cells transferred to mice immunized with Lp/OVA/StII experienced a greater expansion than when the recipients were injected with the vesicles without St, mostly exhibiting a memory phenotype. Consequently, Lp/OVA/StII induced a more potent effector function, as shown by CTLs, in vivo assays. Furthermore, treatment of E.G7-OVA tumor-bearing mice with Lp/OVA/StII significantly reduced tumor growth being more noticeable in the preventive assay. The contribution of CD4 + and CD8 + T cells to CTL and antitumor activity, respectively, was elucidated. Interestingly, the irreversibly inactive variant of the StI mutant StI W111C, encapsulated with OVA into Lp, elicited a similar OVA-specific CTL response to that observed with Lp/OVA/StII or vesicles encapsulating recombinant StI or the reversibly inactive StI W111C dimer. These findings suggest the relative independence between StII pore-forming activity and its immunomodulatory properties. In addition, StII-induced in vitro maturation of dendritic cells might be supporting these properties. These results are the first evidence, to our knowledge, that StII, a pore-forming protein from a marine eukaryotic organism, encapsulated into Lp functions as an adjuvant to induce a robust specific CTL response. Copyright © 2017 by The American Association of Immunologists, Inc.

  14. 2-Methoxyestradiol protects against IgG immune complex-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein β activities.

    Science.gov (United States)

    Yan, Chunguang; Shen, Yanfei; Sun, Qiqing; Yuan, Dong; Tang, Huifang; Gao, Hongwei

    2017-05-01

    Increasing evidences indicate that 2-Methoxyestradiol (2ME2) plays an essential role in protecting against inflammatory responses. However, its effect on IgG immune complex (IC)-induced acute lung injury (ALI) remains enigmatic. In the study, by using i.p. administration of 2ME2, we evaluated its influence on IgG IC-induced pulmonary injury in mice. We found that during IgG IC-induced ALI, mice treated by 2ME2 displayed a substantial decrease in vascular permeability and neutrophil influx (represented by myeloperoxidase activity) when compared with their counterparts receiving vehicle treatment. Furthermore, 2ME2 treatment significantly decreased pro-inflammatory mediator production and inflammatory cell, especially neutrophil accumulation in bronchoalveolar lavage fluids (BALFs) upon IgG IC stimulation. In vitro, IgG IC-triggered inflammatory mediator production was markedly down-regulated by 2ME2 in macrophages. Moreover, we verified that the activation of the transcription factors, NF-κB and CCAAT/enhancer-binding protein (C/EBP) β, were inhibited by 2ME2 in IgG IC-challenged macrophages. We demonstrated that alleviation of NF-κB-dependent transcription might be associated with reduced phosphorylation of NF-κB p65, and reduction of C/EBP activation was directly linked to its expression. In addition, we discovered that IgG IC-stimulated phosphorylation of both p38 MAPK and ERK1/2 was alleviated by 2ME2. These data indicated a novel strategy for blockade of IgG IC-induced inflammatory activities. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Microdosed Lipid-Coated (67)Ga-Magnetite Enhances Antigen-Specific Immunity by Image Tracked Delivery of Antigen and CpG to Lymph Nodes.

    Science.gov (United States)

    Ruiz-de-Angulo, Ane; Zabaleta, Aintzane; Gómez-Vallejo, Vanessa; Llop, Jordi; Mareque-Rivas, Juan C

    2016-01-26

    Development of vaccines to prevent and treat emerging new pathogens and re-emerging infections and cancer remains a major challenge. An attractive approach is to build the vaccine upon a biocompatible NP that simultaneously acts as accurate delivery vehicle and radiotracer for PET/SPECT imaging for ultrasensitive and quantitative in vivo imaging of NP delivery to target tissues/organs. Success in developing these nanovaccines will depend in part on having a "correct" NP size and accommodating and suitably displaying antigen and/or adjuvants (e.g., TLR agonists). Here we develop and evaluate a NP vaccine based on iron oxide-selective radio-gallium labeling suitable for SPECT((67)Ga)/PET((68)Ga) imaging and efficient delivery of antigen (OVA) and TLR 9 agonists (CpGs) using lipid-coated magnetite micelles. OVA, CpGs and rhodamine are easily accommodated in the hybrid micelles, and the average size of the construct can be controlled to be ca. 40 nm in diameter to target direct lymphatic delivery of the vaccine cargo to antigen presenting cells (APCs) in the lymph nodes (LNs). While the OVA/CpG-loaded construct showed effective delivery to endosomal TLR 9 in APCs, SPECT imaging demonstrated migration from the injection site to regional and nonregional LNs. In correlation with the imaging results, a range of in vitro and in vivo studies demonstrate that by using this microdosed nanosystem the cellular and humoral immune responses are greatly enhanced and provide protection against tumor challenge. These results suggest that these nanosystems have considerable potential for image-guided development of targeted vaccines that are more effective and limit toxicity.

  16. Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: implications for immune-mediated cancer therapy.

    Directory of Open Access Journals (Sweden)

    Ivy Wilkinson-Ryan

    Full Text Available One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs. This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5 has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses.

  17. Adsorption of recombinant poxvirus L1-protein to aluminum hydroxide/CpG vaccine adjuvants enhances immune responses and protection of mice from vaccinia virus challenge.

    Science.gov (United States)

    Xiao, Yuhong; Zeng, Yuhong; Alexander, Edward; Mehta, Shyam; Joshi, Sangeeta B; Buchman, George W; Volkin, David B; Middaugh, C Russell; Isaacs, Stuart N

    2013-01-02

    The stockpiling of live vaccinia virus vaccines has enhanced biopreparedness against the intentional or accidental release of smallpox. Ongoing research on future generation smallpox vaccines is providing key insights into protective immune responses as well as important information about subunit-vaccine design strategies. For protein-based recombinant subunit vaccines, the formulation and stability of candidate antigens with different adjuvants are important factors to consider for vaccine design. In this work, a non-tagged secreted L1-protein, a target antigen on mature virus, was expressed using recombinant baculovirus technology and purified. To identify optimal formulation conditions for L1, a series of biophysical studies was performed over a range of pH and temperature conditions. The overall physical stability profile was summarized in an empirical phase diagram. Another critical question to address for development of an adjuvanted vaccine was if immunogenicity and protection could be affected by the interactions and binding of L1 to aluminum salts (Alhydrogel) with and without a second adjuvant, CpG. We thus designed a series of vaccine formulations with different binding interactions between the L1 and the two adjuvants, and then performed a series of vaccination-challenge experiments in mice including measurement of antibody responses and post-challenge weight loss and survival. We found that better humoral responses and protection were conferred with vaccine formulations when the L1-protein was adsorbed to Alhydrogel. These data demonstrate that designing vaccine formulation conditions to maximize antigen-adjuvant interactions is a key factor in smallpox subunit-vaccine immunogenicity and protection. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Lack of Epstein-Barr virus- and HIV-specific CD27- CD8+ T cells is associated with progression to viral disease in HIV-infection

    NARCIS (Netherlands)

    van Baarle, Debbie; Kostense, Stefan; Hovenkamp, Egbert; Ogg, Graham; Nanlohy, Nening; Callan, Margaret F. C.; Dukers, Nicole H. T. M.; McMichael, Andrew J.; van Oers, Marinus H. J.; Miedema, Frank

    2002-01-01

    OBJECTIVE: Despite readily detectable virus-specific CD8+ T cells in most HIV-infected patients, immune surveillance is eventually lost, leading to progression to AIDS. To investigate the underlying mechanism of this loss of immune control phenotypic analysis of HIV- and Epstein-Barr virus

  19. Enhanced

    Directory of Open Access Journals (Sweden)

    Martin I. Bayala

    2014-06-01

    Full Text Available Land Surface Temperature (LST is a key parameter in the energy balance model. However, the spatial resolution of the retrieved LST from sensors with high temporal resolution is not accurate enough to be used in local-scale studies. To explore the LST–Normalised Difference Vegetation Index relationship potential and obtain thermal images with high spatial resolution, six enhanced image sharpening techniques were assessed: the disaggregation procedure for radiometric surface temperatures (TsHARP, the Dry Edge Quadratic Function, the Difference of Edges (Ts∗DL and three models supported by the relationship of surface temperature and water stress of vegetation (Normalised Difference Water Index, Normalised Difference Infrared Index and Soil wetness index. Energy Balance Station data and in situ measurements were used to validate the enhanced LST images over a mixed agricultural landscape in the sub-humid Pampean Region of Argentina (PRA, during 2006–2010. Landsat Thematic Mapper (TM and Moderate Resolution Imaging Spectroradiometer (EOS-MODIS thermal datasets were assessed for different spatial resolutions (e.g., 960, 720 and 240 m and the performances were compared with global and local TsHARP procedures. Results suggest that the Ts∗DL technique is the most adequate for simulating LST to high spatial resolution over the heterogeneous landscape of a sub-humid region, showing an average root mean square error of less than 1 K.

  20. Immune-enhancing effect of nano-DNA vaccine encoding a gene of the prME protein of Japanese encephalitis virus and BALB/c mouse granulocyte-macrophage colony-stimulating factor.

    Science.gov (United States)

    Zhai, Yongzhen; Zhou, Yan; Li, Ximei; Feng, Guohe

    2015-07-01

    Plasmid-encoded granulocyte-macrophage colony-stimulating factor (GM‑CSF) is an adjuvant for genetic vaccines; however, how GM-CSF enhances immunogenicity remains to be elucidated. In the present study, it was demonstrated that injection of a plasmid encoding the premembrane (prM) and envelope (E) protein of Japanese encephalitis virus and mouse GM-CSF (pJME/GM-CSF) into mouse muscle recruited large and multifocal conglomerates of macrophages and granulocytes, predominantly neutrophils. During the peak of the infiltration, an appreciable number of immature dendritic cells (DCs) appeared, although no T and B-cells was detected. pJME/GM-CSF increased the number of splenic DCs and the expression of major histocompatibility complex class II (MHCII) on splenic DC, and enhanced the antigenic capture, processing and presentation functions of splenic DCs, and the cell-mediated immunity induced by the vaccine. These findings suggested that the immune-enhancing effect by pJME/GM-CSF was associated with infiltrate size and the appearance of integrin αx (CD11c)+cells. Chitosan-pJME/GM-CSF nanoparticles, prepared by coacervation via intramuscular injection, outperformed standard pJME/GM-CSF administrations in DC recruitment, antigen processing and presentation, and vaccine enhancement. This revealed that muscular injection of chitosan‑pJME/GM-CSF nanoparticles may enhance the immunoadjuvant properties of GM-CSF.

  1. DNA immunization with fusion of CTLA-4 to hepatitis B virus (HBV core protein enhanced Th2 type responses and cleared HBV with an accelerated kinetic.

    Directory of Open Access Journals (Sweden)

    Ying Yin

    Full Text Available BACKGROUND: Typically, DNA immunization via the intramuscular route induces specific, Th1-dominant immune responses. However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4 primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model. Thus, we addressed the question in the mouse model how the Th1/Th2 bias of primed immune responses by a DNA vaccine influences hepatitis B virus (HBV clearance. PRINCIPAL FINDINGS: Plasmids expressing HBV core protein (HBcAg or HBV e antigen and HBcAg fused to the extracellular domain of CTLA-4 (pCTLA-4-HBc, CD27, and full length CD40L were constructed. Immunizations of these DNA plasmids induced HBcAg-specific antibody and cytotoxic T-cell responses in mice, but with different characteristics regarding the titers and subtypes of specific antibodies and intensity of T-cell responses. The plasmid pHBc expressing HBcAg induced an IgG2a-dominant response while immunizations of pCTLA-4-HBc induced a balanced IgG1/IgG2a response. To assess the protective values of the immune responses of different characteristics, mice were pre-immunized with pCTLA-4-HBc and pHBc, and challenged by hydrodynamic injection (HI of pAAV/HBV1.2. HBV surface antigen (HBsAg and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups. The clearance of HBsAg was completed within 16 days in immunized mice while more than 50% of the control mice are still positive for HBsAg on day 22. Stronger HBcAg-specific T-cell responses were primed by pHBc correlating with a more rapid decline of HBcAg expression in liver tissue, while anti-HBs antibody response developed rapidly in the mice immunized with pCTLA-4-HBc, indicating that the Th1/Th2 bias of vaccine-primed immune responses influences the mode of viral clearance. CONCLUSION: Viral clearance could be efficiently achieved by Th1/Th2-balanced

  2. Enhancing mucosal immunity in mice by recombinant adenovirus expressing major epitopes of porcine circovirus-2 capsid protein delivered with cytosine-phosphate-guanosine oligodeoxynucleotides

    OpenAIRE

    Chang, Hong-tao; He, Xiu-yuan; Liu, Yu-feng; Chen, Lu; Guo, Quan-hai; Yu, Qiu-ying; Zhao, Jun; Wang, Xin-Wei; Yang, Xia; Wang, Chuan-qing

    2014-01-01

    A recombinant replication-defective adenovirus expressing the major epitopes of porcine circovirus-2 (PCV-2) capsid protein (rAd/Cap/518) was previously constructed and shown to induce mucosal immunity in mice following intranasal delivery. In the present study, immune responses induced by intranasal immunization with a combination of rAd/Cap/518 and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) were evaluated in mice. The levels of PCV-2-specific IgG in serum and IgA in saliva...

  3. Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma

    Science.gov (United States)

    Barta, S. K.; Samuel, M. S.; Xue, X.; Wang, D.; Lee, J. Y.; Mounier, N.; Ribera, J.-M.; Spina, M.; Tirelli, U.; Weiss, R.; Galicier, L.; Boue, F.; Little, R. F.; Dunleavy, K.; Wilson, W. H.; Wyen, C.; Remick, S. C.; Kaplan, L. D.; Ratner, L.; Noy, A.; Sparano, J. A.

    2015-01-01

    Background We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. Patients and methods We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989–1995), early cART (1996–2000), recent cART (2001–2004), and contemporary cART era (2005–2010). Results Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL. PMID:25632071

  4. A new cell line for high throughput HIV-specific antibody-dependent cellular cytotoxicity (ADCC) and cell-to-cell virus transmission studies.

    Science.gov (United States)

    Orlandi, Chiara; Flinko, Robin; Lewis, George K

    2016-06-01

    Several lines of evidence indicate that antibody-dependent cellular cytotoxicity (Wren et al., 2013) is important in the pathogenesis of HIV-1 infection. Namely, ADCC is induced during natural HIV-1 infection or in HIV-1 vaccine studies, the latter demonstrated by the RV144 vaccine trial. To expedite the assessment of ADCC in studies of HIV, we have developed a high throughput assay. We have optimized the rapid fluorometric antibody-mediated cytotoxicity assay (RFADCC) by transfecting the EGFP-CEM-NKr cell line to constitutively express SNAP-tagged CCR5. This cell line can then serve as a source of HIV-specific targets when coated with monomeric gp120, spinoculated with inactivated intact virions, infected by cell-free viral diffusion or infected by cell-to-cell transmission of virus. The optimized strategy has two significant advantages over the original RFADCC method: First, the preparation of detectable target cells is less labor intensive and faster as it does not rely on multiple staining and washing steps for target cells. Second, because the target cell markers GFP and SNAP are constitutively expressed, the assay provides highly reproducible data. These strengths make the optimized RFADCC assay suitable not only for studies of HIV-1 specific cytotoxicity but also for studies of cell-cell transmission of virus. In conclusion, this assay provides a new generation T cell line that can expedite large clinical studies as well as research studies in humans or non-human primates. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Mosquito immunity.

    Science.gov (United States)

    Hillyer, Julián F

    2010-01-01

    Throughout their lifetime, mosquitoes are exposed to pathogens during feeding, through breaks in their cuticle and following pathogen-driven cuticular degradation. To resist infection, mosquitoes mount innate cellular and humoral immune responses that are elicited within minutes of exposure and can lead to pathogen death via three broadly defined mechanisms: lysis, melanization and hemocyte-mediated phagocytosis. This chapter reviews our current understanding of the mosquito immune system, with an emphasis on the physical barriers that prevent pathogens from entering the body, the organs and tissues that regulate immune responses and the mechanistic and molecular bases of immunity.

  6. Regulation of HIV-Gag Expression and Targeting to the Endolysosomal/Secretory Pathway by the Luminal Domain of Lysosomal-Associated Membrane Protein (LAMP-1) Enhance Gag-Specific Immune Response

    Science.gov (United States)

    Lucas, Carolina Gonçalves de Oliveira; Rigato, Paula Ordonhez; Gonçalves, Jorge Luiz Santos; Sato, Maria Notomi; Maciel, Milton; Peçanha, Ligia Maria Torres; August, J. Thomas; de Azevedo Marques, Ernesto Torres; de Arruda, Luciana Barros

    2014-01-01

    We have previously demonstrated that a DNA vaccine encoding HIV-p55gag in association with the lysosomal associated membrane protein-1 (LAMP-1) elicited a greater Gag-specific immune response, in comparison to a DNA encoding the native gag. In vitro studies have also demonstrated that LAMP/Gag was highly expressed and was present in MHCII containing compartments in transfected cells. In this study, the mechanisms involved in these processes and the relative contributions of the increased expression and altered traffic for the enhanced immune response were addressed. Cells transfected with plasmid DNA constructs containing p55gag attached to truncated sequences of LAMP-1 showed that the increased expression of gag mRNA required p55gag in frame with at least 741 bp of the LAMP-1 luminal domain. LAMP luminal domain also showed to be essential for Gag traffic through lysosomes and, in this case, the whole sequence was required. Further analysis of the trafficking pathway of the intact LAMP/Gag chimera demonstrated that it was secreted, at least in part, associated with exosome-like vesicles. Immunization of mice with LAMP/gag chimeric plasmids demonstrated that high expression level alone can induce a substantial transient antibody response, but targeting of the antigen to the endolysosomal/secretory pathways was required for establishment of cellular and memory response. The intact LAMP/gag construct induced polyfunctional CD4+ T cell response, which presence at the time of immunization was required for CD8+ T cell priming. LAMP-mediated targeting to endolysosomal/secretory pathway is an important new mechanistic element in LAMP-mediated enhanced immunity with applications to the development of novel anti-HIV vaccines and to general vaccinology field. PMID:24932692

  7. Booster immunization of children with an acellular pertussis vaccine enhances Th2 cytokine production and serum IgE against pertussis toxin but not against common allergens

    OpenAIRE

    MILLS, KINGSTON

    2000-01-01

    PUBLISHED Acellular pertussis vaccines (Pa) protect against severe pertussis in children. However, serum antibody responses decline quickly after immunization. Studies in animal models suggest that cell-mediated immunity also contributes to protection against Bordetella pertussis, and it has already been demonstrated that Pa induce T cells that secrete type-1 and type-2 cytokines in children. In this study we examined the persistence of the T cell response and the effect of booster immuniz...

  8. Immune response

    Science.gov (United States)

    ... viruses, and substances that appear foreign and harmful. Information The immune system protects the body from possibly harmful substances by ... reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team. Immune System and Disorders Read more Latest Health News Read ...

  9. A key enzyme of animal steroidogenesis can function in plants enhancing their immunity and accelerating the processes of growth and development.

    Science.gov (United States)

    Shpakovski, George V; Spivak, Svetlana G; Berdichevets, Irina N; Babak, Olga G; Kubrak, Svetlana V; Kilchevsky, Alexander V; Aralov, Andrey V; Slovokhotov, Ivan Yu; Shpakovski, Dmitry G; Baranova, Ekaterina N; Khaliluev, Marat R; Shematorova, Elena K

    2017-11-14

    The initial stage of the biosynthesis of steroid hormones in animals occurs in the mitochondria of steroidogenic tissues, where cytochrome P450SCC (CYP11A1) encoded by the CYP11A1 gene catalyzes the conversion of cholesterol into pregnenolone - the general precursor of all the steroid hormones, starting with progesterone. This stage is missing in plants where mitochondrial cytochromes P450 (the mito CYP clan) have not been found. Generating transgenic plants with a mitochondrial type P450 from animals would offer an interesting option to verify whether plant mitochondria could serve as another site of P450 monooxygenase reaction for the steroid hormones biosynthesis. For a more detailed comparison of steroidogenic systems of Plantae and Animalia, we have created and studied transgenic tobacco and tomato plants efficiently expressing mammalian CYP11A1 cDNA. The detailed phenotypic characterization of plants obtained has shown that through four generations studied, the transgenic tobacco plants have reduced a period of vegetative development (early flowering and maturation of bolls), enlarged biomass and increased productivity (quantity and quality of seeds) as compared to the only empty-vector containing or wild type plants. Moreover, the CYP11A1 transgenic plants show resistance to such fungal pathogen as Botrytis cinerea. Similar valuable phenotypes (the accelerated course of ontogenesis and/or stress resistance) are also visible in two clearly distinct transgenic tomato lines expressing CYP11A1 cDNA: one line (No. 4) has an accelerated rate of vegetative development, while the other (No. 7) has enhanced immunity to abiotic and biotic stresses. The progesterone level in transgenic tobacco and tomato leaves is 3-5 times higher than in the control plants of the wild type. For the first time, we could show the compatibility in vivo of even the most specific components of the systems of biosynthesis of steroid hormones in Plantae and Animalia. The hypothesis is

  10. Blocking herpes simplex virus 2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes.

    Science.gov (United States)

    Awasthi, Sita; Huang, Jialing; Shaw, Carolyn; Friedman, Harvey M

    2014-08-01

    Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents

  11. Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition.

    Science.gov (United States)

    Gao, Liquan; Zhang, Chenran; Gao, Duo; Liu, Hao; Yu, Xinhe; Lai, Jianhao; Wang, Fan; Lin, Jian; Liu, Zhaofei

    2016-01-01

    "Training" the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvβ6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8(+) cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.

  12. Co-administration of Bacillus subtilis RJGP16 and Lactobacillus salivarius B1 strongly enhances the intestinal mucosal immunity of piglets.

    Science.gov (United States)

    Deng, Jun; Li, Yunfeng; Zhang, Jinhua; Yang, Qian

    2013-02-01

    Probiotics, including Bacillus spp. and Lactobacillus, are potential replacements for low dose in-feed antibiotics for pig. This study aimed to evaluate the effect of the co-administration of Bacillus subtilis RJGP16 and Lactobacillus salivarius B1 as potential probiotics to stimulate local immune responses. Thirty two newborn piglets were divided into four groups and orally administrated with different combination of probiotics (none; RJGP16; B1; RJGP16 and B1) at the age of 0, 7 and 11 days. We analysed the parameters of the mucosal immunity of piglets a week after weaning. Our results showed that the gene expression of interleukin (IL)-6 in the duodenum and ileum, porcine beta-defensins (pBD)-2 in the duodenum were significantly increased (pmucosal immunity than the administration of each bacterium alone. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Live-attenuated auxotrophic mutant of Salmonella Typhimurium expressing immunogenic HA1 protein enhances immunity and protective efficacy against H1N1 influenza virus infection.

    Science.gov (United States)

    Kamble, Nitin Machindra; Hyoung, Kim Je; Lee, John Hwa

    2017-07-01

    To evaluate the efficacy of attenuated Salmonella Typhimurium (JOL912) as a live bacterial vaccine vector. The JOL912 engineered to deliver HA1 protein from influenza A/Puerto Rico/8/1934 (H1N1; PR8) virus was coined as JOL1635 and further evaluated for immunogenicity and protective efficacy. The JOL1635 stably harbored the HA1 gene within pMMP65 plasmid with periplasmic expression and effective delivery of HA1 protein to RAW264.7 cells. The JOL1635 immunized chickens showed the significant increase in HA1-specific IgG, sIgA antibody, IFN-γ, IL-6 cytokine and cellular immune responses. The postoral challenge, the JOL1635-immunized chickens showed a faster clearance of PR8 virus cloacal shedding than the control group. Generated JOL1635 can establish specific immunogenicity and protection against the PR8 virus in chickens.

  14. Immune challenge by intraperitoneal administration of lipopolysaccharide directs gene expression in distinct blood-brain barrier cells toward enhanced prostaglandin E(2) signaling.

    Science.gov (United States)

    Vasilache, Ana Maria; Qian, Hong; Blomqvist, Anders

    2015-08-01

    The cells constituting the blood-brain barrier are critical for the transduction of peripheral immune signals to the brain, but hitherto no comprehensive analysis of the signaling events that occur in these cells in response to a peripheral inflammatory stimulus has been performed. Here, we examined the inflammatory transcriptome in blood-brain barrier cells, including endothelial cells, pericytes, and perivascular macrophages, which were isolated by fluorescent-activated cell sorting, from non-immune-challenged mice and from mice stimulated by bacterial wall lipopolysaccharide. We show that endothelial cells and perivascular macrophages display distinct transcription profiles for inflammatory signaling and respond in distinct and often opposing ways to the immune stimulus. Thus, endothelial cells show induced PGE2 synthesis and transport with attenuation of PGE2 catabolism, increased expression of cytokine receptors and down-stream signaling molecules, and downregulation of adhesion molecules. In contrast, perivascular macrophages show downregulation of the synthesis of prostanoids other than PGE2 and of prostaglandin catabolism, but upregulation of interleukin-6 synthesis. Pericytes were largely unresponsive to the immune stimulation, with the exception of downregulation of proteins involved in pericyte-endothelial cell communication. While the endothelial cells account for most of the immune-induced gene expression changes in the blood-brain barrier, the response of the endothelial cells occurs in a concerted manner with that of the perivascular cells to elevate intracerebral levels of PGE2, hence emphasizing the critical role of PGE2 in immune-induced signal transduction across the blood-brain barrier. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Co-immunization with interlukin-18 enhances the protective efficacy of liposomes encapsulated recombinant Cu-Zn superoxide dismutase protein against Brucella abortus.

    Science.gov (United States)

    Singha, Harisankar; Mallick, Amirul Islam; Jana, Chandrakanta; Fatima, Nishat; Owais, Mohammad; Chaudhuri, Pallab

    2011-06-24

    Brucellosis is a worldwide zoonotic disease caused by Brucella abortus and a number of closely related species. Brucellosis has severe impact on the health and economic prosperity of the developing countries due to the persistent nature of infection and unavailability of effective control measures. The Cu-Zn superoxide dismuatse (SOD) protein of Brucella have been extensively studied as a major antigen involved in bacterial evading mechanism of host defence. Being a critical pro-inflammatory cytokine interleukin-18 (IL-18) plays key role in induction of immune mediated protection against intracellular pathogens. In the present study, we aimed to investigate the immunogenic potential of fusogenic liposomes (escheriosomes) encapsulated recombinant Cu-Zn SOD (rSOD) protein alone or in combination with recombinant IL-18 (rIL-18). Escheriosomes encapsulated rSOD mediated immune responses were further increased upon co-immunization with rIL-18. Furthermore, immunization with escheriosomes encapsulated rSOD alone or in combination with rIL-18, increased resistance in mice against challenge with B. abortus 544. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation.

    NARCIS (Netherlands)

    Nabbe, K.C.A.M.; Lent, P.L.E.M. van; Holthuysen, A.E.M.; Sloetjes, A.W.; Koch, A.E.; Radstake, T.R.D.J.; Berg, W.B. van den

    2005-01-01

    During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcgamma receptors (FcgammaRs) (mainly FcgammaRI), cytokines (e.g. IL-1), and enzymes (matrix metalloproteinases (MMPs)). IL-13, a T helper 2 (Th2) cytokine abundantly found in synovial fluid of patients with

  17. Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis

    DEFF Research Database (Denmark)

    Løbner, Morten; Walsted, Anette; Larsen, Rune

    2008-01-01

    The effect of consumption of Immulina, a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis, on adaptive immune responses was investigated by evaluation of changes in leukocyte responsiveness to two foreign recall antigens, Candida albicans (CA) and tetanus...

  18. Human monoclonal antibodies against anthrax lethal factor and protective antigen act independently to protect against Bacillus anthracis infection and enhance endogenous immunity to anthrax

    NARCIS (Netherlands)

    Albrecht, Mark T.; Li, Han; Williamson, E. Diane; LeButt, Chris S.; Flick-Smith, Helen C.; Quinn, Conrad P.; Westra, Hans; Galloway, Darrell; Mateczun, Alfred; Goldman, Stanley; Groen, Herman; Baillie, Les W. J.

    2007-01-01

    The unpredictable nature of bioterrorism and the absence of real-time detection systems have highlighted the need for an efficient postexposure therapy for Bacillus anthracis infection. One approach is passive immunization through the administration of antibodies that mitigate the biological action

  19. Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells

    NARCIS (Netherlands)

    de Vos, Paul; Mujagic, Zlatan; de Haan, Bart J.; Siezen, Roland J.; Bron, Peter A.; Meijerink, Marjolein; Wells, Jerry M.; Masclee, Ad A. M.; Boekschoten, Mark V.; Faas, Marijke M.; Troost, Freddy J.

    2017-01-01

    Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or

  20. Subunit vaccine candidate AMM down-regulated the regulatory T cells and enhanced the protective immunity of BCG on a suitable schedule.

    Science.gov (United States)

    Luo, Y; Jiang, W; Da, Z; Wang, B; Hu, L; Zhang, Y; An, R; Yu, H; Sun, H; Tang, K; Tang, Z; Wang, Y; Jing, T; Zhu, B

    2012-03-01

    Mycobacterium bovis bacillus Calmette-Guérin (BCG) priming and subunit vaccine boosting strategies are urgently needed to improve the protective efficacy of BCG in adult population. However, the schedule of subunit vaccine boosting is not well investigated, especially the optimal immune responses and vaccine immunization schedules are still not clear. We have constructed a novel subunit vaccine candidate consisting of fusion protein Ag85B-Mpt64 (190-198)-Mtb8.4 (AMM) in a complex adjuvant composed of dimo-thylidioctyl ammonium bromide (DDA) and BCG polysaccharide nucleic acid (BCG-PSN). In this study, we compared the effect of different boosting schedules of the subunit vaccine in the prime-boost strategies. C57BL/6 mice were primed with BCG first and then boosted with the AMM vaccine once at 10th week, twice at 8th, 10th week, or thrice at 6th, 8th, 10th week, respectively. The immune responses were evaluated at the 14th and 20th weeks, respectively. Twelve weeks after the last immunization, the mice were challenged with virulent Mycobacterium tuberculosis strain H37Rv, and the protective effect was evaluated. The results showed that BCG priming and the AMM vaccine boosting twice induced the strongest antigen-specific IFN-γ and IL-2 production, down-regulated CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) and had the best protective effect among all groups, while boosting thrice induced the strongest IL-4 production and did not improve BCG-primed protection significantly. Boosting BCG with the AMM vaccine twice instead of once or thrice induced strong Th1-type immunity and down-regulated Tregs significantly, which correlated with the best protection against M. tuberculosis infection in mice. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

  1. Can Probiotics Reduce Inflammation and Enhance Gut Immune Health in People Living with HIV: Study Designs for the Probiotic Visbiome for Inflammation and Translocation (PROOV IT) Pilot Trials.

    Science.gov (United States)

    Kim, Connie J; Walmsley, Sharon L; Raboud, Janet M; Kovacs, Colin; Coburn, Bryan; Rousseau, Rodney; Reinhard, Robert; Rosenes, Ron; Kaul, Rupert

    2016-07-01

    Despite substantial improvements in HIV outcomes with combination antiretroviral therapy (cART), morbidity and mortality remain above population norms. The gut mucosal immune system is not completely restored by cART, and the resultant microbial translocation may contribute to chronic inflammation, inadequate CD4 T-cell recovery, and increased rates of serious non-AIDS events. Since the microbial environment surrounding a CD4 T cell may influence its development and function, we hypothesize that probiotics provided during cART might reduce inflammation and improve gut immune health in HIV-positive treatment-naïve individuals (PROOV IT I) and individuals with suboptimal CD4 recovery on cART (PROOV IT II). These prospective, double-blinded, randomized, placebo-controlled, multicenter pilot studies will assess the impact of the probiotic Visbiome at 900 billion bacteria daily. Forty HIV positive cART-naïve men will be randomized in the PROOV IT I study, coincident with antiretroviral initiation, and be followed for 24 weeks. In PROOV IT II, 36 men on cART, but with a CD4 T-cell count below 350 cells/mm(3) will be followed for 48 weeks. The primary outcome for both studies is the comparison of blood CD8 T-cell immune activation. Secondary analyses will include comparison of blood inflammatory biomarkers, microbial translocation, blood and gut immunology and HIV levels, the bacterial community composition, diet, intestinal permeability, and the safety, adherence and tolerability of the study product. These studies will evaluate the ability of probiotics as a safe and tolerable therapeutic intervention to reduce systemic immune activation and to accelerate gut immune restoration in people living with HIV.

  2. Immunization for Women

    Science.gov (United States)

    ... immunization for the entire family. Diseases & Vaccines Overview Immunization Schedules Talk to you doctor about your immunization ... years Immunization Schedule for Children, 7-18 years Immunization News September 29, 2017 CDC released a new ...

  3. Candida Immunity

    Directory of Open Access Journals (Sweden)

    Julian R. Naglik

    2014-01-01

    Full Text Available The human pathogenic fungus Candida albicans is the predominant cause of both superficial and invasive forms of candidiasis. C. albicans primarily infects immunocompromised individuals as a result of either immunodeficiency or intervention therapy, which highlights the importance of host immune defences in preventing fungal infections. The host defence system utilises a vast communication network of cells, proteins, and chemical signals distributed in blood and tissues, which constitute innate and adaptive immunity. Over the last decade the identity of many key molecules mediating host defence against C. albicans has been identified. This review will discuss how the host recognises this fungus, the events induced by fungal cells, and the host innate and adaptive immune defences that ultimately resolve C. albicans infections during health.

  4. Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses.

    Science.gov (United States)

    Dowling, David J; Scott, Evan A; Scheid, Annette; Bergelson, Ilana; Joshi, Sweta; Pietrasanta, Carlo; Brightman, Spencer; Sanchez-Schmitz, Guzman; Van Haren, Simon D; Ninković, Jana; Kats, Dina; Guiducci, Cristiana; de Titta, Alexandre; Bonner, Daniel K; Hirosue, Sachiko; Swartz, Melody A; Hubbell, Jeffrey A; Levy, Ofer

    2017-11-01

    Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow-derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited T H -polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4 + T-cell numbers. TLR8 agonist

  5. Mosaic vaccines elicit CD8+ T cell responses in monkeys that confer immune coverage of diverse HIV strains

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, Will [Los Alamos National Laboratory; Korber, Bette [Los Alamos National Laboratory

    2009-01-01

    Creation of a successful HIV vaccine will require the development of a strategy to generate cellular immunity with sufficient cross-clade breadth to deal with the extreme genetic diversity of the virus. Polyvalent mosaic immunogens derived from in silica recombination of natural strains of HIV are designed to induce cellular immune responses that maximally cover the sequence diversity of circulating virus isolates. Immunization of rhesus monkeys with plasmid DNA and recombinant vaccinia virus vaccine constructs expressing either consensus immunogens or polyvalent mosaic immunogens elicited a CD4+ T lymphocyte-biased response with comparably broad epitope-specific total T lymphocyte specificities. However, immunization with the mosaic immunogens induced HIV-specific CD8+ T lymphocyte responses with markedly greater depth and breadth. Therefore, the use of polyvalent mosaic immunogens is a promising strategy for a global vaccine for HIV.

  6. Innate immunity

    African Journals Online (AJOL)

    not listed in Table 1, epithelial cells and endothelial cells, and to a lesser extent other types of structural cells such as fibroblasts and smooth-muscle cells, are critically involved in promoting both innate and adaptive immune responses. In the case of epithelial cells, this is achieved via production of pro-inflammatory.

  7. Immune Evasion, Immunopathology and the Regulation of the Immune System

    Directory of Open Access Journals (Sweden)

    Bruno Faivre

    2013-02-01

    Full Text Available Costs and benefits of the immune response have attracted considerable attention in the last years among evolutionary biologists. Given the cost of parasitism, natural selection should favor individuals with the most effective immune defenses. Nevertheless, there exists huge variation in the expression of immune effectors among individuals. To explain this apparent paradox, it has been suggested that an over-reactive immune system might be too costly, both in terms of metabolic resources and risks of immune-mediated diseases, setting a limit to the investment into immune defenses. Here, we argue that this view neglects one important aspect of the interaction: the role played by evolving pathogens. We suggest that taking into account the co-evolutionary interactions between the host immune system and the parasitic strategies to overcome the immune response might provide a better picture of the selective pressures that shape the evolution of immune functioning. Integrating parasitic strategies of host exploitation can also contribute to understand the seemingly contradictory results that infection can enhance, but also protect from, autoimmune diseases. In the last decades, the incidence of autoimmune disorders has dramatically increased in wealthy countries of the northern hemisphere with a concomitant decrease of most parasitic infections. Experimental work on model organisms has shown that this pattern may be due to the protective role of certain parasites (i.e., helminths that rely on the immunosuppression of hosts for their persistence. Interestingly, although parasite-induced immunosuppression can protect against autoimmunity, it can obviously favor the spread of other infections. Therefore, we need to think about the evolution of the immune system using a multidimensional trade-off involving immunoprotection, immunopathology and the parasitic strategies to escape the immune response.

  8. Enhanced Th1 and Th2 immune response induction by Human Papilloma virus Type 16 E7 DNA vaccine in a tumoric murine model

    Directory of Open Access Journals (Sweden)

    Alireza Mohebbi

    2017-01-01

    Full Text Available Background and Objectives: Human papilloma virus (HPV is known as the etiologic agent of cervical cancer and second common cancer among women. HPV viruses with the elevated risk of infection have more potentiality to cause cancer. The carcinogenesis in these viruses is accomplished by oncoproteins such as E7. Employing DNA vaccines which code specific antigens such as E7 is a novel therapeutic approach against such cancers. Methods: In the present study, plasmid coding HPV16 E7 was administered intracutaneously to C57BL/6 tumoric mice models for investigation of its immunostimulating potential. PcDNA3.1+ vector was used as control vector. After immunization, spleen of animals were removed. Then, release of lactate dehydrogenase (LDH was evaluated to address the cytotoxic activity (CTL induced by cellular immunity in spleenocytes. Interferon-γ (IFN-γ and interleukin-4 (IL-4 cytokines were also analyzed as profiles of Th1 and Th2, respectively. Anti-inflammatory cytokine interleukin-10 (IL-10 levels were also investigated in tumor microenvironments. Results: Our results showed that CTL activity was higher among samples receiving HPV16 E7 coding vector in comparison to the group receiving pcDNA3.1+ control vector (P < 0.05. Levels of IFN-γ and IL-4 were also higher in the group receiving HPV16 E7 plasmid in comparison to the control group (P < 0.05. Similarly, IL-10 levels were significantly lower in tumor carrying mice groups receiving HPV16 DNA vaccine compare to PBS and pcDNA3.1 receiving control groups. Conclusion: HPV16 E7 expressing DNA vaccine could increase the release of LDH due to immune system CTL activity. Elevation in IFN-γ and IL-4 levels as well as IL-10 reduction indicates an increase in both Th1 and Th2 profiles resulted by using potent DNA vaccine coding HPV16 E7 in tumor animal model.

  9. Local Delivery of OncoVEX(mGM-CSF) Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade.

    Science.gov (United States)

    Moesta, Achim K; Cooke, Keegan; Piasecki, Julia; Mitchell, Petia; Rottman, James B; Fitzgerald, Karen; Zhan, Jinghui; Yang, Becky; Le, Tiep; Belmontes, Brian; Ikotun, Oluwatayo F; Merriam, Kim; Glaus, Charles; Ganley, Kenneth; Cordover, David H; Boden, Andrea M; Ponce, Rafael; Beers, Courtney; Beltran, Pedro J

    2017-10-15

    Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEX(mGM-CSF) (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8(+) depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEX(mGM-CSF) cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3(+)/CD8(+)) was observed in