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Sample records for murine immune responses

  1. Cytokines and Immune Responses in Murine Atherosclerosis.

    PubMed

    Kusters, Pascal J H; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and regulation of inflammation. In recent years, many studies have investigated the role of these molecules in experimental models of atherosclerosis. While some cytokines such as TNF or IFNγ clearly had atherogenic effects, others such as IL-10 were found to be atheroprotective. However, studies investigating the different cytokines in experimental atherosclerosis revealed that the cytokine system is complex with both disease stage-dependent and site-specific effects. In this review, we strive to provide an overview of the main cytokines involved in atherosclerosis and to shed light on their individual role during atherogenesis.

  2. Effects of sodium fluoride on immune response in murine macrophages.

    PubMed

    De la Fuente, Beatriz; Vázquez, Marta; Rocha, René Antonio; Devesa, Vicenta; Vélez, Dinoraz

    2016-08-01

    Excessive fluoride intake may be harmful for health, producing dental and skeletal fluorosis, and effects upon neurobehavioral development. Studies in animals have revealed effects upon the gastrointestinal, renal and reproductive systems. Some of the disorders may be a consequence of immune system alterations. In this study, an in vitro evaluation is made of fluoride immunotoxicity using the RAW 264.7 murine macrophage line over a broad range of concentrations (2.5-75mg/L). The results show that the highest fluoride concentrations used (50-75mg/L) reduce the macrophage population in part as a consequence of the generation of reactive oxygen and/or nitrogen species and consequent redox imbalance, which in turn is accompanied by lipid peroxidation. A decrease in the expression of the antiinflammatory cytokine Il10 is observed from the lowest concentrations (5mg/L). High concentrations (50mg/L) in turn produce a significant increase in the proinflammatory cytokines Il6 and Mip2 from 4h of exposure. In addition, cell phagocytic capacity is seen to decrease at concentrations of ≥20mg/L. These data indicate that fluoride, at high concentrations, may affect macrophages and thus immune system function - particularly with regard to the inflammation autoregulatory processes, in which macrophages play a key role. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Murine immune responses to oral BCG immunization in the presence or absence of prior BCG sensitization.

    PubMed

    Cross, Martin L; Lambeth, Matthew R; Aldwell, Frank E

    2010-02-01

    Oral delivery of live Mycobacterium bovis BCG in a lipid matrix invokes cell-mediated immune (CMI) responses in mice and consequent protection against pulmonary challenge with virulent mycobacteria. To investigate the influence of prior BCG sensitization on oral vaccine efficacy, we assessed CMI responses and BCG colonization of the alimentary tract lymphatics 5 months after oral vaccination, in both previously naive mice and in mice that had been sensitized to BCG by injection 6 months previously. CMI responses did not differ significantly between mice that received subcutaneous BCG followed by oral BCG and those that received either injected or oral BCG alone. In vivo BCG colonization was predominant in the mesenteric lymph nodes after oral vaccination; this colonizing ability was not influenced by prior BCG sensitization. From this murine model study, we conclude that although prior parenteral-route BCG sensitization does not detrimentally affect BCG colonization after oral vaccination, there is no significant immune-boosting effect of the oral vaccine either.

  4. Defining the Immune Response to Ehrlichia species Using Murine Models

    PubMed Central

    Chapes, Stephen K.; Ganta, Roman R.

    2008-01-01

    Pathogenic bacteria belonging to the family Anaplasmataceae include species of the genera Ehrlichia and Anaplasma. Ehrlichia chaffeensis, first known as the causative agent of human monocytic ehrlichiosis, also infects several vertebrate hosts including white-tailed deer, dogs, coyotes and goats. E. chaffeensis is transmitted from the bite of an infected hard tick, such as Amblyomma americanum. E. chaffeensis and other tick-transmitted pathogens have adapted to both the tick and vertebrate host cell environments. Although E. chaffeensis persists in both vertebrate and tick hosts for long periods of time, little is known about that process. Immunological studies will be valuable in assessing how the pathogen persists in nature in both vertebrate and invertebrate hosts. Understanding the host immune response to the pathogen originating from dual host backgrounds is also important to develop effective methods of diagnosis, control and treatment. In this paper, we provide our perspective of the current understanding of the immune response against E. chaffeensis in relation to other related Anaplasmataceae pathogens. PMID:19028013

  5. The Murine Humoral Immune Response to Hepatitis B Surface Antigen: Idiotype Network Pathways.

    NASA Astrophysics Data System (ADS)

    Schick, Michael Roy

    Recognition of a wide spectrum in disease outcomes following Hepatitis B Virus (HBV) infection has led to the suggestion that individual differences may be due to characteristics of the immune response. HBV, a hepatotropic virus, is not directly cytopathic to the host hepatocytes but the cellular damage which does not occur may be due to the host's own immune response. It is this variety in immune response capabilities following natural infection or vaccination which led to the present study in which the murine humoral immune response to hepatitis B surface antigen (HBsAg) was examined. Following immunization with purified HBsAg an anti-HBs response could be detected in 19 inbred strains of mice. The response, which varied among the strains, was linked to the major histocompatibility complex (MHC). Among high responders to HBsAg were two strains in which a poor response to a single epitope could be detected. Although quantitatively serum from these strains resembled serum from other high responders, there was a major difference in the qualitative aspects. Included within this study was the role of idotype networks within the murine anti-HBs response. By directly targeting HBsAg-specific B cells within the framework of an idiotype network by an Ab-2, it was possible to circumvent T cell-dependent regulation of an immune response. In each of five inbred strains of mice immunized with a polyclonal rabbit Ab-2 an Ab-3 population with HBsAg-specificity (Ab -1^') was induced. These mice were also immunized with HBsAg resulting in a higher anti-HBs response as compared to HBsAg immunization alone in all of the strains tested except for one. The response in this strain, normally a low responder to HBsAg, indicated that the mechanisms for genetic restriction of the anti -HBs response was still active, although it was not apparent during anti-Id immunization. The effects of an anti-Id on the murine antibody response to HBsAg may lead to insights on the presence of idiotype

  6. Effect of ammonium metavanadate on the murine immune response

    SciTech Connect

    Cohen, M.D.; Wei, C.I.; Tan, H.; Kao, K.J.

    1986-01-01

    Female B/sub 6/C/sub 3/F/sub 1/ mice were exposed to ammonium metavanadate (NH/sub 4/VO/sub 3/) by intraperitoneal injection every 3 d at 2.5, 5.0, or 10 mg V/kg for 3, 6, or 9 w and were then assayed for alterations in immunoresponsiveness. Resistance to Escherichia coli endotoxin lethality increased in a dose-dependent manner up to 6 w of exposure, while resistance to viable gram-positive Listeria lethality was depressed in a dose-dependent manner. Comparison of LD20 values indicated a 250-fold decrease in resistance to Listeria at the lowest vanadium exposure and a 40% increase in resistance to endotoxin after the highest vanadium exposure. Peritoneal macrophage phagocytic capacities were decreased in a dose-dependent manner, but viabilities remained unaffected. Rosetting capacity of splenic lymphocytes was increased following vanadium exposure. Liver and splenic enlargement was observed, and examination of splenic tissue indicated enhanced formation of megakaryocytes and red blood cell precursors. Subchronic exposure to vanadium may thus disrupt the normal function of the immune system.

  7. Lipopolysaccharide activates innate immune responses in murine intestinal myofibroblasts through multiple signaling pathways

    PubMed Central

    Walton, Kristen L. W.; Holt, Lisa; Sartor, R. Balfour

    2009-01-01

    Myofibroblasts (MF) play an important role in intestinal wound healing. A compromised epithelial barrier exposes intestinal subepithelial MF to luminal bacterial products. However, responses of murine intestinal MF to bacterial adjuvants and potential roles of intestinal MF in innate immune responses are not well defined. Our aims in this study were to determine innate immune responses and intracellular signaling pathways of intestinal MF exposed to LPS, a prototypic Toll-like receptor (TLR) ligand. Expression of TLR4 in primary murine intestinal MF cultures was confirmed by RT-PCR and Western blotting. LPS-induced secretion of prostaglandin E2 (PGE2), interleukin (IL)-6, and keratinocyte-derived chemokines (KC) was measured by ELISA. Intracellular responses to LPS were assessed by Western blotting for NF-κB p65, Iκ-Bα, Akt, p38 MAP kinase, and cyclooxygenase-2 (COX-2). LPS induced rapid phosphorylation of NF-κB p65, Akt, and p38 MAPK and degradation of Iκ-Bα. LPS induced expression of COX-2 and secretion of PGE2 (2.0 ± 0.8-fold induction vs. unstimulated cells), IL-6 (6.6 ± 0.4-fold induction), and KC (12.5 ± 0.4-fold induction). Inhibition of phosphoinositide-3 (PI3)-kinase, p38 MAPK, or NF-κB pathways reduced LPS-induced PGE2, IL-6, and KC secretion. These studies show that primary murine intestinal MF respond to LPS, evidenced by activation of NF-κB, PI3-kinase, and MAPK signaling pathways and secretion of proinflammatory molecules. Inhibition of these pathways attenuated LPS-dependent PGE2, IL-6, and KC production, indicating that LPS activates MF by multiple signaling pathways. These data support the hypothesis that MF are a component of the innate immune system and may exert paracrine effects on adjacent epithelial and immune cells by responding to luminal bacterial adjuvants. PMID:19136385

  8. Peptidorhamnomannan negatively modulates the immune response in a scedosporiosis murine model.

    PubMed

    Xisto, Mariana I D S; Liporagi-Lopes, Livia Cristina; Muñoz, Julián Esteban; Bittencourt, Vera C B; Santos, Giulia M P; Dias, Lucas S; Figueiredo, Rodrigo T; Pinto, Márcia R; Taborda, Carlos P; Barreto-Bergter, Eliana

    2016-11-01

    In this study, we analyzed the impact of immunization with the peptidorhamnomannan (PRM) from the cell wall of the fungus Scedosporium (Lomentospora) prolificans in a murine model of invasive scedosporiosis. Immunization with PRM decreased the survival of mice infected with S. prolificans. Immunization of mice with PRM led to decreased secretion of pro-inflammatory cytokines and chemokines but did not affect the secretion of IL-10. Mice immunized with PRM showed an increase in IgG1 secretion, which is an immunoglobulin linked to a nonprotective response. Splenocytes isolated from mice infected with S. prolificans and immunized with PRM showed no differences in the percentages of Th17 cells and no increase in the frequency of the CD4(+)CD62L(Low) T cell population. PRM-immunized mice showed a significant increase in the percentage of Treg cells. In summary, our results indicated that immunization with PRM did not assist or improve the immunological response against S. prolificans infection. PRM exacerbated the infection process by reducing the inflammatory response, thereby facilitating colonization, virulence and dissemination by the fungus.

  9. Usefulness of the murine model to study the immune response against Histoplasma capsulatum infection.

    PubMed

    Sahaza, Jorge H; Pérez-Torres, Armando; Zenteno, Edgar; Taylor, Maria Lucia

    2014-05-01

    The present paper is an overview of the primary events that are associated with the histoplasmosis immune response in the murine model. Valuable data that have been recorded in the scientific literature have contributed to an improved understanding of the clinical course of this systemic mycosis, which is caused by the dimorphic fungus Histoplasma capsulatum. Data must be analyzed carefully, given that misinterpretation could be generated because most of the available information is based on experimental host-parasite interactions that used inappropriate proceedings, i.e., the non-natural route of infection with the parasitic and virulent fungal yeast-phase, which is not the usual infective phase of the etiological agent of this mycosis. Thus, due to their versatility, complexity, and similarities with humans, several murine models have played a fundamental role in exploring the host-parasite interaction during H. capsulatum infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis

    PubMed Central

    Knight, Jason S.; Luo, Wei; O’Dell, Alexander A.; Yalavarthi, Srilakshmi; Zhao, Wenpu; Subramanian, Venkataraman; Guo, Chiao; Grenn, Robert C.; Thompson, Paul R.; Eitzman, Daniel T.; Kaplan, Mariana J.

    2014-01-01

    Rationale Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. Objective To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Methods and Results Apolipoprotein-E (Apoe)−/− mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe−/− mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Conclusions Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses. PMID:24425713

  11. Effect of Fusarium toxins, T2-toxin and diacetoxyscirpenol on murine T-independent immune responses.

    PubMed Central

    Rosenstein, Y; Kretschmer, R R; Lafarge-Frayssinet, C

    1981-01-01

    Trichothecenes mycotoxins, T2-toxin and diacetoxyscirpenol were investigated for their effect upon T-independent murine immune responses. Both anti-polyvinylpyrrolidone and anti-dinitrophenylficoll responses were enhanced by chronic administration of these toxins. Spleen cells from T2-toxin-treated animals revealed significantly less Thy 1.2+ cells than controls. Spleen cells from Fusarium crude extract-treated animals had a depressed response to phytohaemagglutinin (PHA) as compared with controls. Normal recipients given spleen cells from T2-toxin-treated mice were shown to generate approximately 50% less plaque-forming cells against sheep red blood cells than controls. It is suggested that these effects occur as a result of altered T suppressor-cell function. PMID:6976308

  12. Analysis of the Murine Immune Response to Pulmonary Delivery of Precisely Fabricated Nano- and Microscale Particles

    PubMed Central

    Roberts, Reid A.; Shen, Tammy; Allen, Irving C.; Hasan, Warefta; DeSimone, Joseph M.; Ting, Jenny P. Y.

    2013-01-01

    Nanomedicine has the potential to transform clinical care in the 21st century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs. PMID:23593509

  13. Similarities in murine infection and immune response to Borrelia bissettii and Borrelia burgdorferi sensu stricto.

    PubMed

    Leydet, Brian F; Liang, Fang Ting

    2015-12-01

    In 1982, Borrelia burgdorferi sensu stricto (ss) was identified as the aetiological agent of Lyme disease. Since then an increasing number of Borrelia burgdorferi sensu lato (sl) species have been isolated in the United States. To date, many of these species remain understudied despite mounting evidence associating them with human illness. Borrelia bissettii is a spirochaete closely related to B. burgdorferi that has been loosely associated with human illness. Using an experimental murine infection model, we compared the infectivity and humoral immune response with a North American isolate of B. bissettii and B. burgdorferi using culture, molecular and serological methods. The original B. bissettii cultures were unable to infect immunocompetent mice, but were confirmed to be infectious after adaptation in immunodeficient animals. B. bissettii infection resulted in spirochaete burdens similar to B. burgdorferi in skin, heart and bladder whereas significantly lower burdens were observed in the joint tissues. B. bissettii induced an antibody response similar to B. burgdorferi as measured by both immunoblotting and the C6 ELISA. Additionally, this isolate of B. bissettii was sequenced on the Ion Torrent PGM, which successfully identified many genes orthologous to mammalian virulence factors described in B. burgdorferi. Similarities seen between both infections in this well-characterized murine model contribute to our understanding of the potential pathogenic nature of B. bissettii. Infection dynamics of B. bissettii, and especially the induced humoral response, are similar to B. burgdorferi, suggesting this species may contribute to the epidemiology of human borreliosis.

  14. T-bet modulates the antibody response and immune protection during murine malaria.

    PubMed

    Oakley, Miranda S; Sahu, Bikash R; Lotspeich-Cole, Leda; Majam, Victoria; Thao Pham, Phuong; Sengupta Banerjee, Aditi; Kozakai, Yukiko; Morris, Sheldon L; Kumar, Sanjai

    2014-09-01

    CD4(+) T-cell subtypes govern the synthesis of different Ab isotypes and other immune functions. The influence of CD4(+) T-cell differentiation programs on isotype switching and other aspects of host immunological networks during malaria infection are currently poorly understood. Here, we used Tbx21(-/-) mice deficient for T-bet, a regulator of Th1 CD4(+) T-cell differentiation, to examine the effect of Th1 CD4(+) T cells on the immune protection to nonlethal murine malaria Plasmodium yoelii 17XNL. We found that Tbx21(-/-) mice exhibited significantly lower parasite burden that correlated with elevated levels of IgG1, indicating that T-bet-dependent Ab isotype switching may be responsible for lower parasite burden. Absence of T-bet was also associated with a transient but significant loss of T cells during the infection, suggesting that T-bet may suppress malaria-induced apoptosis or induce proliferation of T cells. However, Tbx21(-/-) mice produced greater numbers of Foxp3(+) CD25(+) regulatory CD4(+) T cells, which may contribute to the early contraction of T cells. Lastly, Tbx21(-/-) mice exhibited unimpaired production of IFN-γ by a diverse repertoire of immune cell subsets and a selective expansion of IFN-γ-producing T cells. These observations may have implications in malaria vaccine design.

  15. Breathprints of model murine bacterial lung infections are linked with immune response.

    PubMed

    Bean, Heather D; Jiménez-Díaz, Jaime; Zhu, Jiangjiang; Hill, Jane E

    2015-01-01

    In this model study, we explored the host's contribution of breath volatiles to diagnostic secondary electrospray ionisation-mass spectrometry (SESI-MS) breathprints for acute bacterial lung infections, their correlation with the host's immune response, and their use in identifying the lung pathogen. Murine airways were exposed to Pseudomonas aeruginosa and Staphylococcus aureus bacterial cell lysates or to PBS (controls), and their breath and bronchoalveolar lavage fluid (BALF) were collected at six time points (from 6 to 120 h) after exposure. Five to six mice per treatment group and four to six mice per control group were sampled at each time. Breath volatiles were analysed using SESI-MS and the BALF total leukocytes, polymorphonuclear neutrophils, lactate dehydrogenase activity, and cytokine concentrations were quantified. Lysate exposure breathprints contain host volatiles that persist for up to 120 h; are pathogen specific; are unique from breathprints of controls, active infections and cleared infections; and are correlated with the host's immune response. Bacterial lung infections induce changes to the host's breath volatiles that are selective and specific predictors of the source of infection. Harnessing the pathogen-specific volatiles in the host's breath may provide useful information for detecting latent bacterial lung infections and managing the spread of respiratory diseases. Copyright ©ERS 2015.

  16. Breathprints of model murine bacterial lung infections are linked with immune response

    PubMed Central

    Bean, Heather D.; Jiménez-Díaz, Jaime; Zhu, Jiangjiang; Hill, Jane E.

    2015-01-01

    In this model study, we explored the host’s contribution of breath volatiles to diagnostic secondary electrospray ionisation-mass spectrometry (SESI-MS) breathprints for acute bacterial lung infections, their correlation with the host’s immune response, and their use in identifying the lung pathogen. Murine airways were exposed to Pseudomonas aeruginosa and Staphylococcus aureus bacterial cell lysates or to PBS (controls), and their breath and bronchoalveolar lavage fluid (BALF) were collected at six time points (from 6 to 120 h) after exposure. Five to six mice per treatment group and four to six mice per control group were sampled at each time. Breath volatiles were analysed using SESI-MS and the BALF total leukocytes, polymorphonuclear neutrophils, lactate dehydrogenase activity, and cytokine concentrations were quantified. Lysate exposure breathprints contain host volatiles that persist for up to 120 h; are pathogen specific; are unique from breathprints of controls, active infections and cleared infections; and are correlated with the host’s immune response. Bacterial lung infections induce changes to the host’s breath volatiles that are selective and specific predictors of the source of infection. Harnessing the pathogen-specific volatiles in the host’s breath may provide useful information for detecting latent bacterial lung infections and managing the spread of respiratory diseases. PMID:25323243

  17. Murine macrophage inflammatory cytokine production and immune activation in response to Vibrio parahaemolyticus infection

    USDA-ARS?s Scientific Manuscript database

    Vibrio parahaemolyticus is the most common cause of bacterial seafood-related illness in the United States. Currently, there is a dearth of literature regarding immunity to infection with this pathogen. Here we studied V. parahaemolyticus-infected RAW 264.7 murine macrophage detecting both pro- and...

  18. Non-thermal nanoelectroablation of UV-induced murine melanomas stimulates an immune response.

    PubMed

    Nuccitelli, Richard; Tran, Kevin; Lui, Kaying; Huynh, Joanne; Athos, Brian; Kreis, Mark; Nuccitelli, Pamela; De Fabo, Edward C

    2012-09-01

    Non-thermal nanoelectroablation therapy completely ablates UV-induced murine melanomas. C57/BL6-HGF/SF transgenic mice were exposed to UV radiation as pups and began to develop visible melanomas 5-6 months later. We have treated 27 of these melanomas in 14 mice with nanosecond pulsed electric field (nsPEF) therapy delivering 2000 electric pulses each 100 ns long and 30 kV/cm at a rate of 5-7 pulses per second. All nanoelectroablated melanoma tumors began to shrink within a day after treatment and gradually disappeared over a period of 12-29 days. Pyknosis of nuclei was evident within 1 h of nsPEF treatment, and DNA fragmentation as detected by TUNEL staining was evident by 6 h after nsPEF treatment. In a melanoma allograft system, nsPEF treatment was superior to tumor excision at accelerating secondary tumor rejection in immune-competent mice, suggesting enhanced stimulation of a protective immune response by nsPEF-treated melanomas. This is supported by the presence of CD4(+) -T cells within treated tumors as well as within untreated tumors located in mice with other melanomas that had been treated with nanoelectroablation at least 19 days earlier. © 2012 John Wiley & Sons A/S.

  19. Procedures for mucosal immunization and analyses of cellular immune response to candidate HIV vaccines in murine and nonhuman primate models.

    PubMed

    Singh, Shailbala; Nehete, Pramod; Hanley, Patrick; Nehete, Bharti; Yang, Guojun; He, Hong; Anthony, Scott M; Schluns, Kimberly S; Sastry, K Jagannadha

    2014-01-01

    Sampling the mucosal tissues and analyses of immune responses are integral to vaccine-development strategies against human immunodeficiency virus (HIV), which is transmitted predominantly across the oro-genital mucosa. While immune assay development and standardization attempts employ mouse models, immunogenicity and protective efficacy that can be extrapolated to humans are realized only from experiments in nonhuman primates. Here, we describe commonly used practices for immunizations in rhesus macaques (Macaca mulatta) along with procedures for obtaining important mucosal tissues samples from macaques and mice. We also describe detailed protocols for two important assays applicable in mouse as well as primate experiments for determining antigen-specific T cells responses induced after vaccination.

  20. TMV-peptide fusion vaccines induce cell-mediated immune responses and tumor protection in two murine models.

    PubMed

    McCormick, Alison A; Corbo, Tina A; Wykoff-Clary, Sherri; Nguyen, Long V; Smith, Mark L; Palmer, Kenneth E; Pogue, Gregory P

    2006-09-29

    Fusion of peptides to viral carriers has proven an effective method for improving cellular immunity. In this study we explore the ability of a plant virus, Tobacco mosaic virus (TMV), to stimulate cellular immunity by interacting directly with immune cells. Fluorescently labeled TMV was incubated in vitro with murine spleen or lymph node cells, and near quantitative labeling of lymphocytes was achieved after 2 h, which persisted for up to 48 h. Direct TMV uptake and upregulation of the CD86 activation marker was measured in nearly all dendritic cells (DCs) by flow cytometry. To demonstrate that TMV can also provide functional antigen delivery and immune stimulation in vivo, two well-characterized T-cell epitopes that provide protection against tumor challenge in mice were fused to TMV coat protein by genetic manipulation, or by chemical conjugation. Vaccination of C57BL/6 mice elicited measurable cellular responses by interferon gamma (IFN gamma) ELISpot and resulted in significantly improved protection from tumor challenge in both the EG.7-Ova and B16 melanoma models. From these results we conclude that TMV was an effective antigen carrier for inducing cellular immune responses to less than 1 microg of peptide.

  1. Interleukin 37 limits monosodium urate crystal-induced innate immune responses in human and murine models of gout.

    PubMed

    Liu, Lei; Xue, Yu; Zhu, Yingfeng; Xuan, Dandan; Yang, Xue; Liang, Minrui; Wang, Juan; Zhu, Xiaoxia; Zhang, Jiong; Zou, Hejian

    2016-11-18

    Interleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models. We investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model. After inhibition of Mer receptor tyrosine kinase (Mertk), levels of IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL-2) were detected by ELISA and expression of mammalian homologs of the drosophila Mad gene 3 (Smad), suppressor of cytokine signaling 3 (SOCS3), NACHT-LRR-PYD-containing protein 3 (NLRP3), and IL-8R of THP-1 were assessed by qPCR and western blot to explore the molecular mechanisms. Our studies strongly indicated that rhIL-37 played a potent immunosuppressive role in the pathogenesis of experimental gout models both in vitro and in vivo, by downregulating proinflammatory cytokines and chemokines, markedly reducing neutrophil and monocyte recruitment, and mitigating pathological joint inflammation. In our studies, rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to block inflammation, including inhibition of NLRP3 and activation of SOCS3. Mertk signaling participated in rhIL-37 inhibitory pathways in gout models. By inhibition of Mertk, the anti-inflammatory effect of rhIL-37 was partly abrogated, and IL-1R8, Smad3 and S​OCS3 expression were suppressed, whereas NLRP3 expression was reactivated. Our studies reveal that IL-37 limits runaway inflammation initiated by MSU crystal

  2. Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.

    PubMed

    Zhang, Ping; Sun, Baodong; Osada, Takuya; Rodriguiz, Ramona; Yang, Xiao Yi; Luo, Xiaoyan; Kemper, Alex R; Clay, Timothy M; Koeberl, Dwight D

    2012-05-01

    Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best

  3. Immunodominant Liver-Specific Expression Suppresses Transgene-Directed Immune Responses in Murine Pompe Disease

    PubMed Central

    Zhang, Ping; Sun, Baodong; Osada, Takuya; Rodriguiz, Ramona; Yang, Xiao Yi; Luo, Xiaoyan; Kemper, Alex R.; Clay, Timothy M.

    2012-01-01

    Abstract Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression

  4. Antitumor effect and immune response induced by local hyperthermia in B16 murine melanoma: Effect of thermal dose

    PubMed Central

    LI, DAN YE; TANG, YANG PING; ZHAO, LING YUN; GENG, CHUAN YING; TANG, JIN TIAN

    2012-01-01

    This study aimed at investigating the antitumor effect and immune response induced by local high-temperature hyperthermia at different thermal doses in B16 murine melanoma. The screened optimal thermal dose (50°C, 15 min) which was demonstrated to be the most effective in immune response activation was applied to the treatment of lung metastasis. The optimal thermal dose was determined by evaluating the tumor volume change, survival period of tumor-bearing mice, and immune indices including interleukin (IL)-2, interferon (IFN)-γ and TNF-α mRNA expression in the spleen of mice subjected to local hyperthermia at various thermal doses. The activation of the immune response was further investigated by rechallenging the cured mice 60 days after hyperthermia treatment. The screened optimal thermal dose combined with immunoadjuvant compound 48/80 was applied for melanoma lung metastasis. While local hyperthermia effectively inhibited B16 melanoma tumor growth and prolonged the survival period of tumor-bearing mice, the antitumor immunity was significantly enhanced and the effect was thermal dose-dependent. Higher temperatures (≥50°C) induced a significant effect even with a short treatment time (≤15 min). No tumor regrowth was observed for rechallenged B16 melanoma in mice following treatment with local hyperthermia at a higher temperature. Local hyperthermia by optimal thermal dose in combination with immunoadjuvant compound 48/80 is an effective approach for the treatment of B16 melanoma lung metastasis. This study indicated that the use of a local high-temperature hyperthermia protocol inhibits tumor growth and stimulates a favorable antitumor immune response against malignant melanoma. The results of these experiments may have clinical significance for the treatment of melanoma. PMID:23205088

  5. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue

    PubMed Central

    Kosteli, Aliki; Sugaru, Eiji; Haemmerle, Guenter; Martin, Jayne F.; Lei, Jason; Zechner, Rudolf; Ferrante, Anthony W.

    2010-01-01

    Obesity elicits an immune response characterized by myeloid cell recruitment to key metabolic organs, including adipose tissue. However, the response of immune cells to nonpathologic metabolic stimuli has been less well studied, and the factors that regulate the metabolic-dependent accumulation of immune cells are incompletely understood. Here we characterized the response of adipose tissue macrophages (ATMs) to weight loss and fasting in mice and identified a role for lipolysis in ATM recruitment and accumulation. We found that the immune response to weight loss was dynamic; caloric restriction of high-fat diet–fed mice led to an initial increase in ATM recruitment, whereas ATM content decreased following an extended period of weight loss. The peak in ATM number coincided with the peak in the circulating concentrations of FFA and adipose tissue lipolysis, suggesting that lipolysis drives ATM accumulation. Indeed, fasting or pharmacologically induced lipolysis rapidly increased ATM accumulation, adipose tissue chemoattractant activity, and lipid uptake by ATMs. Conversely, dietary and genetic manipulations that reduced lipolysis decreased ATM accumulation. Depletion of macrophages in adipose tissue cultures increased expression of adipose triglyceride lipase and genes regulated by FFA, and increased lipolysis. These data suggest that local lipid fluxes are central regulators of ATM recruitment and that once recruited, ATMs form lipid-laden macrophages that can buffer local increases in lipid concentration. PMID:20877011

  6. Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination.

    PubMed

    Corrado, Alessia; Donato, Paolo; Maccari, Silvia; Cecchi, Raffaella; Spadafina, Tiziana; Arcidiacono, Letizia; Tavarini, Simona; Sammicheli, Chiara; Laera, Donatello; Manetti, Andrea Guido Oreste; Ruggiero, Paolo; Galletti, Bruno; Nuti, Sandra; De Gregorio, Ennio; Bertholet, Sylvie; Seubert, Anja; Bagnoli, Fabio; Bensi, Giuliano; Chiarot, Emiliano

    2016-11-30

    Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use.

  7. Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

    PubMed Central

    Corrado, Alessia; Donato, Paolo; Maccari, Silvia; Cecchi, Raffaella; Spadafina, Tiziana; Arcidiacono, Letizia; Tavarini, Simona; Sammicheli, Chiara; Laera, Donatello; Manetti, Andrea Guido Oreste; Ruggiero, Paolo; Galletti, Bruno; Nuti, Sandra; De Gregorio, Ennio; Bertholet, Sylvie; Seubert, Anja; Bagnoli, Fabio; Bensi, Giuliano; Chiarot, Emiliano

    2016-01-01

    Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use. PMID:27901071

  8. A protective role of murine langerin+ cells in immune responses to cutaneous vaccination with microneedle patches

    PubMed Central

    Pulit-Penaloza, Joanna A.; Esser, E. Stein; Vassilieva, Elena V.; Lee, Jeong Woo; Taherbhai, Misha T.; Pollack, Brian P.; Prausnitz, Mark R.; Compans, Richard W.; Skountzou, Ioanna

    2014-01-01

    Cutaneous vaccination with microneedle patches offers several advantages over more frequently used approaches for vaccine delivery, including improved protective immunity. However, the involvement of specific APC subsets and their contribution to the induction of immunity following cutaneous vaccine delivery is not well understood. A better understanding of the functions of individual APC subsets in the skin will allow us to target specific skin cell populations in order to further enhance vaccine efficacy. Here we use a Langerin-EGFP-DTR knock-in mouse model to determine the contribution of langerin+ subsets of skin APCs in the induction of adaptive immune responses following cutaneous microneedle delivery of influenza vaccine. Depletion of langerin+ cells prior to vaccination resulted in substantial impairment of both Th1 and Th2 responses, and decreased post-challenge survival rates, in mice vaccinated cutaneously but not in those vaccinated via the intramuscular route or in non-depleted control mice. Our results indicate that langerin+ cells contribute significantly to the induction of protective immune responses following cutaneous vaccination with a subunit influenza vaccine. PMID:25130187

  9. Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia

    PubMed Central

    2014-01-01

    Background Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death. Methods We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm-/-). Results ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm-/- mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed. Conclusions Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury. PMID:24884546

  10. Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia.

    PubMed

    Eickmeier, Olaf; Kim, Su Youn; Herrmann, Eva; Döring, Constanze; Duecker, Ruth; Voss, Sandra; Wehner, Sibylle; Hölscher, Christoph; Pietzner, Julia; Zielen, Stefan; Schubert, Ralf

    2014-05-29

    Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death. We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm(-/-)). ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm(-/-) mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed. Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.

  11. Immune Response to Tissue Restricted Self-Antigens Induces Airway Inflammation and Fibrosis Following Murine Lung Transplantation

    PubMed Central

    Subramanian, V.; Ramachandran, S.; Banan, B.; Bharat, A.; Wang, X.; Benshoff, N.; Kreisel, D.; Gelman, A. E.; Mohanakumar, T.

    2014-01-01

    Immune responses against lung-associated self-antigens (self-Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self-Ags, K-alpha-1-tubulin (Kα1T) and Collagen V (Col-V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col-V or in combination to both of these self-Ags. As compared to recipients of isotype control Abs Kα1T Abs and/or Col-V Abs-treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis, This inflammation was also associated the accumulation of Kα1T and Col-V specific IFN-γ+ and IL-17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col-V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic lung transplant rejection where the progressive loss of self-tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts. PMID:25220332

  12. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses

    PubMed Central

    Liu, Jun; Yuan, Ying; Chen, Wenna; Putra, Juan; Suriawinata, Arief A.; Schenk, Austin D.; Miller, Halli E.; Guleria, Indira; Barth, Richard J.; Huang, Yina H.; Wang, Li

    2015-01-01

    V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer. PMID:25964334

  13. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.

    PubMed

    Liu, Jun; Yuan, Ying; Chen, Wenna; Putra, Juan; Suriawinata, Arief A; Schenk, Austin D; Miller, Halli E; Guleria, Indira; Barth, Richard J; Huang, Yina H; Wang, Li

    2015-05-26

    V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.

  14. Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction.

    PubMed

    Pène, Frédéric; Zuber, Benjamin; Courtine, Emilie; Rousseau, Christophe; Ouaaz, Fatah; Toubiana, Julie; Tazi, Asmaa; Mira, Jean-Paul; Chiche, Jean-Daniel

    2008-12-15

    Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 x 10(6) CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-alpha and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

  15. Antibody-mediated immunity in CFW mice infected with Mycobacterium lepraemurium. Humoral immune response in murine leprosy.

    PubMed Central

    Rojas-Espinosa, O; Casoluengo-Méndez, M; Díaz, G V

    1976-01-01

    A depression in antibody-mediated immunity (AMI) measured both in terms of circulating antibody and plaque-forming cells in the spleen was observed in CFW mice infected with M. lepraemurium when sheep red blood cells (SRBC) and human gammaglobulin (HGG) were used as antigens. The impairment in AMI was evident only after 75 days of infection thereafter the antibody response to SRBC antigen progressively decreased until the last day of experimentation (135 days). Within the first 60 days of infection no alteration in AMI was observed with the HGG antigen while the response to the SRBC antigen was significantly higher in the infected animals than in uninfected controls. PMID:795574

  16. Nutritional status and immune response in murine experimental Jorge Lobo's disease.

    PubMed

    Barbosa, Adriana Sierra Assencio Almeida; Diório, Suzana Madeira; Pedrini, Silvia Cristina Barboza; Silva, Sônia Maria Uso Ruiz; Sartori, Beatriz Gomes Carreira; Calvi, Sueli Aparecida; Pereira, Paulo Câmara Marques; Vilani-Moreno, Fátima Regina

    2015-09-01

    There are no studies investigating the role of nutritional status and immunity associated with Jorge Lobo's disease. The objective of this study was to evaluate the effects of protein-calorie malnutrition on the immune response of BALB/c mice inoculated with Lacazia loboi. In this study,the animals were divided into four groups: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. The animals of groups G1 and G2 were submitted to malnutrition for 20 days and once installed the animals were inoculated intradermally into the footpad. After 4 months, they were euthanised for the isolation of peritoneal lavage cells and removal of the footpad. The production of IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α, H2 O2 and nitric oxide (NO) was evaluated in the peritoneal lavage cells. The footpad was evaluated regarding the size of macroscopic lesions, number of fungi and viability index. The results showed that the infection did not exert great influence on the body weight of the mice and previous malnutrition was an unfavourable factor for viability index, number of fungi, macroscopic lesion size in the footpad and production of H2 O2 , NO, IL-12, IL-10 and IFN-γ, suggesting that malnutrition significantly altered fungal activity and peritoneal cells. The results suggest considerable interaction between nutrition and immunity in Jorge Lobo's disease.

  17. Innate and adaptive immune response to chronic pulmonary infection of hyphae of Aspergillus fumigatus in a new murine model.

    PubMed

    Wang, Fengyuan; Zhang, Caiyun; Jiang, Yuan; Kou, Caixia; Kong, Qingtao; Long, Nanbiao; Lu, Ling; Sang, Hong

    2017-09-19

    The pathogenesis of chronic pulmonary aspergillosis (CPA) has seldom been studied due partly to a lack of animal models. Since hypha is the main morphology colonizing the airway in CPA, it's critical to study the immune reaction to chronic pulmonary infection of hyphae of Aspergillus fumigatus, which also has seldom been studied in vivo before. We established a novel murine model of chronic pulmonary infection of hyphae by challenging immunocompetent mice with tightly-structured hyphae balls intratracheally, and described the ensuing immunoreaction to hyphae and conidia, and the pathogenesis of CPA. Our experiment proved that the hyphae balls could induce a chronic pulmonary infection for 28 days with a considerable recrudescence at day 28 post-infection. Lungs infected with hyphae balls were remarkable for the many neutrophils and macrophages that flooded into airway lumens, with peribronchiolar infiltration of leukocytes. There was a transient increase of Th2 cells and Th17 cells at day 7 post-infection in the lung tissue. In contrast, lungs infected with conidia showed no peribronchiolar infiltration of leukocytes, but an influx of a great number of macrophages, and a much less number of neutrophils in the lumen. Besides, conidia activated the co-response of Th1, Th2 and Th17 cells with an increase of Treg cells in the lung tissue (quite different from most previous studies). We established a new murine model of chronic infection of hyphae to mimic the formation of CPA, and provide a new marker for different immune responses to hyphae and conidia.

  18. Evaluation of the Murine Immune Response to Xenopsylla cheopis Flea Saliva and Its Effect on Transmission of Yersinia pestis

    PubMed Central

    Bosio, Christopher F.; Viall, Austin K.; Jarrett, Clayton O.; Gardner, Donald; Rood, Michael P.; Hinnebusch, B. Joseph

    2014-01-01

    Background/Aims Arthropod-borne pathogens are transmitted into a unique intradermal microenvironment that includes the saliva of their vectors. Immunomodulatory factors in the saliva can enhance infectivity; however, in some cases the immune response that develops to saliva from prior uninfected bites can inhibit infectivity. Most rodent reservoirs of Yersinia pestis experience fleabites regularly, but the effect this has on the dynamics of flea-borne transmission of plague has never been investigated. We examined the innate and acquired immune response of mice to bites of Xenopsylla cheopis and its effects on Y. pestis transmission and disease progression in both naïve mice and mice chronically exposed to flea bites. Methods/Principal Findings The immune response of C57BL/6 mice to uninfected flea bites was characterized by flow cytometry, histology, and antibody detection methods. In naïve mice, flea bites induced mild inflammation with limited recruitment of neutrophils and macrophages to the bite site. Infectivity and host response in naïve mice exposed to flea bites followed immediately by intradermal injection of Y. pestis did not differ from that of mice infected with Y. pestis without prior flea feeding. With prolonged exposure, an IgG1 antibody response primarily directed to the predominant component of flea saliva, a family of 36–45 kDa phosphatase-like proteins, occurred in both laboratory mice and wild rats naturally exposed to X. cheopis, but a hypersensitivity response never developed. The incidence and progression of terminal plague following challenge by infective blocked fleas were equivalent in naïve mice and mice sensitized to flea saliva by repeated exposure to flea bites over a 10-week period. Conclusions Unlike what is observed with many other blood-feeding arthropods, the murine immune response to X. cheopis saliva is mild and continued exposure to flea bites leads more to tolerance than to hypersensitivity. The immune response to flea

  19. The impact of environmental enrichment on the murine inflammatory immune response

    PubMed Central

    Brod, Samuel; Gobbetti, Thomas; Gittens, Beatrice; Ono, Masahiro; D’Acquisto, Fulvio

    2017-01-01

    Living in a mentally and physically stimulating environment has been suggested to have a beneficial effect on the immune response. This study investigates these effects, utilizing a 2-week program of environmental enrichment (EE) and 2 models of acute inflammation: zymosan-induced peritonitis (ZIP) and the cecal ligation and puncture (CLP) model of sepsis. Our results revealed that following exposure to EE, mice possessed a significantly higher circulating neutrophil to lymphocyte ratio compared with control animals. When subject to ZIP, EE animals exhibit enhanced neutrophil and macrophage influx into their peritoneal cavity. Corresponding results were found in CLP, where we observed an improved capacity for enriched animals to clear systemic microbial infection. Ex vivo investigation of leukocyte activity also revealed that macrophages from EE mice presented an enhanced phagocytic capacity. Supporting these findings, microarray analysis of EE animals revealed the increased expression of immunomodulatory genes associated with a heightened and immunoprotective status. Taken together, these results provide potentially novel mechanisms by which EE influences the development and dynamics of the immune response. PMID:28405616

  20. Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

    PubMed Central

    Jeudy, Sheila; Wardrop, Katherine E.; Alessi, Amy; Dominov, Janice A.

    2011-01-01

    Laminin α2 (LAMA2)-deficient congenital muscular dystrophy is a severe, early-onset disease caused by abnormal levels of laminin 211 in the basal lamina leading to muscle weakness, transient inflammation, muscle degeneration and impaired mobility. In a Lama2-deficient mouse model for this disease, animal survival is improved by muscle-specific expression of the apoptosis inhibitor Bcl-2, conferred by a MyoD-hBcl-2 transgene. Here we investigated early disease stages in this model to determine initial pathological events and effects of Bcl-2 on their progression. Using quantitative immunohistological and mRNA analyses we show that inflammation occurs very early in Lama2-deficient muscle, some aspects of which are reduced or delayed by the MyoD-hBcl-2 transgene. mRNAs for innate immune response regulators, including multiple Toll-like receptors (TLRs) and the inflammasome component NLRP3, are elevated in diseased muscle compared with age-matched controls expressing Lama2. MyoD-hBcl-2 inhibits induction of TLR4, TLR6, TLR7, TLR8 and TLR9 in Lama2-deficient muscle compared with non-transgenic controls, and leads to reduced infiltration of eosinophils, which are key death effector cells. This congenital disease model provides a new paradigm for investigating cell death mechanisms during early stages of pathogenesis, demonstrating that interactions exist between Bcl-2, a multifunctional regulator of cell survival, and the innate immune response. PMID:21850221

  1. Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immune therapeutic responses

    PubMed Central

    Kong, Ling-Yuan; Wu, Adam S.; Doucette, Tiffany; Wei, Jun; Priebe, Waldemar; Fuller, Gregory N.; Qiao, Wei; Sawaya, Raymond; Rao, Ganesh; Heimberger, Amy B.

    2010-01-01

    Purpose Pre-clinical murine model systems used for the assessment of therapeutics have not been predictive of human clinical responses, primarily because their clonotypic nature does not recapitulate the heterogeneous biology and immunosuppressive mechanisms of humans. Relevant model systems with mice that are immunologically competent are needed to evaluate the efficacy of therapeutic agents, especially immunotherapeutics. Experimental Design Using the RCAS/Ntv-a system, mice were engineered to co-express platelet-derived growth factor receptor (PDGF)-B + B-cell lymphoma (Bcl)-2 under the control of the glioneuronal-specific Nestin promoter. The degree and type of tumor-mediated immunosuppression was determined in these endogenously arising gliomas based upon the presence of macrophages and regulatory T cells (Tregs). The immunotherapeutic agent, WP1066, was tested in vivo to assess therapeutic efficacy and immune modulation. Results N-tva mice were injected with RCAS vectors to express PDGF-B + Bcl-2, resulting in both low- and high-grade gliomas. Consistent with observations in human high-grade gliomas, mice with high-grade gliomas also developed a marked intratumoral influx of macrophages that was influenced by tumor signal transducer and activator of transduction (STAT) 3 expression. The presence of intratumoral F4/80 macrophages was a negative prognosticator for long-term survival. In mice expressing both PDGF-B + Bcl-2 that were treated with WP1066, there was 55.5% increase in median survival time (P< 0.01), with an associated inhibition of intratumoral STAT3 and macrophages. Conclusions Although randomization is necessary for including mice in a therapeutic trial, these murine model systems are more suitable for testing therapeutics, and especially immune therapeutics, in the context of translational studies. PMID:20921210

  2. Experimental Murine Candidiasis: Pathological and Immune Responses in T-Lymphocyte-Depleted Mice

    PubMed Central

    Giger, Donald K.; Domer, Judith E.; Moser, Stephen A.; McQuitty, J. T.

    1978-01-01

    Mice depleted of T-lymphocytes by thymectomy and irradiation (TXB) and immunologically competent mice were compared for gross and histological pathology as well as immune responses after cutaneous and/or intravenous challenge with Candida albicans. In response to a first cutaneous inoculation with viable Candida, TXB, sham-operated (SXB), and unmanipulated (normal) mice, all developed lesions of comparable size, duration, and histopathology. When challenged a second time cutaneously, normal and SXB mice developed lesions which were greatly increased in size when compared with those produced by a first cutaneous infection, whereas TXB mice developed lesions comparable in size to those initiated by the first infection. Histologically, the first and second lesions in all animals were acute abscesses predominantly comprised of polymorphonuclear leukocytes. The larger second lesions in SXB and normal mice were accompanied by detectable circulating antibody and by delayed hypersensitivity. Neither circulating antibody nor delayed hypersensitivity were stimulated in the TXB mice. When challenged intravenously, all previously uninfected mice, regardless of T-cell status, were equally susceptible to C. albicans. Contrary to SXB or normal mice, however, TXB mice which had been infected cutaneously were not more resistant to a subsequent intravenous challenge as judged by 6-week survival. The results suggest that T-cells do not play a significant role in innate resistance of mice to systemic candidiasis, but that such cells are important in the development of acquired resistance. PMID:309437

  3. Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis▿

    PubMed Central

    Mallevaey, Thierry; Fontaine, Josette; Breuilh, Laetitia; Paget, Christophe; Castro-Keller, Alexandre; Vendeville, Catherine; Capron, Monique; Leite-de-Moraes, Maria; Trottein, François; Faveeuw, Christelle

    2007-01-01

    CD1d-restricted natural killer T (NKT) cells represent a heterogeneous population of innate memory immune cells expressing both NK and T-cell markers distributed into two major subsets, i.e., invariant NKT (iNKT) cells, which express exclusively an invariant T-cell receptor (TCR) α chain (Vα14Jα18 in mice), and non-iNKT cells, which express more diverse TCRs. NKT cells quickly produce Th1- and/or Th2-type cytokines following stimulation with glycolipid antigen (Ag) and, through this property, play potent immunoregulatory roles in autoimmune diseases, cancer, and infection. No study has addressed the role of NKT cells in metazoan parasite infections so far. We show that during murine schistosomiasis, the apparent frequency of both iNKT cells and non-iNKT cells decreased in the spleen as early as 3 weeks postinfection (p.i.) and that both populations expressed a greater amount of the activation marker CD69 at 6 weeks p.i., suggesting an activated phenotype. Two different NKT-cell-deficient mouse models, namely, TCR Jα18−/− (exclusively deficient in iNKT cells) and CD1d−/− (deficient in both iNKT and non-iNKT cells) mice, were used to explore the implication of these subsets in infection. We show that whereas both iNKT and non-iNKT cells do not have a major impact on the immune response during the early phase (1 and 4 weeks) of infection, they exert important, although opposite, effects on the immune response during the acute phase of the disease (7 and 12 weeks), after schistosome egg production. Indeed, iNKT cells contribute to Th1 cell differentiation whereas non-iNKT cells might be mostly implicated in Th2 cell differentiation in response to parasite Ag. Our findings suggest, for the first time, that helminths activate both iNKT and non-iNKT cells in vivo, enabling them to differentially influence the Th1/Th2 balance of the immune response. PMID:17353286

  4. Murine immune response induced by Leishmania major during the implantation of paraffin tablets.

    PubMed

    Reis, Maria Letícia Costa; Ferreira, Vanessa Martins; Zhang, Xia; Gonçalves, Ricardo; Vieira, Leda Quércia; Tafuri, Washington Luiz; Mosser, David M; Tafuri, Wagner Luiz

    2010-11-01

    We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT-PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL-10 mRNA expression than controls with very little expression of IFN-γ. In contrast, both IFN-γ and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP-1α was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation.

  5. Murine immune response induced by Leishmania major during the implantation of paraffin tablets

    PubMed Central

    Reis, Maria Letícia Costa; Ferreira, Vanessa Martins; Zhang, Xia; Gonçalves, Ricardo; Vieira, Leda Quércia; Tafuri, Washington Luiz; Mosser, David M.

    2011-01-01

    We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT-PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL-10 mRNA expression than controls with very little expression of IFN-γ. In contrast, both IFN-γ and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP-1α was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation. PMID:20857143

  6. Graphene Oxide Attenuates Th2-Type Immune Responses, but Augments Airway Remodeling and Hyperresponsiveness in a Murine Model of Asthma

    PubMed Central

    2015-01-01

    Several lines of evidence indicate that exposure to nanoparticles (NPs) is able to modify airway immune responses, thus facilitating the development of respiratory diseases. Graphene oxide (GO) is a promising carbonaceous nanomaterial with unique physicochemical properties, envisioned for a multitude of medical and industrial applications. In this paper, we determined how exposure to GO modulates the allergic pulmonary response. Using a murine model of ovalbumin (OVA)-induced asthma, we revealed that GO, given at the sensitization stage, augmented airway hyperresponsiveness and airway remodeling in the form of goblet cell hyperplasia and smooth muscle hypertrophy. At the same time, the levels of the cytokines IL-4, IL-5, and IL-13 were reduced in broncho-alveolar lavage (BAL) fluid in GO-exposed mice. Exposure to GO during sensitization with OVA decreased eosinophil accumulation and increased recruitment of macrophages in BAL fluid. In line with the cytokine profiles, sensitization with OVA in the presence of GO stimulated the production of OVA-specific IgG2a and down-regulated the levels of IgE and IgG1. Moreover, exposure to GO increased the macrophage production of the mammalian chitinases, CHI3L1 and AMCase, whose expression is associated with asthma. Finally, molecular modeling has suggested that GO may directly interact with chitinase, affecting AMCase activity, which has been directly proven in our studies. Thus, these data show that GO exposure attenuates Th2 immune response in a model of OVA-induced asthma, but leads to potentiation of airway remodeling and hyperresponsiveness, with the induction of mammalian chitinases. PMID:24847914

  7. Immunomodulation in host-protective immune response against murine tuberculosis through regulation of the T regulatory cell function.

    PubMed

    Das, Shibali; Halder, Kuntal; Goswami, Avranil; Chowdhury, Bidisha Paul; Pal, Nishith K; Majumdar, Subrata

    2015-11-01

    Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is characterized by an infection in lung and spleen. In the present study, we have elucidated the mechanism by which Mycobacterium indicus pranii renders protection in in vivo Mycobacterium tuberculosis infection. We observed that Mycobacterium indicus pranii treated infected C57BL/6 mice showed a strong host-protective Th1 immune response along with a marked decrease in immunosuppressive cytokines, TGF-β, and IL-10-secreting CD4(+) T cells. This Mycobacterium indicus pranii mediated decrease in immunosuppressive cytokines was correlated with the reduction in the elevated frequency of CD4(+)CD25(+) T regulatory cells, along with the reduced TGF-β production from these T regulatory cells in tuberculosis-infected mice. This reduction in the T regulatory cell population was a result of effective modulation of STAT4-STAT5 transcription factor counter-regulation by Mycobacterium indicus pranii, which in turn, reduced the immunosuppressive activity of T regulatory cells. Thus, these findings put forward a detailed mechanistic insight into Mycobacterium indicus pranii mediated regulation of the T regulatory cell functioning during experimental murine tuberculosis, which might be helpful in combating Mycobacterium-induced pathogenesis.

  8. Heterologous Immunity and Persistent Murine Cytomegalovirus Infection

    PubMed Central

    Che, Jenny W.; Daniels, Keith A.; Selin, Liisa K.

    2016-01-01

    ABSTRACT One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of heterologous immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study heterologous immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV+MCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMV+LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57727–734, and the normally subdominant LCMV epitope L2062–2069, indicating a profound private specificity effect in heterologous immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus. IMPORTANCE This study extends our understanding of heterologous immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as

  9. Human anti-murine immune response following administration of radiolabeled monoclonal antibodies

    SciTech Connect

    Reynolds, J.C.; Carrasquillo, J.C.; Larson, S.M.

    1985-05-01

    The author's purpose is to measure circulating anti-murine immunoglobulin antibodies (HAMA) in patients who previously received radiolabeled monoclonal antibodies (MoAb) for tumor imaging and therapy. Because the presence of HAMA may negate further use of MoAb in patients, it is important to determine the frequency and rate of HAMA development. Patients received radiolabeled MoAb Fab 96.5 (IgG2a), Fab 48.7 (IgG1), T101 (IgG2a), B72.3 (IgG1), 9.2.27 (IgG2a) and 791T/36 (IgG2b). HAMA was measured by incubating I-125 labeled 96.5, 48.7 or B72.3 with serum and isolating human IgG with Staphyloccocal protein A cells by centrifugation. The assays were capable of detecting HAMA concentrations which bound 20 ng/ml of monoclonal antibody. 12 of 37 patients who received IgG developed HAMA within 4 months of a single injection. For one patient this occurred as early as 1 week post injection. 2 of 18 patients who received Fab developed HAMA. One of these patients received multiple injections of MoAb. 2 of 3 patients who received IgG2B were positive for HAMA. There was no apparent difference in the positive HAMA when antibody or fragment was given SubQ or IV. The authors conclude that the use of IgG MoAb are more likely to lead to the development of antimurine immunoglobulin antibodies.

  10. Murine immune responses to a Plasmodium vivax-derived chimeric recombinant protein expressed in Brassica napus

    PubMed Central

    2011-01-01

    Background To develop a plant-based vaccine against Plasmodium vivax, two P. vivax candidate proteins were chosen. First, the merozoite surface protein-1 (MSP-1), a major asexual blood stage antigen that is currently considered a strong vaccine candidate. Second, the circumsporozoite protein (CSP), a component of sporozoites that contains a B-cell epitope. Methods A synthetic chimeric recombinant 516 bp gene encoding containing PvMSP-1, a Pro-Gly linker motif, and PvCSP was synthesized; the gene, named MLC, encoded a total of 172 amino acids. The recombinant gene was modified with regard to codon usage to optimize gene expression in Brassica napus. The Ti plasmid inducible gene transfer system was used for MLC chimeric recombinant gene expression in B. napus. Gene expression was confirmed by polymerase chain reaction (PCR), beta-glucuronidase reporter gene (GUS) assay, and Western blot. Results The MLC chimeric recombinant protein expressed in B. napus had a molecular weight of approximately 25 kDa. It exhibited a clinical sensitivity of 84.21% (n = 38) and a clinical specificity of 100% (n = 24) as assessed by enzyme-linked immunosorbent assay (ELISA). Oral immunization of BALB/c mice with MLC chimeric recombinant protein successfully induced antigen-specific IgG1 production. Additionally, the Th1-related cytokines IL-12 (p40), TNF, and IFN-γ were significantly increased in the spleens of the BALB/c mice. Conclusions The chimeric MLC recombinant protein produced in B. napus has potential as both as an antigen for diagnosis and as a valuable vaccine candidate for oral immunization against vivax malaria. PMID:21529346

  11. Effects of fly ash inhalation on murine immune function: effects on systemic response

    SciTech Connect

    Eskew, M.L.; Zarkower, A.; Scheuchenzuber, W.J.; Graham, J.A.

    1982-08-01

    Mice were exposed to fly ash at levels ranging from 728-2221 ..mu..g/m/sup 3/ respirable for varying periods of time, and several immunological parameters were measured. Little change was noted in splenic response to mitogens or cytolytic ability. Splenic lymphocytes from fly ash-exposed mice incorporated significantly more thymidine following subcutaneous sensitization with BCG, although no differences were noted in response of these lymphocytes to PPD. Fly ash exposure of greater than 1 week caused a suppression of antibody response to aerosols of Escherichia coli in the spleen, but not in the mediastinal lymph nodes. Following 3-4 weeks of fly ash exposure, no changes in splenic antibody responses were noted following intravenous injections of LPS or intratracheal injections of DNP-Ficoll. However, after 9 months exposure at higher concentrations of fly ash, splenic plaque-forming responses were significantly suppressed after both aerosol and intratracheal exposure to antigen.

  12. Experimental Vaccine Induces Th1-driven Immune Responses and Resistance to Neisseria gonorrhoeae Infection in a Murine Model

    PubMed Central

    Liu, Yingru; Hammer, Laura A.; Liu, Wensheng; Hobbs, Marcia M.; Zielke, Ryszard A.; Sikora, Aleksandra E.; Jerse, Ann E.; Egilmez, Nejat K.; Russell, Michael W.

    2017-01-01

    Female mice were immunized intravaginally with gonococcal outer membrane vesicles (OMV) plus microencapsulated IL-12, and challenged using an established model of genital infection with Neisseria gonorrhoeae. Whereas sham-immunized and control animals cleared the infection in 10–13 days, those immunized with OMV plus IL-12 cleared infection with homologous gonococcal strains in 6–9 days. Significant protection was also seen after challenge with antigenically distinct strains of N. gonorrhoeae, and protective anamnestic immunity persisted for at least 6 months after immunization. Serum and vaginal IgG and IgA antibodies were generated against antigens expressed by homologous and heterologous strains. Iliac lymph node CD4+ T cells secreted IFNγ, but not IL-4, in response to immunization, and produced IL-17 in response to challenge regardless of immunization. Antigens recognized by immunized mouse serum included several shared between gonococcal strains, including two identified by immunoproteomics approaches as EF-Tu and PotF3. Experiments with immunodeficient mice showed that protective immunity depended upon IFNγ and B cells, presumably to generate antibodies. The results demonstrated that immunity to gonococcal infection can be induced by immunization with a non-living gonococcal antigen, and suggest that efforts to develop a human vaccine should focus on strategies to generate Th1-driven immune responses in the genital tract. PMID:28272393

  13. Murine cell-mediated immune response recognizes an enterovirus group-specific antigen(s).

    PubMed Central

    Beck, M A; Tracy, S M

    1989-01-01

    Splenocytes taken from mice inoculated with coxsackievirus B3 (CVB3) (Nancy) developed an in vitro proliferative response against CVB3 antigen. This response could not be detected earlier than 8 days postinoculation but could be detected up to 28 days after exposure to CB3. CVB3-sensitized splenocytes responded not only to the CVB3 antigen but to other enteroviruses as well. This response was found to be enterovirus specific in that no response was detected to a non-enteroviral picornavirus, encephalomyocarditis virus, or to an unrelated influenza virus. The generation of a splenocyte population capable of responding to an enterovirus group antigen(s) was not limited to inoculation of mice with CVB3, as similar responses were generated when mice were inoculated with CVB2. Cell subset depletions revealed that the major cell type responding to the enterovirus group antigen(s) was the CD4+ T cell. Current evidence suggests that the group antigen(s) resides in the structural proteins of the virus, since spleen cells from mice inoculated with a UV-inactivated, highly purified preparation of CVB3 virions also responded in vitro against enteroviral antigens. PMID:2476566

  14. Fine Mapping of Murine Antibody Responses to Immunization with a Novel Soluble Form of Hepatitis C Virus Envelope Glycoprotein Complex

    PubMed Central

    Ruwona, Tinashe B.; Giang, Erick; Nieusma, Travis

    2014-01-01

    ABSTRACT The hepatitis C virus (HCV) envelope glycoprotein E1E2 complex is a candidate vaccine antigen. Previous immunization studies of E1E2 have yielded various results on its ability to induce virus-neutralizing antibodies in animal models and humans. The murine model has become a vital tool for HCV research owing to the development of humanized mice susceptible to HCV infection. In this study, we investigated the antibody responses of mice immunized with E1E2 and a novel soluble form of E1E2 (sE1E2) by a DNA prime and protein boost strategy. The results showed that sE1E2 elicited higher antibody titers and a greater breadth of reactivity than the wild-type cell-associated E1E2. However, immune sera elicited by either immunogen were only weakly neutralizing. In order to understand the contrasting results of binding and serum neutralizing activities, epitopes targeted by the polyclonal antibody responses were mapped and monoclonal antibodies (MAbs) were generated. The results showed that the majority of serum antibodies were directed to the E1 region 211 to 250 and the E2 regions 421 to 469, 512 to 539, 568 to 609, and 638 to 651, instead of the well-known immunodominant E2 hypervariable region 1 (HVR1). Unexpectedly, in MAb analysis, ∼12% of MAbs isolated were specific to the conserved E2 antigenic site 412 to 423, and 85% of them cross-neutralized multiple HCV isolates. The epitopes recognized by these MAbs are similar but distinct from the previously reported HCV1 and AP33 broadly neutralizing epitopes. In conclusion, E1E2 can prime B cells specific to conserved neutralizing epitopes, but the levels of serum neutralizing antibodies elicited are insufficient for effective virus neutralization. The sE1E2 constructs described in this study can be a useful template for rational antigen engineering. IMPORTANCE Hepatitis C virus infects 2 to 3% of the world's population and is a leading cause of liver failures and the need for liver transplantation. The virus

  15. Murine Dendritic Cells Pulsed with Whole Tumor Lysates Mediate Potent Antitumor Immune Responses in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Fields, R. C.; Shimizu, K.; Mule, J. J.

    1998-08-01

    The highly efficient nature of dendritic cells (DC) as antigen-presenting cells raises the possibility of uncovering in tumor-bearing hosts very low levels of T cell reactivity to poorly immunogenic tumors that are virtually undetectable by other means. Here, we demonstrate the in vitro and in vivo capacities of murine bone marrow-derived, cytokine-driven DC to elicit potent and specific anti-tumor responses when pulsed with whole tumor lysates. Stimulation of naive spleen-derived T cells by tumor lysate-pulsed DC generated tumor-specific proliferative cytokine release and cytolytic reactivities in vitro. In addition, in two separate strains of mice with histologically distinct tumors, s.c. injections of DC pulsed with whole tumor lysates effectively primed these animals to reject subsequent lethal challenges with viable parental tumor cells and, important to note, also mediated significant reductions in the number of metastases established in the lungs. Tumor rejection depended on host-derived CD8+ T cells and, to a lesser extent, CD4+ T cells. Spleens from mice that had rejected their tumors contained specific precursor cytotoxic T lymphocytes. The use of whole tumor lysates as a source of tumor-associated antigen(s) for pulsing of DC circumvents several limitations encountered with other methods as well as provides certain distinct advantages, which are discussed. These data serve as rationale for our recent initiation of a phase I clinical trial of immunization with autologous tumor lysate-pulsed DC in adult and pediatric cancer patients.

  16. PEG modified liposomes containing CRX-601 adjuvant in combination with methylglycol chitosan enhance the murine sublingual immune response to influenza vaccination.

    PubMed

    Oberoi, Hardeep S; Yorgensen, Yvonne M; Morasse, Audrey; Evans, Jay T; Burkhart, David J

    2016-02-10

    The mucosa is the primary point of entry for pathogens making it an important vaccination site to produce a protective mucosal immune response. While the sublingual (SL) mucosa presents several barriers to vaccine penetration, its unique anatomy and physiology makes it one of the best options for mucosal vaccination. Efficient and directed delivery of adjuvants and antigens to appropriate immune mediators in the SL tissue will aid in development of effective SL vaccines against infectious diseases. Herein we demonstrate a robust immune response against influenza antigens co-delivered sublingually with engineered liposomes carrying the synthetic Toll-like receptor-4 agonist, CRX-601. Liposome modification with PEG copolymers (Pluronics), phospholipid-PEG conjugates and chitosan were evaluated for their ability to generate an immune response in a SL murine influenza vaccine model. Phospholipid-PEG conjugates were more effective than Pluronic copolymers in generating stable, surface neutral liposomes. SL vaccination with surface modified liposomes carrying CRX-601 adjuvant generated significant improvements in flu-specific responses compared with unmodified liposomes. Furthermore, the coating of modified liposomes with methylglycol chitosan produced the most effective flu-specific immune response. These results demonstrate efficient SL vaccine delivery utilizing a combination of a muco-adhesive and surface neutral liposomes to achieve a robust mucosal and systemic immune response.

  17. T-2 toxin impairs murine immune response to respiratory reovirus and exacerbates viral bronchiolitis

    SciTech Connect

    Li Maoxiang; Harkema, Jack R.; Islam, Zahidul; Cuff, Chistopher F.; Pestka, James J. . E-mail: Pestka@msu.edu

    2006-11-15

    Exposure to immunosuppressive environmental contaminants is a possible contributing factor to increased occurrence of viral respiratory diseases. The objective of this study was to test the hypothesis that the trichothecene mycotoxin T-2 toxin (T-2), a frequent food contaminant, alters host resistance to lung infection by reovirus, a model respiratory virus. Balb/c mice (4 week old) were treated intraperitoneally with T-2 toxin (1.75 mg/kg bw) or saline vehicle and then intranasally instilled 2 h later with 10{sup 7} plaque forming unit (PFU) of reovirus, strain Lang (T1/L) or saline vehicle. At 10 days post-instillation (PI), both virus plaque-forming responses and reovirus L2 gene expression were 10-fold higher in lungs of T-2-treated mice compared to controls. No-effect and lowest-effect levels for T-2-induced suppression of reovirus clearance were 20 and 200 {mu}g/kg bw, respectively. Respiratory reovirus infection resulted in a mild bronchiolitis with minimal alveolitis, which was markedly exacerbated by T-2 pretreatment. Reovirus exposure induced marked increases in total cells, neutrophils and lymphocytes at 3 and 7 days PI in bronchial alveolar lavage fluid (BALF) whereas macrophages were increased only at 7 days PI. Although prior T-2 exposure attenuated total cell and macrophage counts in BALF of control and infected mice at 3 days PI, the toxin potentiated total cell, macrophage, neutrophil and lymphocyte counts in infected mice at 7 days PI. At 3 days PI, T-2 suppressed reovirus-induced IFN-{gamma} elevation in BALF, but enhanced production of IL-6 and MCP-1. T-2 pretreatment also suppressed reovirus-specific mucosal IgA responses in lung and enteric tract, but potentiated serum IgA and IgG responses. Taken together, T-2 increased lung viral burden, bronchopneumonia and pulmonary cellular infiltration in reovirus-infected mice. These effects might be attributable to reduced alveolar macrophage levels as well as modulated cytokine and mucosal Ig

  18. Evaluation of trained immunity by β-1, 3 (d)-glucan on murine monocytes in vitro and duration of response in vivo.

    PubMed

    Garcia-Valtanen, Pablo; Guzman-Genuino, Ruth Marian; Williams, David L; Hayball, John D; Diener, Kerrilyn R

    2017-03-14

    The β-1, 3 (d)-glucan (β-glucan) present in the cell wall of Candida albicans induces epigenetic changes in human monocytes resulting in primed macrophages exhibiting increased cytokine responsiveness to reinfection. This phenomenon is referred to as trained immunity or innate immune memory. However, whether β-glucan can reprogramme murine monocytes in vitro or induce lasting effects in vivo has yet to be elucidated. Thus, purified murine spleen-derived monocytes were primed with β-glucan in vitro and assessed for markers of differentiation and survival. Important macrophage cell markers during monocyte-to-macrophage differentiation were downregulated and survival enhanced due to partial inhibition of apoptosis. Increased survival and not the β-glucan training effect explained the elevated production of tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) induced by subsequent lipopolysaccharide (LPS) challenge. In vivo, 4 days after systemic administration of β-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFα, IL-6 and IL-10, an effect shown to be short lived as enhanced cytokine production was lost by day 20. Here, we have characterised murine macrophages derived from β-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of β-glucan in vivo declines within a 3-week period.Immunology and Cell Biology advance online publication, 14 March 2017; doi:10.1038/icb.2017.13.

  19. CpG oligodeoxynucleotides augment the murine immune response to the Yersinia pestis F1-V vaccine in bubonic and pneumonic models of plague.

    PubMed

    Amemiya, Kei; Meyers, Jennifer L; Rogers, Taralyn E; Fast, Randy L; Bassett, Anthony D; Worsham, Patricia L; Powell, Bradford S; Norris, Sarah L; Krieg, Arthur M; Adamovicz, Jeffrey J

    2009-04-06

    The current U.S. Department of Defense candidate plague vaccine is a fusion between two Yersinia pestis proteins: the F1 capsular protein, and the low calcium response (Lcr) V-protein. We hypothesized that an immunomodulator, such as CpG oligodeoxynucleotide (ODN)s, could augment the immune response to the plague F1-V vaccine in a mouse model for plague. CpG ODNs significantly augmented the antibody response and efficacy of a single dose of the plague vaccine in murine bubonic and pneumonic models of plague. In the latter study, we also found an overall significant augmentation the immune response to the individual subunits of the plague vaccine by CpG ODN 2006. In a long-term, prime-boost study, CpG ODN induced a significant early augmentation of the IgG response to the vaccine. The presence of CpG ODN induced a significant increase in the IgG2a subclass response to the vaccine up to 5 months after the boost. Our studies showed that CpG ODNs significantly augmented the IgG antibody response to the plague vaccine, which increased the probability of survival in murine models of plague (P<0.0001).

  20. A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model.

    PubMed

    Kim, Julius W; Miska, Jason; Young, Jacob S; Rashidi, Aida; Kane, J Robert; Panek, Wojciech K; Kanojia, Deepak; Han, Yu; Balyasnikova, Irina V; Lesniak, Maciej S

    2017-06-16

    Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system's response following viral infection by comparing replication-incompetent and replication-competent adenoviral vectors. Our findings suggest that cell death caused by replication-competent adenoviral vectors is required to induce a significant anti-tumor immune response and survival benefits in immunocompetent mice bearing intracranial glioma. We observed significant changes in the repertoire of immune cells in the brain and draining lymph nodes and significant recruitment of CD103+ dendritic cells (DCs) in response to oncolytic adenoviral therapy, suggesting the active role of the immune system in anti-tumor response. Our data suggest that the response to oncolytic virotherapy is accompanied by local and systemic immune responses and should be taken in consideration in the future design of the clinical studies evaluating oncolytic virotherapy in patients with glioblastoma multiforme (GBM).

  1. Anaphylatoxin-mediated regulation of the immune response. I. C3a- mediated suppression of human and murine humoral immune responses

    PubMed Central

    1982-01-01

    The C3a fragment of the third component of complement was found to have immunosuppressive properties. C3a is capable of suppressing both specific and polyclonal antibody responses. In contrast, C3a had no effect on antigen- or mitogen-induced B or T cell proliferative responses. The carboxy-terminal arginine is essential for C3a to exhibit its immunosuppressive properties. The serum carboxypeptidase inhibitor 2-mercaptomethyl-5-guanodinopentanoic acid, which prevents cleavage of the terminal arginine that would produce C3ades Arg-77, allowed us to assay the effects of C3a on in vitro immune response systems where serum is required. When the terminal arginine is removed from C3a, the resulting C3ades Arg-77 molecule is nonsuppressive. Helper T lymphocytes are the target of C3a-mediated suppression of the immune response. Substitution of T cells by soluble T cell factors was found to abrogate the C3a suppressive activity. PMID:6978374

  2. Probing the immune and healing response of murine intestinal mucosa by time-lapse 2-photon microscopy of laser-induced lesions with real-time dosimetry

    PubMed Central

    Orzekowsky-Schroeder, Regina; Klinger, Antje; Freidank, Sebastian; Linz, Norbert; Eckert, Sebastian; Hüttmann, Gereon; Gebert, Andreas; Vogel, Alfred

    2014-01-01

    Gut mucosa is an important interface between body and environment. Immune response and healing processes of murine small intestinal mucosa were investigated by intravital time-lapse two-photon excited autofluorescence microscopy of the response to localized laser-induced damage. Epithelial lesions were created by 355-nm, 500-ps pulses from a microchip laser that produced minute cavitation bubbles. Size and dynamics of these bubbles were monitored using a novel interferometric backscattering technique with 80 nm resolution. Small bubbles (< 2.5 µm maximum radius) merely resulted in autofluorescence loss of the target cell. Larger bubbles (7-25 µm) affected several cells and provoked immigration of immune cells (polymorphonuclear leucocytes). Damaged cells were expelled into the lumen, and the epithelium healed within 2 hours by stretching and migration of adjacent epithelial cells. PMID:25360369

  3. Genetic control of T cell responsiveness to the Friend murine leukemia virus envelope antigen. Identification of class II loci of the H-2 as immune response genes

    PubMed Central

    1988-01-01

    T cells primed specifically for the envelope glycoprotein of Friend murine leukemia helper virus (F-MuLV) were prepared by immunizing mice with a recombinant vaccinia virus that expressed the entire env gene of F-MuLV. Significant proliferative responses of F-MuLV envelope- specific, H-2a/b T cells were observed when the T cells were stimulated with antigen-pulsed peritoneal exudate cells (PEC) having the b allele at the K, A beta, A alpha, and E beta loci of the H-2. On the other hand, PEC having only the kappa allele at these loci did not induce the envelope-specific T cell proliferation, even when the PEC had the b allele at the E alpha, S, or D loci. F-MuLV envelope-specific proliferation of H-2a/b T cells under the stimulation of antigen- pulsed, H-2a/b PEC was specifically blocked with anti-I-Ab and anti-I- Ek mAbs but not with anti-Kb, anti-Kk, or anti-I-Ak mAbs. Moreover, (B10.MBR x A/WySn)F1 mice that have the b allele only at the K locus but not in I-A subregion were nonresponders to the envelope glycoprotein, and the bm12 mutation at the A beta locus completely abolished the T cell responsiveness to this antigen. These results indicate that proliferative T cells recognize a limited number of epitopes on F-MuLV envelope protein in the context of I-Ab, hybrid I- Ak/b, and/or hybrid I-Ek/b class II MHC molecules but fail to recognize the same envelope protein in the context of I-Ak or I-Ek molecules. This influence of the H-2I region on T cell recognition of the envelope glycoprotein appeared to control in vivo induction of protective immunity against Friend virus complex after immunization with the vaccinia-F-MuLV env vaccine. Thus, these results provide, for the first time, direct evidence for Ir gene-controlled responder/nonresponder phenotypes influencing the immune response to a pathogenic virus of mice. PMID:3141552

  4. Characterization and Protective Potential of the Immune Response to Taenia solium Paramyosin in a Murine Model of Cysticercosis

    PubMed Central

    Vázquez-Talavera, José; Solís, Carlos F.; Terrazas, Luis I.; Laclette, Juan P.

    2001-01-01

    Paramyosin has been proposed as a vaccine candidate in schistosomiasis and filariasis. However, limited information is available about its protective potential against cysticercosis and the immune response it induces. Immunization of mice with recombinant full-length paramyosin of Taenia solium (TPmy) results in about a 52% reduction in parasite burden after a subsequent challenge by intraperitoneal inoculation of Taenia crassiceps cysticerci. Immunization assays using recombinant fragments of TPmy, corresponding approximately to thirds on the amino, central, or carboxyl regions, suggest that protective epitopes are located mostly in the amino-end third. Proliferation assays using T cells obtained from mice immunized with the full-length recombinant TPmy also showed a preferential response to the amino-terminal fragment. In contrast, antibodies in the sera from these mice predominantly recognize epitopes located in the carboxyl-terminal fragment, being the immunoglobulin G1 subclass, the predominant antibody isotype. Characterization of the cellular immune response induced against the protective amino-terminal fragment reveals production of gamma interferon and interleukin-2, but not interleukin-4, suggesting a Th1-like profile. PMID:11500411

  5. Induction of murine immune responses by DNA encoding a 23-kDa antigen of Cryptosporidium parvum.

    PubMed

    Ehigiator, Humphrey N; Romagnoli, Pablo; Priest, Jeffrey W; Secor, W Evan; Mead, Jan R

    2007-09-01

    Cp23 has been identified as one of the immunodominant antigens involved in the immune response to Cryptosporidium parvum infection. Thus, in this study, Cp23 antigen was investigated as a vaccine candidate using the DNA vaccine model in adult interleukin-12 (IL-12) knockout (KO) mice, which are susceptible to C. parvum infection. Our data show that subcutaneous immunization in the ear with DNA encoding Cp23 (Cp23-DNA) cloned into the pUMVCb4 vector induced a significant anti-Cp23 immunoglobulin G1 (IgG1) and IgG2a antibody response and specific in vitro spleen cell proliferation to recombinant Cp23 as compared to control mice. Long-term memory responses were also detected after administration of the Cp23-DNA vaccine. Furthermore, Cp23-DNA vaccination induced a 50-60% reduction in oocysts shedding, indicating a partial protection against C. parvum infection in IL-12 KO mice. However, it is possible that this protective response was nonspecific because mice immunized with vector only also exhibited lower oocyst shedding than the naive controls. These results suggest that DNA encoding for immunodominant C. parvum antigens may provide an effective means of eliciting humoral and cellular responses and possibly in generating protective immunity against C. parvum infections in mammals.

  6. Antigen specific immune response in Chlamydia muridarum genital infection is dependent on murine microRNAs-155 and -182

    PubMed Central

    Keck, Jonathon; Koundinya, Gopala Krishna Lanka; Castillo, Kevin; Hobel, Sabrina; Chambers, James P.; Yu, Jieh-Juen; Guentzel, M. Neal; Aigner, Achim; Christenson, Lane K.; Arulanandam, Bernard P.

    2016-01-01

    Anti-chlamydial immunity involves efficient presentation of antigens (Ag) to effector cells resulting in Ag-specific immune responses. There is limited information on inherent underlying mechanisms regulating these events. Previous studies from our laboratory have established that select microRNAs (miRs) function as molecular regulators of immunity in Chlamydia muridarum (Cm) genital infection. In this report, we investigated immune cell type-specific miRs, i.e. miR-155 and -182, and the role in Ag-specific immunity. We observed significant up-regulation of miR-155 in C57BL/6 bone marrow derived dendritic cells (BMDC), and miR-182 in splenic Ag-specific CD4+ T-cells. Using mimics and inhibitors, we determined that miR-155 contributed to BMDC activation following Cm infection. Co-cultures of miR-155 over-expressed in BMDC and miR-182 over-expressed in Ag-specific CD4+ T-cells, or miR-155−/− BMDC with miR-182 inhibitor treated Ag-specific CD4+ T-cells, resulted in IFN-γ production comparable to Ag-specific CD4+ T-cells isolated from Cm infected mice. Additionally, miR-182 was significantly up-regulated in intranasally vaccinated mice protected against Cm infection. In vivo depletion of miR-182 resulted in reduction in Ag-specific IFN-γ and genital pathology in Cm infected mice. To the best of our knowledge, this is the first study to report an interaction of miR-155 (in Cm infected DC) and miR-182 (in CD4+ T-cell) resulting in Ag specific immune responses against genital Cm. PMID:27556515

  7. PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

    PubMed

    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.

  8. Impairment of the cellular immune response in acute murine toxoplasmosis: regulation of interleukin 2 production and macrophage-mediated inhibitory effects.

    PubMed Central

    Haque, S; Khan, I; Haque, A; Kasper, L

    1994-01-01

    Depression of the cellular immune response to Toxoplasma gondii has been reported in both mice and humans. The present study was undertaken to determine the kinetics and mechanism of the observed downregulation of interleukin 2 (IL-2) production during experimental murine toxoplasmosis. For these investigations, the cell-mediated immune response to the wild type (PTg) was compared with that to the less-virulent mutant parasite (PTgB), which is deficient in the major surface antigen, p30 (SAG-1). Spleen cells from infected A/J mice failed to proliferate in response to Toxoplasma antigens during the first week of infection. Both PTg- and PTgB-infected A/J mice exhibited a significant reduction in the concanavalin A (Con A)-induced lymphoproliferative response. Further, the response of splenocytes from mice infected with the wild-type parasite was significantly diminished compared with that of mice infected with PTgB. The lymphoproliferative response to Con A reached its nadir at day 7 and remained below control levels for at least 14 days postinfection. By day 21 postinfection, the response to Con A and to Toxoplasma antigens was restored to the level observed prior to day 7. Con A-stimulated culture supernatants of spleen cells from mice on day 7 postinfection contained significantly less IL-2 than normal mice. There was no significant difference in the numbers of binding sites or capacity of high-affinity IL-2 receptors between infected and normal mouse splenocytes as determined by Scatchard analysis. Exogenous IL-2 at different concentrations failed to restore the proliferative response of lymphocytes from infected mice to Con A. Adherent macrophages from 7-day-infected mice were able to suppress IL-2 production by normal splenocytes following stimulation with Con A. The inhibitory activity mediated by infected cells was reversed by the antibody to IL-10 but not transforming growth factor beta. There were insignificant levels of nitric oxide production in both

  9. Differential requirements of MyD88 and TRIF pathways in TLR4-mediated immune responses in murine B cells.

    PubMed

    Yanagibashi, Tsutomu; Nagai, Yoshinori; Watanabe, Yasuharu; Ikutani, Masashi; Hirai, Yoshikatsu; Takatsu, Kiyoshi

    2015-01-01

    LPS stimulates the TLR4/Myeloid differentiation protein-2 (MD-2) complex and promotes a variety of immune responses in B cells. TLR4 has two main signaling pathways, MyD88 and Toll/IL-1R (TIR)-domain-containing adaptor-inducing interferon-β (TRIF) pathways, but relatively few studies have examined these pathways in B cells. In this study, we investigated MyD88- or TRIF-dependent LPS responses in B cells by utilizing their knockout mice. Compared with wild-type (WT) B cells, MyD88(-/-) B cells were markedly impaired in up-regulation of CD86 and proliferation induced by lipid A moiety of LPS. TRIF(-/-) B cells were also impaired in these responses compared with WT B cells, but showed better responses than MyD88(-/-) B cells. Regarding class switch recombination (CSR) elicited by lipid A plus IL-4, MyD88(-/-) B cells showed similar patterns of CSR to WT B cells. However, TRIF(-/-) B cells showed the impaired in the CSR. Compared with WT and MyD88(-/-) B cells, TRIF(-/-) B cells exhibited reduced cell division, fewer IgG1(+) cells per division, and decreased activation-induced cytidine deaminase (Aicda) mRNA expression in response to lipid A plus IL-4. Finally, IgG1 production to trinitrophenyl (TNP)-LPS immunization was impaired in TRIF(-/-) mice, while MyD88(-/-) mice exhibited increased IgG1 production. Thus, MyD88 and TRIF pathways differently regulate TLR4-induced immune responses in B cells.

  10. Subchronic Infection of Porphyromonas gingivalis and Tannerella forsythia Stimulates an Immune Response but Not Arthritis in Experimental Murine Model.

    PubMed

    Hernández-Aguas, Jorday; Montiel-Hernández, José Luis; De La Garza-Ramos, Myriam A; Ruiz-Ramos, Rosa Velia; Escamilla García, Erandi; Guzmán-García, Mario Alberto; Ayón-Haro, Esperanza Raquel; Garza-Elizondo, Mario Alberto

    2017-01-01

    Studies have proposed that Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf) promote a nonspecific inflammatory response that could produce systemic disease. Oral inoculation of Pg and Tf on the immune and arthritis response was evaluated in BALB/C mice divided into four groups: (1) sham; (2) food contaminated with Pg/Tf; (3) complete Freund's adjuvant (CFA) + Pg/Tf; and (4) CFA alone. CFA was administered subcutaneously on days 1 and 14. The arthritis response was monitored for 21 days after day 14 of CFA administration. IL-1β and IL-6 were determined in serum. T cell activation was evaluated by CD25 in salivary lymph nodes or mouse spleen. Pad inflammation appeared by day 19 in the CFA group, but animals with bacteria inoculation presented a delay. A significant increase in IL-6 was found in Groups 3 and 4, but not with respect to IL-1β. We observed an increase in CD25 in cells derived from cervical nodes and in animals with bacteria inoculation and CFA. A local immune response was observed in mice inoculated with Pg and Tf (T cell activation); a systemic response was observed with CFA. Since pad inflammation was delayed by bacterial inoculation this suggests that local T cell activation could decrease pad inflammation.

  11. Subchronic Infection of Porphyromonas gingivalis and Tannerella forsythia Stimulates an Immune Response but Not Arthritis in Experimental Murine Model

    PubMed Central

    Hernández-Aguas, Jorday; Montiel-Hernández, José Luis; Ruiz-Ramos, Rosa Velia; Escamilla García, Erandi; Guzmán-García, Mario Alberto; Ayón-Haro, Esperanza Raquel; Garza-Elizondo, Mario Alberto

    2017-01-01

    Studies have proposed that Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf) promote a nonspecific inflammatory response that could produce systemic disease. Oral inoculation of Pg and Tf on the immune and arthritis response was evaluated in BALB/C mice divided into four groups: (1) sham; (2) food contaminated with Pg/Tf; (3) complete Freund's adjuvant (CFA) + Pg/Tf; and (4) CFA alone. CFA was administered subcutaneously on days 1 and 14. The arthritis response was monitored for 21 days after day 14 of CFA administration. IL-1β and IL-6 were determined in serum. T cell activation was evaluated by CD25 in salivary lymph nodes or mouse spleen. Pad inflammation appeared by day 19 in the CFA group, but animals with bacteria inoculation presented a delay. A significant increase in IL-6 was found in Groups 3 and 4, but not with respect to IL-1β. We observed an increase in CD25 in cells derived from cervical nodes and in animals with bacteria inoculation and CFA. A local immune response was observed in mice inoculated with Pg and Tf (T cell activation); a systemic response was observed with CFA. Since pad inflammation was delayed by bacterial inoculation this suggests that local T cell activation could decrease pad inflammation. PMID:28676826

  12. Pathogenesis and immunity in murine salmonellosis.

    PubMed Central

    Hsu, H S

    1989-01-01

    Salmonella is traditionally described as a facultative intracellular parasite, and host macrophages are regarded as the primary effector cells in both native and acquired immunity in mouse typhoid. This concept has not been unanimously accepted in the literature. Based on cell culture experiments and electron microscopic examinations of infected tissues, we observed that virulent Salmonella typhimurium is killed within polymorphs and macrophages of guinea pigs and mice. In a systemic disease, the organism propagates primarily in the extracellular locations of sinusoids and tissue lesions and within hepatocytes. Hence, it is more likely to be an extracellular pathogen and its virulence is directly related to its antiphagocytic property. The conspicuous absence of macrophages in the primary lesions of murine salmonellosis disputes the likelihood of their significant role in native resistance to the disease. Acquired cellular immunity is expressed as an enhanced antibacterial activity of macrophages facilitated by cytophilic antibodies rather than as an altered antibacterial action of immune macrophages. It is proposed that acquired immunity in murine salmonellosis is a synergistic manifestation of the innate capacity of polymorphs and macrophages to destroy ingested salmonellae, the activated antibacterial functions of macrophages mediated by cytophilic antibodies, the opsonic and agglutinating actions of antiserum, and the accelerated inflammation associated with delayed hypersensitivity to bacterial antigens. Unlike live attenuated vaccines, nonviable vaccines offer a significant, though not a solid, protection against subsequent challenges. Images PMID:2687679

  13. Impact of sex and age on bone marrow immune responses in a murine model of trauma-hemorrhage.

    PubMed

    Schneider, Christian P; Schwacha, Martin G; Chaudry, Irshad H

    2007-01-01

    Although studies have demonstrated that trauma markedly alters the bone marrow immune responses, sex and age are crucial determinants under such conditions and have not been extensively examined. To study this, 21- to 27-day-old (premature), 6- to 8-wk-old (mature), and 20- to 24-mo-old (aged) male and female (proestrus) C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30 +/- 5 mmHg for 90 min) followed by fluid resuscitation. Twenty-four hours after resuscitation, bone marrow cells were harvested. Trauma-hemorrhage induced an increased number of the early pluripotent stem cell-associated bone marrow cell subsets (Sca1(+)CD34(-)CD117(+/-)lin(+/-)) in young mice. The CD117(+) proportion of these cell subsets increased in mature proestrus females, but not in males. Aged males displayed significant lower numbers of Sca1(+)CD34(-)CD117(+/-)lin(+/-) cells compared with young male mice. Trauma-hemorrhage also increased development of granulocyte/macrophage progenitor cells (CD11b(+)Gr-1(+)). Proliferative responses to granulocyte macrophage colony-stimulating factor were maintained in mature and aged proestrus females, but decreased in young mice and mature males. Augmented differentiation into monocyte/macrophage lineage in mature and aged proestrus females was observed and associated with the maintained release of TNF-alpha and IL-6. Conversely, increased IL-10 and PGE(2) production was observed in the male trauma-hemorrhage groups. Thus, sex- and age-specific effects in bone marrow differentiation and immune responses after trauma-hemorrhage occur, which are likely to contribute to the sex- and age-related differences in the systemic immune responses under such conditions.

  14. Effect of orally administered soy milk fermented with Lactobacillus plantarum LAB12 and physical exercise on murine immune responses.

    PubMed

    Appukutty, M; Ramasamy, K; Rajan, S; Vellasamy, S; Ramasamy, R; Radhakrishnan, A K

    2015-01-01

    Probiotics are live microorganisms that confer health benefits through the gastrointestinal microbiota. This nutritional supplement may benefit athletes who undergo rigorous training by maintaining their gastrointestinal functions and overall health. In this study the influence of moderate physical exercise using a graded treadmill exercise, alone or in combination with the consumption of a soy product fermented with Lactobacillus plantarum LAB12 (LAB12), on tumour necrosis factor alpha (TNF-α) responses was investigated in a murine model. Male BALB/c mice were randomly divided into four groups of six mice each (control, exercise alone, LAB12 and LAB12 + exercise). Mice treated with the potential probiotic LAB12 were orally gavaged for 42 days. At autopsy, blood and spleen from the animals were collected. The splenocytes were cultured in the presence of a mitogen, concanavalin A (Con A). The amount of TNF-α produced by the Con A-stimulated splenocytes was quantified using ELISA, while their proliferation was determined using the [(3)H]-thymidine incorporation method. This study shows that LAB12-supplemented and exercise-induced mice showed marked increase (P<0.05) in cell proliferation compared to the control animals. TNF-α production was suppressed (P<0.05) in the LAB12 group compared to the untreated mice. These results demonstrate that supplementation with LAB12 has immunomodulatory effects, under conditions of moderate physical exercise, which may have implications for human athletes. Further investigation in human trials is warranted to confirm and extrapolate these findings.

  15. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.

    PubMed

    Mathios, Dimitrios; Park, Chul-Kee; Marcus, Warren D; Alter, Sarah; Rhode, Peter R; Jeng, Emily K; Wong, Hing C; Pardoll, Drew M; Lim, Michael

    2016-01-01

    Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.

  16. Viral isolation and systemic immune responses after intracameral inoculation of herpes simplex virus type 1 in Igh-1-disparate congenic murine strains.

    PubMed

    Hemady, R; Tauber, J; Ihley, T M; Opremcak, E M; Foster, C S

    1990-11-01

    Igh-1-disparate congenic murine strains differ in their susceptibility to develop contralateral chorioretinitis after intracameral (AC) inoculation with Herpes simplex virus type 1 (HSV-1): 75% of BALB/cByJ (Igh-1a) and 5% of C.B-17 (Igh-1b) develop necrotizing chorioretinitis. To determine the mechanism of influence of host genetics on development of contralateral chorioretinitis, the authors did viral isolation studies in contralateral eyes, determined in vivo and in vitro T-cell responses, and HSV-antibody levels at various times after AC inoculation of BALB/cByJ and C.B-17 mice with HSV-1. Viral isolation was similar in both mouse strains (P less than 0.2). Similarities in systemic immune responses included suppressed delayed-type hypersensitivity responses 5 days, cytotoxic T-lymphocyte and lymphocyte proliferation responses 8 days, and viral neutralizing antibody titers 5 days postinoculation (PI). Differences in systemic immune responses included: (1) delayed-type hypersensitivity responses were not suppressed in C.B-17 mice (P greater than 0.1) and were hyperactive in BALB/cByJ mice (P less than 0.025) 10 days PI and (2) HSV-neutralizing antibody production was higher in C.B-17 mice 10 days PI. These data suggest that the mere presence of HSV-1 in the uninoculated eye is insufficient for the development of chorioretinitis. Virus-specific delayed-type hypersensitivity reactions might be involved in the pathogenesis of retinitis in BALB/cByJ mice; and virus-neutralizing antibodies and suppressed HSV-specific delayed-type hypersensitivity reactions might be instrumental in the protection enjoyed by C.B-17 mice.

  17. Antitumor activity of orally administered maitake α-glucan by stimulating antitumor immune response in murine tumor

    PubMed Central

    Masuda, Yuki; Nakayama, Yoshiaki; Tanaka, Akihiro; Naito, Kenta; Konishi, Morichika

    2017-01-01

    Maitake α-glucan, YM-2A, isolated from Grifola frondosa, has been characterized as a highly α-1,6-branched α-1,4 glucan. YM-2A has been shown to possess an anti-virus effect in mice; however, it does not directly inhibit growth of the virus in vitro, indicating that the anti-virus effect of YM-2A might be associated with modulation of the host immune system. In this study, we found that oral administration of YM-2A could inhibit tumor growth and improve survival rate in two distinct mouse models of colon-26 carcinoma and B16 melanoma. Orally administered YM-2A enhanced antitumor immune response by increasing INF-γ-expressing CD4+ and CD8+ cells in the spleen and INF-γ-expressing CD8+ cells in tumor-draining lymph nodes. In vitro study showed that YM-2A directly activated splenic CD11b+ myeloid cells, peritoneal macrophages and bone marrow-derived dendritic cells, but did not affect splenic CD11b- lymphocytes or colon-26 tumor cells. YM-2A is more slowly digested by pancreatic α-amylase than are amylopectin and rabbit liver glycogen, and orally administered YM-2A enhanced the expression of MHC class II and CD86 on dendritic cells and the expression of MHC class II on macrophages in Peyer’s patches. Furthermore, in vitro stimulation of YM-2A increased the expression of pro-inflammatory cytokines in Peyer’s patch CD11c+ cells. These results suggest that orally administered YM-2A can activate dendritic cells and macrophages in Peyer’s patches, inducing systemic antitumor T-cell response. Thus, YM-2A might be a candidate for an oral therapeutic agent in cancer immunotherapy. PMID:28278221

  18. Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

    PubMed Central

    Fuhrmann, Franziska; Lischke, Timo; Gross, Fridolin; Scheel, Tobias; Bauer, Laura; Kalim, Khalid Wasim; Radbruch, Andreas; Herzel, Hanspeter; Hutloff, Andreas; Baumgrass, Ria

    2016-01-01

    The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount. DOI: http://dx.doi.org/10.7554/eLife.20616.001 PMID:28035902

  19. Mucosal immunization with a flagellin-adjuvanted Hgp44 vaccine enhances protective immune responses in a murine Porphyromonas gingivalis infection model.

    PubMed

    Puth, Sao; Hong, Seol Hee; Park, Mi Jin; Lee, Hye Hwa; Lee, Youn Suhk; Jeong, Kwangjoon; Kang, In-Chol; Koh, Jeong Tae; Moon, Byounggon; Park, Sang Chul; Rhee, Joon Haeng; Lee, Shee Eun

    2017-06-12

    Chronic periodontitis is caused by interactions between the oral polymicrobial community and host factors. Periodontal diseases are associated with dysbiotic shift in oral microbiota. Vaccination against periodontopathic bacteria could be a fundamental therapeutic to modulate polymicrobial biofilms. Because oral cavity is the site of periodontopathic bacterial colonization, mucosal vaccines should provide better protection than vaccines administered systemically. We previously reported that bacterial flagellin is an excellent mucosal adjuvant. In this study, we investigated whether mucosal immunization with a flagellin-adjuvanted polypeptide vaccine induces protective immune responses using a Porphyromonas gingivalis infection model. We employed the Hgp44 domain polypeptide of Arg-gingipain A (RgpA) as a mucosal antigen. Intranasal (IN) immunization induced a significantly higher Hgp44-specific IgG titer in the serum of mice than sublingual (SL) administration. The co-administration of flagellin potentiated serum IgG responses for both the IN and SL vaccinations. On the other hand, the anti-Hgp44-specific IgA titer in the saliva was comparable between IN and SL vaccinations, suggesting SL administration as more compliant vaccination route for periodontal vaccines. The co-administration of flagellin significantly potentiated the secretory IgA response in saliva also. Furthermore, mice administered a mixture of Hgp44 and flagellin via the IN and SL routes exhibited significant reductions in alveolar bone loss induced by live P. gingivalis infections. An intranasally administered Hgp44-flagellin fusion protein induced a comparable level of Hgp44-specific antibody responses to the mixture of Hgp44 and flagellin. Overall, a flagellin-adjuvanted Hgp44 antigen would serve an important component for a multivalent mucosal vaccine against polymicrobial periodontitis.

  20. Oral administration of Lactococcus lactis subsp. lactis JCM5805 enhances lung immune response resulting in protection from murine parainfluenza virus infection.

    PubMed

    Jounai, Kenta; Sugimura, Tetsu; Ohshio, Konomi; Fujiwara, Daisuke

    2015-01-01

    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.

  1. Comparative effects of carbapenems on bacterial load and host immune response in a Klebsiella pneumoniae murine pneumonia model.

    PubMed

    Hilliard, Jamese J; Melton, John L; Hall, LeRoy; Abbanat, Darren; Fernandez, Jeffrey; Ward, Christine K; Bunting, Rachel A; Barron, A; Lynch, A Simon; Flamm, Robert K

    2011-02-01

    Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

  2. Innate immune responses to Pseudomonas aeruginosa infection

    PubMed Central

    Lavoie, Elise G.; Wangdi, Tamding; Kazmierczak, Barbara I.

    2011-01-01

    Innate immune responses play a critical role in controlling acute infections due to Pseudomonas aeruginosa in both mice and in humans. In this review we focus on innate immune recognition and clearance mechanisms that are important for controlling P. aeruginosa in the mammalian lung, with particular attention to those that influence the outcome of in vivo infection in murine models. PMID:21839853

  3. Synergistic combination of murine bone marrow-derived dendritic cells loaded ex vivo with whole tumor lysate and systemic chemotherapy mediates antitumor immune responses in vivo.

    PubMed

    Salem, Mohamed L; Nassef, Mohamed; Gomaa, Soha; Essa, Ibrahim

    2017-09-01

    In order to get mature dendritic cells (DC) that is a crucial prerequisite for success in tumor immunotherapy protocols. Herein, we assumed that administration of murine bone marrow (BM)-derived DC (BM-DC), loaded ex vivo with whole Ehrlich ascites carcinoma (EAC) lysate, in the context of systemic chemotherapy cyclophosphamide (CTX) to induce antitumor immune responses, may be a good strategy to improve the presentation of tumor-specific antigens to the immune system. In the first series of experiments, BM cells generated either from BM of naïve mice or from BM of EAC-bearing mice were cultured in the presence of GM-CSF and IL-4 for 6days. At day 7, cells were loaded for 48h with one of the following maturation agents: EAC lysate (1mg/ml), poly-inosinic: polycytidylic acid [poly(I:C)] (25μg/ml) or mRNA encoding human telomerase reverse transcriptase (hTERT-mRNA) (2μg/ml). In the second series of experiments, EAC-bearing mice were intraperitoneally (i.p.) injected with CTX followed by i.p. vaccination with DC, loaded ex vivo with EAC lysate. DC yield and the phenotypic expression of maturity-related surface markers of DC (i.e. CD11b and CD11c) in both series of experiments were investigated. As a result, a significant decrease in the number of DC generated from poly(I:C)-supplemented BM culture from EAC-bearing mice has been detected. Loading of BM cells with poly(I:C), EAC lysate or hTERT-mRNA could induce the expression of CD11b and CD11c. Additionally, vaccination of EAC-bearing mice with DC loaded ex vivo with EAC lysate following CTX treatment, resulted in increases in the percentage of multiple populations of CD11b(+)CD11c(+) in BM, spleen and peripheral blood (PB). To conclude, further researches to clarify the mechanism involved in DC maturation are crucial not only to comprehend DC biology but also to optimize DC immunotherapy protocols. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Effects of diallyl trisulfide on induction of apoptotic death in murine leukemia WEHI-3 cells in vitro and alterations of the immune responses in normal and leukemic mice in vivo.

    PubMed

    Hung, Fang-Ming; Shang, Hung-Sheng; Tang, Nou-Ying; Lin, Jen-Jyh; Lu, Kung-Wen; Lin, Jing-Pin; Ko, Yang-Ching; Yu, Chien-Chih; Wang, Hai-Lung; Liao, Jung-Chi; Lu, Hsu-Feng; Chung, Jing-Gung

    2015-11-01

    Diallyl trisulfide (DATS), a chemopreventive dietary constituent and extracted from garlic, has been shown to against cultured many types of human cancer cell liens but the fate of apoptosis in murine leukemia cells in vitro and immune responses in leukemic mice remain elusive. Herein, we clarified the actions of DATS on growth inhibition of murine leukemia WEHI-3 cells in vitro and used WEHI-3 cells to generate leukemic mice in vivo, following to investigate the effects of DATS in animal model. In in vitro study, DATS induced apoptosis of WEHI-3 cells through the G0/G1 phase arrest and induction of caspase-3 activation. In in vivo study DATS decreased the weight of spleen of leukemia mice but did not affect the spleen weight of normal mice. DATS promoted the immune responses such as promotions of the macrophage phagocytosis and NK cell activities in WEHI-3 leukemic and normal mice. However, DATS only promotes NK cell activities in normal mice. DATS increases the surface markers of CD11b and Mac-3 in leukemia mice but only promoted CD3 in normal mice. In conclusion, the present study indicates that DATS induces cell death through induction of apoptosis in mice leukemia WHEI-3 cells. DATS also promotes immune responses in leukemia and normal mice in vivo.

  5. Isolation, modulatory functions on murine B cell development and antigen-specific immune responses of BP11, a novel peptide from the chicken bursa of Fabricius.

    PubMed

    Liu, Xiao-Dong; Feng, Xiu-Li; Zhou, Bin; Cao, Rui-Bing; Li, Xin-Feng; Ma, Zhi-Yong; Chen, Pu-Yan

    2012-05-01

    The bursa of Fabricius (BF) is the central humoral immune organ unique to birds which plays important roles in B lymphocyte differentiation. Here, a new bursal peptide (BP11) with the amino acid sequence DVAGKLPDNRT was identified and characterized from BF. It was proved that BP11 promoted CFU pre-B formation, and regulated B cell differentiation, including increase the percentage of immature and mature B cells in BM cells co-cultured with IL-7. BP11 also exerted immunomodulatory function on antigen-specific immune responses in BALB/c mice immunized with inactivated influence virus (AIV, H9N2 subtype) vaccine, including enhancing AIV-specific antibody and cytokine production. Furthermore, it was noteworthy that BP11 stimulated antibody productions and potentiates the Th1 and Th2-type immune responses in dose-dependent manner in chicken. These results suggested that BP11 might be highly relevant for the development of avian immune system.

  6. Transfusion of antibody-opsonized red blood cells results in a shift in the immune response from the red blood cell to the antibody in a murine model.

    PubMed

    Brinc, Davor; Le-Tien, Hoang; Crow, Andrew R; Semple, John W; Freedman, John; Lazarus, Alan H

    2010-09-01

    It is well known that infusion of immunoglobulin (Ig)G-coated cells results in an inhibited antigen-specific humoral immune response compared to the cells themselves, a phenomenon termed antibody-mediated immune suppression (AMIS). Although this AMIS effect has been well described with many different types of cells as well as vaccines and insoluble antigens, the mechanisms behind this effect remain unresolved. To study AMIS in a broad context, three different models of AMIS were studied. In the first, mice were transfused with sheep red blood cells (SRBCs) versus IgG-coated SRBCs. In the second, SRBCs expressing the antigen hen egg white lysozyme (HEL) were studied, and the third model consisted of the diphtheria/tetanus vaccine in the absence versus presence of anti-tetanus IgG. The antibody responses to the SRBCs and HEL-SRBCs, as well as the vaccine, were analyzed for up to 4 weeks after challenge. In these mouse models of immunization, the IgG-coated RBCs or HEL-RBCs induced an antibody response against the IgG, rather than against the RBCs. The decreased response to the RBCs was directly related to the increase of the response against the IgG. The inhibitory AMIS effect using the vaccine strategy again showed an immune response against the IgG, concurrent with a decrease in the immune response against the specific vaccine component targeted. This work demonstrates that, under AMIS conditions, the IgG itself becomes the focus of B cells in the immune system, suggesting a potential mechanism of B-cell regulation. © 2010 American Association of Blood Banks.

  7. Modulation of the Immune Response to DNA Vaccine Encoding Gene of 8-kDa Subunit of Echinococcus granulosus Antigen B Using Murine Interleukin-12 Plasmid in BALB/c Mice

    PubMed Central

    AZIZI, Hakim; KAZEMI, Bahram; BANDEHPOUR, Mojgan; MOHEBALI, Mehdi; KHAMESIPOUR, Ali; ARYAEIPOUR, Mojgan; YAGHOOBI, Hajar; ROKNI, Mohammad Bagher

    2016-01-01

    Background: The current study was designed to evaluate immune responses induced by DNA vaccines encoding 8-kDa subunit of antigen B (HydI) of Echinococcus granulosus and murine interleukin 12 (IL-12) as genetic adjuvants in BALB/c mice. Methods: Expression plasmid pcDNA3.1 containing HydI (pcHyd1) as vaccine along with the murine interleukin 12 (pcMIL12) as adjuvant were used. Thirty-five mice in the five experimental groups received PBS, empty pcDNA3.1, pcHydІ, pcMIL-12, and pcHydІ+ pcMIL-12 in days zero, 14th and 28th. Two weeks after the last immunization, evaluation of the immune response was performed by evaluating the proliferation of splenic lymphocytes, IFN-γ and IL-4, determination of IgG isotyping titer. Results: Mice that received the pcHydI+pcMIL12 exhibited higher levels of lymphocyte proliferation compared to mice that received the pcHydI alone (P<0.001), and produced significantly more IFN-γ in comparison to other groups (P< 0.001). In addition, they produced significantly less IL-4 than mice receiving the PBS and the empty plasmid (P<0.023). The IgG2a levels were clearly higher in pcHydI+pcMIL12 group in comparison with the groups of pcHydI alone, empty plasmid, and PBS. In contrast, IgG1 was elevated in the group of pcHydI. Conclusion: Co-delivery of IL-12 with DNA encoding 8-kDa subunit of antigen B was effective significantly in inducing the immune response in mice. PMID:28127359

  8. Antigen-Specific Gut Inflammation and Systemic Immune Responses Induced by Prolonging Wheat Gluten Sensitization in BALB/c Murine Model.

    PubMed

    Vijaykrishnaraj, M; Mohan Kumar, B V; Muthukumar, S P; Kurrey, Nawneet K; Prabhasankar, P

    2017-09-11

    Gluten-related diseases such as wheat allergy, celiac disease, and gluten intolerance are widespread around the globe to genetically predisposed individuals. The present study aims to develop a wheat-gluten induced BALB/c murine model for addressing wheat-gluten related disorders by sensitizing the wheat gluten through the route of intraperitoneal and oral challenge in prolonged days. During the sensitization, the sera were collected for specific antigliadin antibodies response and proinflammatory markers quantification. Ex vivo primary cells and organs were collected for subsequent analysis of inflammatory profile. Prolonging sensitization of gluten can moderate the antigen-specific inflammatory markers such as IL-1β, IL-4, IL-15, IL-6, IFN-γ and TNF-α levels in mice sera. However, ex vivo primary cells of splenocytes (SPLs) and intestinal epithelial lymphocytes (IELs) significantly increased the IL-6, IL-15, IL-1β, and IL-4 levels in G+ (gliadin and gluten) treated cells. Histopathology staining of jejunum sections indicates enterocyte degeneration in the apical part of villi and damage of tight junctions in G+ (gliadin and gluten) sensitized murine model. Immunohistochemistry of embedded jejunum sections showed significant expression of positive cells of IL-15, tTG and IL-4 in G+ sensitized murine model. In contrast, all markers of gluten-related disorders are expressed exclusively such as tTG, ZO-1, IL-15, IL-6, IL-4, and intestinal inflammation was mediated by iNOS, COX-2, TLR-4 and NF-kBp50 signaling mechanism in G+ sensitized mice.

  9. Immune Responses in Neonates

    PubMed Central

    Basha, Saleem; Surendran, Naveen; Pichichero, Michael

    2015-01-01

    Neonates have little immunological memory and a developing immune system, which increases their vulnerability to infectious agents. Recent advances in understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequency of lymphocytes, antigenic dose and mode of exposure. Studies in neonatal mouse models and human umbilical cord blood cells demonstrate the capability of neonatal immune cells to produce immune responses similar to adults in some aspects but not others. This review focuses mainly on the developmental and functional mechanisms of the human neonatal immune system. In particular, the mechanism of innate and adaptive immunity and the role of neutrophils, antigen presenting cells, differences in subclasses of T lymphocytes (Th1, Th2, Tregs) and B cells are discussed. In addition, we have included the recent developments in neonatal mouse immune system. Understanding neonatal immunity is essential to development of therapeutic vaccines to combat newly emerging infectious agents. PMID:25088080

  10. A T-cell-dependent humoral immune response is preserved during the administration of the nerve agent pre-treatment pyridostigmine bromide in a murine model.

    PubMed

    Griffiths, Gareth D; Telford, Gary; Hooi, Doreen S W; Cook, David L; Wilkinson, Lucy J; Green, Christopher A; Pritchard, David I

    2005-03-01

    Immune regulation, either via the autonomic nervous system or by a proposed "non-neuronal" cholinergic system, suggests that the immune system may be susceptible to perturbation by compounds affecting cholinergic function. Here, the current UK and US nerve agent pre-treatment, pyridostigmine bromide (PB) and the related anti-acetylcholinesterase (AChE) compounds physostigmine (PHY) and BW284c51 were tested for their ability to affect mouse splenocyte function in vitro. In addition, PB, at a dose equivalent to that received during pre-treatment for nerve agent poisoning, was tested for its effect on a T-cell-dependent humoral response to antigen in vivo in the mouse. None of the anti-AChEs tested affected concanavalin A (Con A)-, anti-CD3- or lipopolysaccharide LPS-driven splenocyte proliferation, in vitro, at concentrations expected to give effective nerve agent pre-treatment. However, higher concentrations (>100 microM) particularly of PHY caused some inhibition of the proliferative responses. In vivo, PB or saline was administered via 28-day mini-osmotic pumps to give a 25-40% inhibition of whole blood AChE in the PB-treated animals. During PB or saline administration, primary and secondary doses (i.p.) of sheep red blood cells (SRBC) were given and the humoral response determined by monitoring anti-SRBC IgM and IgG levels. Splenocytes isolated from the experimental animals were also examined for their proliferative and cytokine responses to stimulation. No remarkable effects of PB were seen during the period of AChE inhibition on the humoral immune response. However, a modest elevation in IL-2 and IFN(gamma) in Con A-stimulated lymphocytes was seen in PB-treated animals following pump removal. Overall these data suggest that, in vivo, the SRBC stimulated T-cell-dependent immune response is unaffected by the administration of PB at pre-treatment doses.

  11. Immunization with the cysteine proteinase Ldccys1 gene from Leishmania (Leishmania) chagasi and the recombinant Ldccys1 protein elicits protective immune responses in a murine model of visceral leishmaniasis.

    PubMed

    Ferreira, Josie Haydée L; Gentil, Luciana Girotto; Dias, Suzana Souza; Fedeli, Carlos Eduardo C; Katz, Simone; Barbiéri, Clara Lúcia

    2008-01-30

    The gene Ldccys1 encoding a cysteine proteinase of 30 kDa from Leishmania (Leishmania) chagasi, as well as the recombinant cysteine proteinase rLdccys1, obtained by cloning and expression of the Ldccys1 gene in the pHIS vector, were used to evaluate their ability to induce immune protective responses in BALB/c mice against L. (L.) chagasi infection. Mice were immunized subcutaneously with rLdccys1 plus Bacille Calmette Guerin (BCG) or Propionibacterium acnes as adjuvants or intramuscularly with a plasmid carrying the Ldccys1 gene (Ldccys1/pcDNA3) and CpG ODN as the adjuvant, followed by a booster with rLdccys1 plus CpG ODN. Two weeks after immunization the animals were challenged with 1 x 10(7) amastigotes of L. (L.) chagasi. Both immunization protocols induced significant protection against L. (L.) chagasi infection as shown by a very low parasite load in the spleen of immunized mice compared to the non-immunized controls. However, DNA immunization was 10-fold more protective than immunization with the recombinant protein. Whereas rLdccys1 induced a significant secretion of IFN-gamma and nitric oxide (NO), animals immunized with the Ldccys1 gene increased the production of IgG2a antibodies, IFN-gamma and NO. These results indicated that protection triggered by the two immunization protocols was correlated to a predominant Th1 response.

  12. High-dose cyclophosphamide inhibition of humoral immune response to murine monoclonal antibody 3F8 in neuroblastoma patients: broad implications for immunotherapy.

    PubMed

    Kushner, Brian H; Cheung, Irene Y; Kramer, Kim; Modak, Shakeel; Cheung, Nai-Kong V

    2007-04-01

    The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients. For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8. In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy, > or = 4,000 mg/m2) before 3F8 treatment (P < 0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated <90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at >120 days, P < 0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated <90 days post-MAT versus 13/23 treated >90 days post-MAT (P < 0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P < 0.001), including 5/7 whose 3F8 treatment began <90 days post-MAT. HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.

  13. The cellular and proteomic response of primary and immortalized murine Kupffer cells following immune stimulation diverges from that of monocyte-derived macrophages.

    PubMed

    Tweedell, Rebecca; Tao, Dingyin; Dinglasan, Rhoel R

    2015-01-01

    Kupffer cells (KCs) are the first line of defense in the liver against pathogens, yet several microbes successfully target the liver, bypass immune surveillance, and effectively develop in this tissue. Our current, albeit poor, understanding of KC-pathogen interactions has been largely achieved through the study of primary cells, requiring isolation from large numbers of animals. To facilitate the study of KC biology, an immortalized rat KC line 1, RKC1, was developed. We performed a comparative global proteomic analysis of RKC1 and primary rat KCs (PRKC) to characterize their respective responses to lipopolysaccharide-mediated immune stimulation. We identified patent differences in the proteomic response profile of RKC1 and PRKC to lipopolysaccharide. We observed that PRKC upregulated more immune function pathways and exhibited marked changes in cellular morphology following stimulation. We consequently analyzed the cytoskeletal signaling pathways of these cells in light of the fact that macrophages are known to induce cytoskeletal changes in response to pathogens. Our findings suggest that KCs respond differently to inflammatory stimulus than do monocyte-derived macrophages, and such data may provide insight into how pathogens, such as the malaria parasite, may have evolved mechanisms of liver entry through KCs without detection. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses.

    PubMed

    Zhou, Lian-di; Zhang, Qi-hui; Zhang, Ying; Liu, Jun; Cao, Ya-ming

    2009-04-01

    Lentinan, a (1-3)-beta glucan from Lentinus edodes, is an effective immunostimulatory drug. We tested the effects of lentinan during blood-stage infection by Plasmodium yoelii 17XL (P.y17XL). Pre-treatment of mice with lentinan significantly decreased the parasitemia and increased their survival after infection. Enhanced IL-12, IFN-gamma and NO production induced by lentinan in spleen cells of infected mice revealed that the Th1 immune response was stimulated against malaria infection. In vitro and in vivo, lentinan can result in enhanced expression of MHC II, CD80/CD86, and Toll-like receptors (TLR2/TLR4), and increased production of IL-12 in spleen dendritic cells (DCs) co-cultured with parasitized red blood cells (pRBCs). Moreover, both the number of CD4(+)CD25(+) regulatory T cells (Tregs) and the levels of IL-10 secreted by Tregs were reduced by pre-treatment with lentinan in the spleen of malaria-infected mice. Meanwhile, apoptosis of CD4(+) T cell in spleens of mice pretreated with lentinan was significantly reduced. In summary, lentinan can induce protective Th1 immune responses to control the proliferation of malaria parasites during the blood-stage of P.y17XL infection by stimulating maturation of DCs to inhibit negative regulation of the Th1 immune response by Tregs. Taken together, our findings suggest that lentinan has prophylactic potential for the treatment of malaria.

  15. Induction of a Specific Strong Polyantigenic Cellular Immune Response after Short-Term Chemotherapy Controls Bacillary Reactivation in Murine and Guinea Pig Experimental Models of Tuberculosis▿

    PubMed Central

    Guirado, Evelyn; Gil, Olga; Cáceres, Neus; Singh, Mahavir; Vilaplana, Cristina; Cardona, Pere-Joan

    2008-01-01

    RUTI is a therapeutic vaccine that is generated from detoxified and liposomed Mycobacterium tuberculosis cell fragments that has demonstrated its efficacy in the control of bacillus reactivation after short-term chemotherapy. The aim of this study was to characterize the cellular immune response generated after the therapeutic administration of RUTI and to corroborate the lack of toxicity of the vaccine. Mouse and guinea pig experimental models were infected with a low-dose M. tuberculosis aerosol. RUTI-treated animals showed the lowest bacillary load in both experimental models. RUTI also decreased the percentage of pulmonary granulomatous infiltration in the mouse and guinea pig models. This was not the case after Mycobacterium bovis BCG treatment. Cellular immunity was studied through the characterization of the intracellular gamma interferon (IFN-γ)-producing cells after the splenocytes' stimulation with M. tuberculosis-specific structural and growth-related antigens. Our data show that the difference between the therapeutic administration of BCG and RUTI resides mainly in the stronger activation of IFN-γ+ CD4+ cells and CD8+ cells against tuberculin purified protein derivative, ESAT-6, and Ag85B that RUTI generates. Both vaccines also triggered a specific immune response against the M. tuberculosis structural antigens Ag16kDa and Ag38kDa and a marked mRNA expression of IFN-γ, tumor necrosis factor, interleukin-12, inducible nitric oxide synthase, and RANTES in the lung. The results show that RUTI's therapeutic effect is linked not only to the induction of a Th1 response but also to the stimulation of a quicker and stronger specific immunity against structural and growth-related antigens that reduces both the bacillary load and the pulmonary pathology. PMID:18524883

  16. Enhanced acute immune response in IL-12p35-/- mice is followed by accelerated distinct repair mechanisms in Staphylococcus aureus-induced murine brain abscess.

    PubMed

    Held, Josephin; Preuße, Corinna; Döser, Alexandra; Richter, Lydia; Heppner, Frank L; Stenzel, Werner

    2013-09-01

    Murine Staphylococcus aureus-mediated brain abscess comprises 2 major phases, an initial phase of cerebritis, followed by a healing phase characterized by capsule formation. C57BL/6 wild-type (WT) and IL-12p35(-/-) mice were intracerebrally infected with S. aureus to induce brain abscesses. Clinical disease activity and bacterial load were monitored. The cell populations that were involved, as well as their specific mediators, were analyzed by immunohistochemistry, quantitative real-time polymerase chain reaction, and flow cytometry. In the acute phase, IL-12p35(-/-) mice were protected from disease. This was associated with enhanced recruitment of granulocytes, accompanied by upregulated expression of Il17a, Csf2 (which encodes granulocyte-macrophage colony-stimulating factor), Cxcl1, and Cxcl5, as well as increased expression of proinflammatory mediators, including Nos2 (which encodes inducible nitric oxide synthase), Ptgs2 (which encodes cyclooxygenase 2), and Tnf, that were primarily produced by granulocytes and activated microglia/macrophages. Furthermore, mechanisms associated with beneficial wound healing, including an accelerated formation of a fibrous capsule, were demonstrated by prominent VEGF-A production and collagen deposition driven by an earlier onset of T-helper 2 immunity in the absence of interleukin 12 (IL-12). Brain abscess development is orchestrated by IL-12 at different stages of disease. Our data indicate that IL-12 has a nonprotective role in the acute phase and that IL-12 deficiency results in the accelerated formation of a protective capsule during the healing phase, which we consider crucial for early recovery from disease.

  17. Mexican Trypanosoma cruzi T. cruzi I strains with different degrees of virulence induce diverse humoral and cellular immune responses in a murine experimental infection model.

    PubMed

    Espinoza, B; Rico, T; Sosa, S; Oaxaca, E; Vizcaino-Castillo, A; Caballero, M L; Martínez, I

    2010-01-01

    It is has been shown that the majority of T. cruzi strains isolated from Mexico belong to the T. cruzi I (TCI). The immune response produced in response to Mexican T. cruzi I strains has not been well characterized. In this study, two Mexican T. cruzi I strains were used to infect Balb/c mice. The Queretaro (TBAR/MX/0000/Queretaro)(Qro) strain resulted in 100% mortality. In contrast, no mortality was observed in mice infected with the Ninoa (MHOM/MX/1994/Ninoa) strain. Both strains produced extended lymphocyte infiltrates in cardiac tissue. Ninoa infection induced a diverse humoral response with a higher variety of immunoglobulin isotypes than were found in Qro-infected mice. Also, a stronger inflammatory TH1 response, represented by IL-12p40, IFNgamma, RANTES, MIG, MIP-1beta, and MCP-1 production was observed in Qro-infected mice when compared with Ninoa-infected mice. We propose that an exacerbated TH1 immune response is a likely cause of pathological damage observed in cardiac tissue and the primary cause of death in Qro-infected mice.

  18. Mexican Trypanosoma cruzi T. cruzi I Strains with Different Degrees of Virulence Induce Diverse Humoral and Cellular Immune Responses in a Murine Experimental Infection Model

    PubMed Central

    Espinoza, B.; Rico, T.; Sosa, S.; Oaxaca, E.; Vizcaino-Castillo, A.; Caballero, M. L.; Martínez, I.

    2010-01-01

    It is has been shown that the majority of T. cruzi strains isolated from Mexico belong to the T. cruzi I (TCI). The immune response produced in response to Mexican T. cruzi I strains has not been well characterized. In this study, two Mexican T. cruzi I strains were used to infect Balb/c mice. The Queretaro (TBAR/MX/0000/Queretaro)(Qro) strain resulted in 100% mortality. In contrast, no mortality was observed in mice infected with the Ninoa (MHOM/MX/1994/Ninoa) strain. Both strains produced extended lymphocyte infiltrates in cardiac tissue. Ninoa infection induced a diverse humoral response with a higher variety of immunoglobulin isotypes than were found in Qro-infected mice. Also, a stronger inflammatory TH1 response, represented by IL-12p40, IFNγ, RANTES, MIG, MIP-1β, and MCP-1 production was observed in Qro-infected mice when compared with Ninoa-infected mice. We propose that an exacerbated TH1 immune response is a likely cause of pathological damage observed in cardiac tissue and the primary cause of death in Qro-infected mice. PMID:20396398

  19. Alginate microspheres encapsulated with autoclaved Leishmania major (ALM) and CpG-ODN induced partial protection and enhanced immune response against murine model of leishmaniasis.

    PubMed

    Tafaghodi, Mohsen; Eskandari, Maryam; Khamesipour, Ali; Jaafari, Mahmoud R

    2011-10-01

    A suitable adjuvant and delivery system are needed to enhance efficacy of vaccines against leishmaniasis. In this study, alginate microspheres as an antigen delivery system and CpG-ODN as an immunoadjuvant were used to enhance immune response and induce protection against an experimental autoclaved Leishmania major (ALM) vaccine. Alginate microspheres were prepared by an emulsification technique and the characteristics of the preparation such as size, encapsulation efficiency and release profile of encapsulates were studied. Mean diameter of microspheres was determined using SEM (Scanning Electron Microscopy) and particle size analyzer. The encapsulation efficiency was determined using Lowry protein assay method. The integrity of ALM antigens was assessed using SDS-PAGE. Mean diameter of microspheres was 1.8±1.0μm. BALB/c mice were immunized three times in 3-weeks intervals with ALM+CpG-ODN loaded microspheres [(ALM+CpG)(ALG)], ALM encapsulated alginate microspheres [(ALM)(ALG)], (ALM)(ALG)+CpG, ALM+CpG, ALM alone or PBS. The intensity of infection induced by L. major challenge was assessed by measuring size of footpad swelling. The strongest protection was observed in group of mice immunized with (ALM+CpG)(ALG). The groups of mice received (ALM+CpG)(ALG), (ALM)(ALG)+CpG, (ALM)(ALG) and ALM+CpG were also showed a significantly (P<0.05) smaller footpad swelling compared with the group that received either ALM alone or PBS. The mice immunized with (ALM+CpG)(ALG) or ALM+CpG showed the significantly (P<0.05) highest IgG2a/IgG1 ratio. The IFN-γ level was significantly (P<0.0001) highest in group of mice immunized with either (ALM)(ALG)+CpG or ALM+CpG. It is concluded that alginate microspheres and CpG-ODN adjuvant when are used simultaneously induced protection and enhanced immune response against ALM antigen.

  20. Immune responses to metastases

    SciTech Connect

    Herberman, R.B.; Wiltrout, R.H.; Gorelik, E.

    1987-01-01

    The authors present the changes in the immune system in tumor-bearing hosts that may influence the development of progression of metastases. Included are mononuclear cell infiltration of metastases; alterations in natural resistance mediated by natural killer cells and macrophages; development of specific immunity mediated by T-lymphocytes or antibodies; modulation of tumor-associated antigen expression; and the down-regulation of the immune response to the tumor by several suppressor mechanisms; the augmentation of the immune response and its potential for therapeutic application; includes the prophylaxis of metastases formation by NK cells; the therapy of metastases by augmentation NK-, macrophage-, or T-lymphocyte-mediated responses by biological response modifiers; and the transfer of anticancer activity by cytoxic T-lymphocytes or immunoconjugates of monoclonal antibodies with specificity for tumors.

  1. Effect of Amblyomma maculatum (Acari: Ixodidae) Saliva on the Acute Cutaneous Immune Response to Rickettsia parkeri Infection in a Murine Model

    PubMed Central

    Banajee, K. H.; Verhoeve, V. I.; Harris, E. K.; Macaluso, K. R.

    2016-01-01

    Rickettsia parkeri Luckman (Rickettsiales: Rickettsiaceae) is a pathogenic spotted fever group Rickettsia transmitted by Amblyomma maculatum Koch (Acari: Ixodidae) in the United States. The acute innate immune response to this pathogen and the effect of tick feeding or salivary components on this response is largely unknown. We hypothesized that A. maculatum saliva enhances R. parkeri infection via downregulation of the acute cellular and cytokine immune response. C3H/HeN mice were intradermally inoculated with R. parkeri both with and without A. maculatum saliva. Flow cytometry and microscopic evaluation of inoculation site skin suspensions revealed that neutrophils and macrophages predominated at 6 and 24 h post R. parkeri inoculation, respectively. This cellular influx was significantly downregulated when A. maculatum saliva was inoculated along with R. parkeri. Inflammatory cytokines (interferon γ and interleukins 6 and 10) were significantly elevated after R. parkeri inoculation. However, cytokine concentration and rickettsial load were not significantly modified by A. maculatum saliva during the acute phase of infection. These results revealed that tick saliva inhibits the cutaneous cellular influx during the acute phase of rickettsial infection. Further study is needed to determine the overall impact of this effect on the establishment of rickettsiosis in the host and development of disease. PMID:27521760

  2. CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model

    PubMed Central

    Connolly, Michael; Marketon, Anthony

    2016-01-01

    Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4+ T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID:27239481

  3. Immune enhancement of pulmonary bactericidal activity in murine virus pneumonia.

    PubMed

    Jakab, G J; Green, G M

    1973-11-01

    Bacterial multiplication in the lung associated with murine Sendai virus pneumonia is caused by virus-induced defects in pulmonary bactericidal mechanisms. The nature of this effect has been studied in animals immunized against the challenge bacteria. Mice were immunized against Proteus mirabilis by intraperitoneal inoculation and by aerosol inhalation. After the development of immunity, mice were infected aerogenically with 10(4) TCID(50) of Sendai virus. 7 days later, during the height of the bronchial inflammation and pulmonary consolidation, the mice were challenged with an aerosol of viable (35)S-labeled Proteus mirabilis or (32)P-labeled Staphylococcus aureus.Nonimmunized virus-infected animals showed marked impairment of pulmonary bactericidal activity with subsequent multiplication of the bacterial strain in the case of Proteus mirabilis. Immunized nonvirus-infected animals showed enhancement of pulmonary bactericidal activity for the homologous and heterologous strains in comparison with nonimmunized animals. Virus-infected animals immunized by aerosol showed enhanced bactericidal activity against the homologous but not the heterologous bacterial strain. Neither virus infection nor immunization had a significant effect on the transport of particles in the lung. The data demonstrated that the bacterial multiplication associated with the virus pneumonia was prevented by preceding immunization against the homologous challenge organism. The data suggest a mechanism for controlling bacterial multiplication associated with virus pneumonias.

  4. Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy

    PubMed Central

    MIKYŠKOVÁ, ROMANA; ŠTĚPÁNEK, IVAN; INDROVÁ, MARIE; BIEBLOVÁ, JANA; ŠÍMOVÁ, JANA; TRUXOVÁ, IVA; MOSEROVÁ, IRENA; FUČÍKOVÁ, JITKA; BARTŮŇKOVÁ, JIŘINA; ŠPÍŠEK, RADEK; REINIŠ, MILAN

    2016-01-01

    High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality. PMID:26718011

  5. Cytomegalovirus infection improves immune responses to influenza

    PubMed Central

    Furman, David; Jojic, Vladimir; Sharma, Shalini; Shen-Orr, Shai; Angel, Cesar J Lopez; Onengut-Gumuscu, Suna; Kidd, Brian; Maecker, Holden T; Concannon, Patrick; Dekker, Cornelia L; Thomas, Paul G; Davis, Mark M

    2015-01-01

    Cytomegalovirus (CMV) is a beta-herpes virus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV serostatus. In contrast, CMV-infected young adults exhibited an overall up-regulation of immune components including enhanced antibody responses to influenza vaccination, increased CD8+ T cell sensitivity, and elevated levels of circulating IFN-γ compared to uninfected individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the continued coexistence of CMV and mammals throughout their evolution. PMID:25834109

  6. Immunoglobulin G-mediated regulation of the murine immune response to transfused red blood cells occurs in the absence of active immune suppression: implications for the mechanism of action of anti-D in the prevention of haemolytic disease of the fetus and newborn?

    PubMed Central

    Brinc, Davor; Le-Tien, Hoang; Crow, Andrew R; Siragam, Vinayakumar; Freedman, John; Lazarus, Alan H

    2008-01-01

    Anti-D has been widely and effectively used in Rhesus blood group D negative mothers for the prevention of haemolytic disease of the fetus and newborn; its mechanism of action however, often referred to as antibody-mediated immune suppression (AMIS), remains largely unresolved. We investigated, in a murine model, whether active immune suppression or clonal deletion mediated by anti-red blood cell (RBC) immunoglobulin G (IgG) could explain the phenomenon of AMIS. Transfusion of IgG-opsonized foreign RBCs (i.e. AMIS) strongly attenuated antibody responses compared to transfusion of untreated foreign RBCs. When the AMIS-mice were subsequently transfused with untreated RBCs, no immune suppression was observed at 5 and 35 days after AMIS induction; in fact, the mice responded to retransfusion with untreated RBCs in a manner that was characteristic of a secondary immune response. When IgG-opsonized RBCs were transfused concurrently with untreated RBCs, a dose-dependent reduction of the antibody response was observed. This work suggests that the attenuation of the antibody responsiveness by anti-RBC IgG is not associated with active immune suppression or clonal deletion at either the T-cell or B-cell level; rather, the effect appears more characteristic of B-cell unresponsiveness to IgG-opsonized RBCs. These results may have implications for the understanding of the mechanism of action of anti-D in haemolytic disease of the fetus and newborn. PMID:18266717

  7. Maladjusted host immune responses induce experimental cerebral malaria-like pathology in a murine Borrelia and Plasmodium co-infection model.

    PubMed

    Normark, Johan; Nelson, Maria; Engström, Patrik; Andersson, Marie; Björk, Rafael; Moritz, Thomas; Fahlgren, Anna; Bergström, Sven

    2014-01-01

    In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1β and TNF-α, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.

  8. Exercise boosts immune response.

    PubMed

    Sander, Ruth

    2012-06-29

    Ageing is associated with a decline in normal functioning of the immune system described as 'immunosenescence'. This contributes to poorer vaccine response and increased incidence of infection and malignancy seen in older people. Regular exercise can enhance vaccination response, increase T-cells and boost the function of the natural killer cells in the immune system. Exercise also lowers levels of the inflammatory cytokines that cause the 'inflamm-ageing' that is thought to play a role in conditions including cardiovascular disease; type 2 diabetes; Alzheimer's disease; osteoporosis and some cancers.

  9. Murine immunization by cesium-137 irradiation attenuated Schistosoma mansoni cercariae

    SciTech Connect

    Stek, M. Jr.; Minard, P.; Cruess, D.F.

    1984-06-01

    Cesium-137, becoming a more readily available ionizing gamma radiation source for laboratory use, was shown to effectively attenuate Schistosoma mansoni cercariae for vaccine production. In parallel comparison studies with the murine model, cesium-137 attenuated cercariae consistently afforded better protection than did the cobalt-60 prepared vaccine. Dose-response data indicated that the optimal total irradiation with cesium-137 was between 45 and 50 Krad.

  10. Murine macrophages response to iron.

    PubMed

    Polati, Rita; Castagna, Annalisa; Bossi, Alessandra Maria; Alberio, Tiziana; De Domenico, Ivana; Kaplan, Jerry; Timperio, Anna Maria; Zolla, Lello; Gevi, Federica; D'Alessandro, Angelo; Brunch, Ryan; Olivieri, Oliviero; Girelli, Domenico

    2012-12-05

    Macrophages play a critical role at the crossroad between iron metabolism and immunity, being able to store and recycle iron derived from the phagocytosis of senescent erythrocytes. The way by which macrophages manage non-heme iron at physiological concentration is still not fully understood. We investigated protein changes in mouse bone marrow macrophages incubated with ferric ammonium citrate (FAC 10 μM iron). Differentially expressed spots were identified by nano RP-HPLC-ESI-MS/MS. Transcriptomic, metabolomics and western immunoblotting analyses complemented the proteomic approach. Pattern analysis was also used for identifying networks of proteins involved in iron homeostasis. FAC treatment resulted in higher abundance of several proteins including ferritins, cytoskeleton related proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) at the membrane level, vimentin, arginase, galectin-3 and macrophage migration inhibitory factor (MIF). Interestingly, GAPDH has been recently proposed to act as an alternative transferrin receptor for iron acquisition through internalization of the GAPDH-transferrin complex into the early endosomes. FAC treatment also induced the up-regulation of oxidative stress-related proteins (PRDX), which was further confirmed at the metabolic level (increase in GSSG, 8-isoprostane and pentose phosphate pathway intermediates) through mass spectrometry-based targeted metabolomics approaches. This study represents an example of the potential usefulness of "integarated omics" in the field of iron biology, especially for the elucidation of the molecular mechanisms controlling iron homeostasis in normal and disease conditions. This article is part of a Special Issue entitled: Integrated omics.

  11. Imaging murine NALT following intranasal immunization with flagellin-modified circumsporozoite protein malaria vaccines

    PubMed Central

    Nacer, Adéla; Carapau, Daniel; Mitchell, Robert; Meltzer, Abby; Shaw, Alan; Frevert, Ute; Nardin, Elizabeth H

    2013-01-01

    Intranasal (IN) immunization with a Plasmodium circumsporozoite (CS) protein conjugated to flagellin, a TLR5 agonist, was found to elicit antibody mediated protective immunity in our previous murine studies. To better understand IN elicited immune responses, we examined the nasopharynx-associated lymphoid tissue (NALT) in immunized mice and the interaction of flagellin-modified CS with murine dendritic cells (DC) in vitro. NALT of immunized mice contained a predominance of germinal center (GC) B cells and increased numbers of CD11c+ DC localized beneath the epithelium and within the GC T cell area. We detected microfold (M) cells distributed throughout the NALT epithelial cell layer and DC dendrites extending into the nasal cavity which could potentially function in luminal CS antigen uptake. Flagellin-modified CS taken up by DC in vitro was initially localized within intracellular vesicles followed by a cytosolic distribution. Vaccine modifications to enhance delivery to the NALT and specifically target NALT APC populations will advance development of an efficacious needle-free vaccine for the 40% of the world's population at risk of malaria. PMID:23820750

  12. Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

    PubMed

    Lund, Amanda W; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S; Broggi, Maria A; Spranger, Stefani; Gajewski, Thomas F; Alitalo, Kari; Eikesdal, Hans P; Wiig, Helge; Swartz, Melody A

    2016-09-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.

  13. Lymphatic vessels regulate immune microenvironments in human and murine melanoma

    PubMed Central

    Lund, Amanda W.; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S.; Broggi, Maria A.; Spranger, Stefani; Gajewski, Thomas F.; Alitalo, Kari; Eikesdal, Hans P.

    2016-01-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment. PMID:27525437

  14. Glycobiology of immune responses

    PubMed Central

    Rabinovich, Gabriel A.; van Kooyk, Yvette; Cobb, Brian A.

    2013-01-01

    Unlike their protein “roommates” and their nucleic acid “cousins,” carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners—the microbial (non-self), tumor (altered-self), and host (self)—cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan-binding proteins (mainly C-type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings. PMID:22524422

  15. Triptolide induced cell death through apoptosis and autophagy in murine leukemia WEHI-3 cells in vitro and promoting immune responses in WEHI-3 generated leukemia mice in vivo.

    PubMed

    Chan, Shih-Feng; Chen, Ya-Yin; Lin, Jen-Jyh; Liao, Ching-Lung; Ko, Yang-Ching; Tang, Nou-Ying; Kuo, Chao-Lin; Liu, Kuo-Ching; Chung, Jing-Gung

    2017-02-01

    Triptolide, a traditional Chinese medicine, obtained from Tripterygium wilfordii Hook F, has anti-inflammatory, antiproliferative, and proapoptotic properties. We investigated the potential efficacy of triptolide on murine leukemia by measuring the triptolide-induced cytotoxicity in murine leukemia WEHI-3 cells in vitro. Results indicated that triptolide induced cell morphological changes and induced cytotoxic effects through G0/G1 phase arrest, induction of apoptosis. Flow cytometric assays showed that triptolide increased the production of reactive oxygen species, Ca(2+) release and mitochondrial membrane potential (ΔΨm ), and activations of caspase-8, -9, and -3. Triptolide increased protein levels of Fas, Fas-L, Bax, cytochrome c, caspase-9, Endo G, Apaf-1, PARP, caspase-3 but reduced levels of AIF, ATF6α, ATF6β, and GRP78 in WEHI-3 cells. Triptolide stimulated autophagy based on an increase in acidic vacuoles, monodansylcadaverine staining for LC-3 expression and increased protein levels of ATG 5, ATG 7, and ATG 12. The in vitro data suggest that the cytotoxic effects of triptolide may involve cross-talk between cross-interaction of apoptosis and autophagy. Normal BALB/c mice were i.p. injected with WEHI-3 cells to generate leukemia and were oral treatment with triptolide at 0, 0.02, and 0.2 mg/kg for 3 weeks then animals were weighted and blood, liver, spleen samples were collected. Results indicated that triptolide did not significantly affect the weights of animal body, spleen and liver of leukemia mice, however, triptolide significant increased the cell populations of T cells (CD3), B cells (CD19), monocytes (CD11b), and macrophage (Mac-3). Furthermore, triptolide increased the phagocytosis of macrophage from peripheral blood mononuclear cells (PBMC) but not effects from peritoneum. Triptolide promoted T and B cell proliferation at 0.02 and 0.2 mg/kg treatment when cells were pretreated with Con A and LPS stimulation, respectively; however, triptolide

  16. Excretory-secretory antigens: a suitable candidate for immunization against ocular toxoplasmosis in a murine model.

    PubMed

    Norouzpour Deilami, Kiumars; Daryani, Ahmad; Ahmadpour, Ehsan; Sharif, Mehdi; Dadimoghaddam, Yousef; Sarvi, Shahabeddin; Alizadeh, Ahad

    2014-12-01

    Toxoplasmosis, responsible for ocular impairment, is caused by Toxoplasma gondii. We investigated the effect of Toxoplasma excretory-secretory antigens (ESA) on parasite load and distribution in the eye tissue of a murine model. Case and control groups were immunized with ESA and PBS, respectively. Two weeks after the second immunization, the mice were challenged intraperitoneally with virulent RH strain of Toxoplasma; eye tissue samples of both groups were collected daily (days 1, 2, 3, and the last day before death). Parasite load was determined using real-time quantitative PCR targeted at the B1 gene. Compared to the control group, infected mice that received ESA vaccine presented a considerable decrease in parasite load in the eye tissue, demonstrating the effect of ESA on parasite load and distribution. Diminution of parasite load in mouse eye tissue indicated that ESA might help control disease-related complications and could be a valuable immunization candidate against ocular toxoplasmosis.

  17. B-cell depletion using an anti-CD20 antibody augments antitumor immune responses and immunotherapy in nonhematopoetic murine tumor models.

    PubMed

    Kim, Samuel; Fridlender, Zvi G; Dunn, Robert; Kehry, Marilyn R; Kapoor, Veena; Blouin, Aaron; Kaiser, Larry R; Albelda, Steven M

    2008-06-01

    The role played by B cells in cancer biology is complex and somewhat controversial. Previous studies using genetically engineered mice suggest that B cells may be immunosuppressive and inhibit tumor rejection. However, the effects of B-cell depletion employing an antibody in mice bearing solid tumors has not been tested owing to difficulties in making an effective antimouse CD20 antibody (similar to rituximab). Injection of a newly developed antimouse CD20 antibody was effective in depleting circulating B cells from blood and lymph nodes, although depletion was less complete in the spleen. B-cell depletion slowed the growth of new solid tumors (not expressing CD20) and retarded the growth of established tumors but did not induce tumor regression. However, when the antibody was combined with an active immunotherapy approach using an adenovirus vaccine expressing the human papilloma virus-E7 gene (Ad.E7) in mice bearing TC1 tumors (murine lung cancer cells expressing human papilloma virus-E7), we noted enhanced antitumor effects and increased numbers of tetramer+/CD8+ T cells within the spleens and activated CD8+ T cells within tumors. B-cell depletion using an anti-CD20 antibody was thus effective in retarding tumor growth in multiple solid tumor models and augmenting immunotherapy in a tumor vaccine model. These studies raise the possibility that B-cell depletion may be a useful adjunct in human immunotherapy trials.

  18. Selenium and immune responses

    SciTech Connect

    Kiremidjian-Schumacher, L.; Stotzky, G.

    1987-04-01

    Selenium (Se) affects all components of the immune system, i.e., the development and expression of nonspecific, humoral, and cell-mediated responses. In general, a deficiency in Se appears to result in immunosuppression, whereas supplementation with low doses of Se appears to result in augmentation and/or restoration of immunologic functions. A deficiency of Se has been shown to inhibit (1) resistance to microbial and viral infections, (2) neutrophil function, (3) antibody production, (4) proliferation of T and B lymphocytes in response to mitogens, and (5) cytodestruction by T lymphocytes and NK cells. Supplementation with Se has been shown to stimulate (1) the function of neutrophils, (2) production of antibodies, (3) proliferation of T and B lymphocytes in response to mitogens, (4) production of lymphokines, (5) NK cell-mediated cytodestruction, (6) delayed-type hypersensitivity reactions and allograft rejection, and (7) the ability of a host to reject transplanted malignant tumors. The mechanism(s) whereby Se affects the immune system is speculative. The effects of Se on the function of glutathione peroxidase and on the cellular levels of reduced glutathione and H/sub 2/Se, as well as the ability of Se to interact with cell membranes, probably represent only a few of many regulatory mechanisms. The manipulation of cellular levels of Se may be significant for the maintenance of general health and for the control of immunodeficiency disorders and the chemoprevention of cancer.

  19. Immunostimulatory sequence CpG elicits Th1-type immune responses in inflammatory skin lesions in an atopic dermatitis murine model.

    PubMed

    Wang, Guoying; Fyhrquist-Vanni, Nanna; Wolff, Henrik; Dieu-Nosjean, Marie-Caroline; Kemeny, Lajos; Homey, Bernard; Lauerma, Antti I; Alenius, Harri

    2008-01-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease, for which no fundamental therapy exists. Immunostimulatory sequence CpG (ISS CpG) has potential in reducing susceptibility to allergic diseases and reversing established allergic reactions. To investigate the effects of ISS CpG in the prevention and treatment of AD in an AD murine model. BALB/c mice were epicutaneously exposed to ovalbumin (OVA) for 3 or 4 weeks with a 2-week resting period between each exposure week. ISS i.d. injection was given either on the 1st day of each exposure week (in the prevention experiment) or 3 days before and on the 1st, 4th and 7th day of the last exposure week (in the treatment experiment). Skin biopsy and blood were obtained at the end of the experiments. ISS CpG treatment increased drastically mRNA expression of proinflammatory and Th1-type cytokines and chemokines in OVA-treated skin both in the prevention and treatment experiments. The suppressing effect of ISS CpG on Th2-type cytokines and chemokines was weak and limited to IL-13 and CCL24 in the treatment experiment. No significant reduction in OVA-elicited infiltration of eosinophils and T cells in the skin was seen after ISS administration but infiltration of plasmacytoid dendritic cells was absent in ISS CpG-treated skin. In contrast, ISS injection elicited dramatic infiltration of F4/80+ and CCR5+ cells into the dermis and subcutaneous tissue. Due to unwanted side effects and minor beneficial effects in our model, administration of ISS CpG may not be suitable for the treatment of AD in humans. Copyright 2008 S. Karger AG, Basel.

  20. Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity.

    PubMed

    Patnaik, Akash; Swanson, Kenneth D; Csizmadia, Eva; Solanki, Aniruddh; Landon-Brace, Natalie; Gehring, Marina P; Helenius, Katja; Olson, Brian M; Pyzer, Athalia R; Wang, Lily C; Elemento, Olivier; Novak, Jesse; Thornley, Thomas B; Asara, John M; Montaser, Laleh; Timmons, Joshua J; Morgan, Todd M; Wang, Yugang; Levantini, Elena; Clohessy, John G; Kelly, Kathleen; Pandolfi, Pier Paolo; Rosenblatt, Jacalyn M; Avigan, David E; Ye, Huihui; Karp, Jeffrey M; Signoretti, Sabina; Balk, Steven P; Cantley, Lewis C

    2017-03-08

    Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-cancer innate immune response, resulting in tumor clearance.

  1. Murine model of immune-mediated rejection of the acute lymphoblastic leukemia 70Z/3.

    PubMed

    Labbe, Alain; Tran, Anne H; Paige, Christopher J

    2006-05-01

    70Z/3 is a murine pre-B cell leukemia line derived from BDF(1) mice and has been used in the study of signaling pathways in B cells. 70Z/3 cells were initially found to cause widespread disease upon injections in animals. We have isolated 70Z/3 variants divergent in their capacity to lead to morbidity after injections. One variant, 70Z/3-NL, elicits an immune response protecting the animal from tumor growth. Another variant, 70Z/3-L, does not induce an effective immune response and causes morbidity. We demonstrated that both CD4(+) and CD8(+) T cells are required for the rejection of 70Z/3-NL cells. Interestingly, the immune response generated against 70Z/3-NL cells was found to protect against a challenge with the lethal variant, 70Z/3-L. This indicates that although both lines can be recognized and killed by the immune system, only 70Z/3-NL is capable of inducing a protective response. Further observations, using subclones isolated from 70Z/3-NL, demonstrated that immune recognition of a portion of the cells was sufficient for protection. Depletion of CD4(+) and CD8(+) T cells in animals injected previously with 70Z/3-NL cells showed that T cells, and not Abs, were required for the maintenance of the protection initiated by 70Z/3-NL. We tested the capacity of 70Z/3-NL cells to treat mice challenged with 70Z/3-L. We can delay injections of 70Z/3-NL and still provide protection for the animals. We have a model of immune-mediated rejection which will allow us to dissect the requirements for the initiation of immune responses against an ALL tumor cell line.

  2. Altered Innate and Lymphocytic Immunity in Murine Splenocytes Following Short-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Crucian, Brian E.; Hwang, Shen-An; Actor, Jeffrey K.; Quiriarte, Heather; Sams, Clarence F.

    2011-01-01

    Immune dysregulation has been demonstrated following spaceflight of varying durations and limited in-flight studies indicate this phenomenon may persist during spaceflight. Causes may include microgravity, physiological stress, isolation, confinement and disrupted circadian rhythms. To further investigate the mechanisms associated with flight-associated immune changes, murine splenocytes immune parameters were assessed following 14 day space flight on Space Shuttle mission STS-135.

  3. Identification of a common immune signature in murine and human systemic Salmonellosis

    PubMed Central

    Lee, Seung-Joo; Liang, Li; Juarez, Silvia; Nanton, Minelva R.; Gondwe, Esther N.; Msefula, Chisomo L.; Kayala, Matthew A.; Necchi, Francesca; Heath, Jennifer N.; Hart, Peter; Tsolis, Renée M.; Heyderman, Robert S.; MacLennan, Calman A.; Felgner, Philip L.; Davies, D. Huw; McSorley, Stephen J.

    2012-01-01

    Despite the importance of Salmonella infections in human and animal health, the target antigens of Salmonella-specific immunity remain poorly defined. We have previously shown evidence for antibody-mediating protection against invasive Salmonellosis in mice and African children. To generate an overview of antibody targeting in systemic Salmonellosis, a Salmonella proteomic array containing over 2,700 proteins was constructed and probed with immune sera from Salmonella-infected mice and humans. Analysis of multiple inbred mouse strains identified 117 antigens recognized by systemic antibody responses in murine Salmonellosis. Importantly, many of these antigens were independently identified as target antigens using sera from Malawian children with Salmonella bacteremia, validating the study of the murine model. Furthermore, vaccination with SseB, the most prominent antigenic target in Malawian children, provided mice with significant protection against Salmonella infection. Together, these data uncover an overlapping immune signature of disseminated Salmonellosis in mice and humans and provide a foundation for the generation of a protective subunit vaccine. PMID:22331879

  4. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis

    PubMed Central

    Keely, Simon; Campbell, Eric L.; Baird, Alan W.; Hansbro, Philip M.; Shalwitz, Robert A.; Kotsakis, Anna; McNamee, Eoin N.; Eltzschig, Holger K.; Kominsky, Douglas J.; Colgan, Sean P.

    2013-01-01

    Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by TNBS were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi and clinical, immunological and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared to vehicle controls. Treated groups were pyrexic, but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of IL-1β, IL-6 and TNF-α, while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis. PMID:23695513

  5. Interleukin-27 signaling promotes immunity against endogenously arising murine tumors.

    PubMed

    Natividad, Karlo D T; Junankar, Simon R; Mohd Redzwan, Norhanani; Nair, Radhika; Wirasinha, Rushika C; King, Cecile; Brink, Robert; Swarbrick, Alexander; Batten, Marcel

    2013-01-01

    Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor α (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-γ production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (Treg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent.

  6. Interleukin-27 Signaling Promotes Immunity against Endogenously Arising Murine Tumors

    PubMed Central

    Natividad, Karlo D. T.; Junankar, Simon R.; Mohd Redzwan, Norhanani; Nair, Radhika; Wirasinha, Rushika C.; King, Cecile; Brink, Robert; Swarbrick, Alexander; Batten, Marcel

    2013-01-01

    Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor α (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-γ production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (Treg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent. PMID:23554861

  7. Vesicular stomatitis virus expressing interferon-β is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer.

    PubMed

    Patel, Manish R; Jacobson, Blake A; Ji, Yan; Drees, Jeremy; Tang, Shaogeng; Xiong, Kerry; Wang, Hengbing; Prigge, Jennifer E; Dash, Alexander S; Kratzke, Andrea K; Mesev, Emily; Etchison, Ryan; Federspiel, Mark J; Russell, Stephen J; Kratzke, Robert A

    2015-10-20

    Vesicular stomatitis virus (VSV) is a potent oncolytic virus for many tumors. VSV that produces interferon-β (VSV-IFNβ) is now in early clinical testing for solid tumors. Here, the preclinical activity of VSV and VSV-IFNβ against non-small cell lung cancer (NSCLC) is reported. NSCLC cell lines were treated in vitro with VSV expressing green fluorescence protein (VSV-GFP) and VSV-IFNβ. VSV-GFP and VSV-IFNβ were active against NSCLC cells. JAK/STAT inhibition with ruxolitinib re-sensitized resistant H838 cells to VSV-IFNβ mediated oncolysis. Intratumoral injections of VSV-GFP and VSV-IFNβ reduced tumor growth and weight in H2009 nude mouse xenografts (p < 0.01). A similar trend was observed in A549 xenografts. Syngeneic LM2 lung tumors grown in flanks of A/J mice were injected with VSV-IFNβ intratumorally. Treatment of LM2 tumors with VSV-IFNβ resulted in tumor regression, prolonged survival (p < 0.0001), and cure of 30% of mice. Intratumoral injection of VSV-IFNβ resulted in decreased tumor-infiltrating regulatory T cells (Treg) and increased CD8+ T cells. Tumor cell expression of PDL-1 was increased after VSV-IFNβ treatment. VSV-IFNβ has potent antitumor effects and promotes systemic antitumor immunity. These data support further clinical investigation of VSV-IFNβ for NSCLC.

  8. Suppression of infectious murine leukemia virus in wild mice (Mus musculus) by passive immunization.

    PubMed

    Gardner, M B; Klement, V; Estes, J D; Gilden, R V; Toni, R; Huebner, R J

    1977-06-01

    Passive immunization with heterologous antivirus antiserum beginning at birth successfully suppressed infectious murine leukemia virus expression in Lake Casitas wild mice (Musmusculus) at 5-7 weeks of age.

  9. MART-1 adenovirus-transduced dendritic cell immunization in a murine model of metastatic central nervous system tumor.

    PubMed

    Broder, Howard; Anderson, Andrea; Kremen, Thomas J; Odesa, Sylvia K; Liau, Linda M

    2003-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells that have been shown to play a critical role in the initiation of host immune responses against tumor antigens. In this study, a recombinant adenovirus vector encoding the melanoma-associated antigen, MART-1, was used to transduce murine DCs, which were then tested for their ability to activate cytotoxic T lymphocytes (CTLs) and induce protective immunity against B16 melanoma tumor cells implanted intracranially. Genetic modifications of murine bone marrow-derived DCs to express MART-1 was achieved through the use of an E1-deficient, recombinant adenovirus vector. Sixty-two C57BL/6 mice were immunized subcutaneously with AdVMART-1-transduced DCs (n = 23), untransduced DCs (n = 17), or sterile saline (n = 22). Using the B16 murine melanoma, which naturally expresses the MART-1 antigen, all the mice were then challenged intracranially with viable, unmodified syngeneic B16 tumor cells 7 days later. Splenocytes from representative animals in each group were harvested for standard cytotoxicity (CTL) and enzyme-linked immunospot (ELISPOT) assays. The remaining mice were followed for survival. Immunization of C57BL/6 mice with DCs transduced with an adenoviral vector encoding the MART-1 antigen elicited the development of antigen-specific CTL responses. As evidenced by a prolonged survival curve when compared to control-immunized mice with intracranial B16 tumors, AdMART-1-DC vaccination was able to elicit partial protection against central nervous system tumor challenge in vivo.

  10. S. mansoni Bolsters Anti-Viral Immunity in the Murine Respiratory Tract

    PubMed Central

    Scheer, Sebastian; Krempl, Christine; Kallfass, Carsten; Frey, Stefanie; Jakob, Thilo; Mouahid, Gabriel; Moné, Hélène; Schmitt-Gräff, Annette; Staeheli, Peter; Lamers, Marinus C.

    2014-01-01

    The human intestinal parasite Schistosoma mansoni causes a chronic disease, schistosomiasis or bilharzia. According to the current literature, the parasite induces vigorous immune responses that are controlled by Th2 helper cells at the expense of Th1 helper cells. The latter cell type is, however, indispensable for anti-viral immune responses. Remarkably, there is no reliable literature among 230 million patients worldwide describing defective anti-viral immune responses in the upper respiratory tract, for instance against influenza A virus or against respiratory syncitial virus (RSV). We therefore re-examined the immune response to a human isolate of S. mansoni and challenged mice in the chronic phase of schistosomiasis with influenza A virus, or with pneumonia virus of mice (PVM), a mouse virus to model RSV infections. We found that mice with chronic schistosomiasis had significant, systemic immune responses induced by Th1, Th2, and Th17 helper cells. High serum levels of TNF-α, IFN-γ, IL-5, IL-13, IL-2, IL-17, and GM-CSF were found after mating and oviposition. The lungs of diseased mice showed low-grade inflammation, with goblet cell hyperplasia and excessive mucus secretion, which was alleviated by treatment with an anti-TNF-α agent (Etanercept). Mice with chronic schistosomiasis were to a relative, but significant extent protected from a secondary viral respiratory challenge. The protection correlated with the onset of oviposition and TNF-α-mediated goblet cell hyperplasia and mucus secretion, suggesting that these mechanisms are involved in enhanced immune protection to respiratory viruses during chronic murine schistosomiasis. Indeed, also in a model of allergic airway inflammation mice were protected from a viral respiratory challenge with PVM. PMID:25398130

  11. Human immune responses in cryptosporidiosis

    PubMed Central

    Borad, Anoli; Ward, Honorine

    2010-01-01

    Immune responses play a critical role in protection from, and resolution of, cryptosporidiosis. However, the nature of these responses, particularly in humans, is not completely understood. Both innate and adaptive immune responses are important. Innate immune responses may be mediated by Toll-like receptor pathways, antimicrobial peptides, prostaglandins, mannose-binding lectin, cytokines and chemokines. Cell-mediated responses, particularly those involving CD4+ T cells and IFN-γ play a dominant role. Mucosal antibody responses may also be involved. Proteins mediating attachment and invasion may serve as putative protective antigens. Further knowledge of human immune responses in cryptosporidiosis is essential in order to develop targeted prophylactic and therapeutic interventions. This review focuses on recent advances and future prospects in the understanding of human immune responses to Cryptosporidium infection. PMID:20210556

  12. Immune Response in Human Cerebral Cavernous Malformations

    PubMed Central

    Shi, Changbin; Shenkar, Robert; Du, Hongyan; Duckworth, Edward; Raja, Harish; Batjer, H. Hunt; Awad, Issam A.

    2009-01-01

    Background and Purpose Preliminary observations suggesting the presence of B and plasma cells and oligoclonality of immunoglobulin (Ig) G in cerebral cavernous malformations (CCMs) have motivated a systematic study correlating the infiltration of the immune cells with clinical activity and antigen-triggered immune response in surgically excised lesions. Methods Infiltration of plasma, B, T and HLA-DR expressing cells and macrophages within 23 excised CCMs was related to clinical activity. Relative amounts of Ig isotypes were determined. IgG clonality of mRNA from CCMs was assessed by spectratyping, cloning and sequencing. Results Infiltration of the immune cells ranged widely within CCM lesions and cells were generally co-expressed with each other. Immune cell infiltration did not associate with recent bleeding and lesion growth. Significantly more B lymphocytes in CCM lesions were associated with venous anomaly. More T cells were present in solitary lesions. More T cells and less macrophages were present in CCMs from younger subjects. IgG isotype was present in all CCM lesions. Most lesions also expressed IgM and IgA, with IgM predominance over IgA correlating with recent CCM growth. Oligoclonality was shown in IgG mRNA from CCMs, but not from peripheral blood lymphocytes, with only eight CDR3 sequences observed among 134 clones from two CCM lesions. Conclusions An antigen-directed oligoclonal IgG immune response is present within CCM lesions regardless of recent clinical activity. Apparent differences in immune response in younger patients and in lesions with recent growth will need confirmation in other series. The pathogenicity of oligoclonal immune response will require systematic hypothesis testing in recently available CCM murine models. PMID:19286587

  13. "Concomitant immunity" in murine tumours of non-detectable immunogenicity.

    PubMed Central

    Ruggiero, R. A.; Bustuoabad, O. D.; Bonfil, R. D.; Meiss, R. P.; Pasqualini, C. D.

    1985-01-01

    Various immunization assays were used to demonstrate the lack of immunogenicity of three BALB/c tumours of spontaneous origin and of a fourth one resulting from foreign body tumorigenesis. All four tumours inhibited the growth of a second implant of the same tumour into the contralateral flank. In our tumour models "concomitant immunity" (1) was not mediated by macrophage or T-cell dependent immune reactions: both thymectomized BALB/c and nude mice (treated or untreated with silica) gave the same results as intact mice; (2) showed some degree of non-specificity, inhibiting the growth of a different tumour in 3/4 cases; though, the existence of a specific component could not be discarded; (3) was proportional to the volume of the primary tumour at the time of the second challenge; (4) was dependent on actively growing primary tumour, not being obtained with progressively increasing daily inocula of irradiated tumour cells; (5) was detectable in an actively growing secondary tumour; recurrent growth after partial surgical excision was inhibited and (6) involved cytostasis of the secondary tumour: a syngeneic graft of the overlying skin led to tumour growth while histological studies revealed the presence of viable tumour cells. It is postulated that "concomitant immunity" or resistance can be generated without the active participation of the immune system and that tumour-related factors are, in certain cases, responsible for blocking the growth of secondary tumours. Images Figure 5 PMID:2981538

  14. Maximizing Immune Response to Carbohydrate Antigens on Breast Tumors

    DTIC Science & Technology

    2003-08-01

    antigens expressed on breast tumors. Towards this end we are developing peptide mimotopes of tumor associated carbohydrate antigens as they are T cell...dependent antigens. In our progress to date we have shown the 1) immunization with peptide mimotope activates a specific cellular response to a model murine...tumor cell line; 2) vaccination of mice with peptide eradicates established tumor; 3) Immunization with DNA format of the peptide suppresses tumor

  15. Remune. Immune Response.

    PubMed

    Lai, Derhsing; Jones, Taff

    2002-03-01

    The Immune Response Corp (IRC) is developing Remune, a potential HIV therapeutic vaccine. Remune is based on the Salk Immunogen, which is derived from an HIV isolate which has been inactivated by chemical depletion of glycoprotein 120 (gp120). Preliminary data suggested that Remune, in combination with antiviral drug therapy, results in undetectable levels of HIV. Phase III trials commenced in May 1997 and it was initially expected that registration filings would be made in 1999. However, following interim analysis of the 2500-patient, multicenter, double-blind, pivotal phase III study (study 806) in May 1999, an independent panel recommended concluding the clinical endpoint trial and IRC and licensee, Agouron, decided to pursue alternative regulatory strategies, including initiating two additional phase III surrogate marker trials. Despite this, Agouron gave IRC notice of termination of its continued development in July 2001. In August 2001, IRC informed Agouron that, due to the total number of endpoints to date falling short of that previously assumed by Agouron, it did not intend to continue Agouron's Study 202 of Remune. In July 2001, licensee Trinity Medical Group filed an NDA with the governing health authorities in Thailand for Remune. The Thai FDA certified Immune Response's Remune manufacturing facility as being in compliance with GMP standards, following an on site inspection by Thai officials in November 2001 that was performed as a requirement of Trinity's Thai NDA. As a result of this certification, Trinity expected that a "timely determination" could be made by the Thai FDA. Rhĵne-Poulenc Rorer discontinued its part in the development of Remune, with all manufacturing, marketing and distribution rights reverting to IRC. After Agouron returned rights to Remune in July 2001, IRC heldfull rights in the US, Europe and Japan, while collaborating with its partners Trinity Medical Group and Roemmers Laboratory in the Southeast Asian and Latin American

  16. Ubiquitin signaling in immune responses

    PubMed Central

    Hu, Hongbo; Sun, Shao-Cong

    2016-01-01

    Ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes, including different aspects of immune functions. Ubiquitination regulates pattern-recognition receptor signaling that mediates both innate immune responses and dendritic cell maturation required for initiation of adaptive immune responses. Ubiquitination also regulates the development, activation, and differentiation of T cells, thereby maintaining efficient adaptive immune responses to pathogens and immunological tolerance to self-tissues. Like phosphorylation, ubiquitination is a reversible reaction tightly controlled by the opposing actions of ubiquitin ligases and deubiquitinases. Deregulated ubiquitination events are associated with immunological disorders, including autoimmune and inflammatory diseases. PMID:27012466

  17. Effects of dietary lipids on immune function in a murine sensitisation model.

    PubMed

    Albers, Ruud; Bol, Marianne; Bleumink, Rob; Willems, Astrid; Blonk, Cor; Pieters, Raymond

    2002-09-01

    We have tested the effect of dietary fatty acids on aspects of innate and specific adaptive T helper (Th) 1- and Th2-driven immune responses in a murine sensitisation model using dinitrochlorobenzene as sensitiser. Six groups of fifteen BALB/c mice were fed diets containing 30 % fat (by energy) for 8 weeks. Diets were rich in saturated fatty acids, n-6 polyunsaturated fatty acid (PUFA), or n-3 PUFA, each at a sufficient (11, 35 and 68 mg/kg) and a supplemented vitamin E level (1028, 1031 and 1030 mg/kg respectively). Feeding n-6 PUFA marginally decreased % phagocytosing cells at the low vitamin E level, but had no other effects on immune function. The n-3 PUFA diets decreased production of prostaglandin E2 while increasing oxidative burst and tumour necrosis factor alpha production. In addition adaptive Th1-driven responses (immunoglobulin, Ig)G2a, IgG2b, interferon-gamma:interleukin 4) were decreased, whereas Th2-driven and mucosal immune responses were increased (IgE) or unaffected (IgG1, IgA). Combination with high levels of alpha-tocopherol did not affect the reduced prostaglandin E2 production, augmented the increase of tumour necrosis factor alpha production and tended to ameliorate the selective suppressive effects of n-3 PUFA on certain Th1-driven effects (interferon-gamma:interleukin 4 ratio and IgG2a levels). We conclude that the sensitisation model appears useful for application in nutrition research. It allows a broad assessment of the effects of dietary intervention on various aspects of immune responsiveness, and as such provides a valuable model to assess, characterise and rank effects of foods and/or nutrients on a range of immune functions, including Th1-Th2 polarisation.

  18. Cellular immune responses to HIV

    NASA Astrophysics Data System (ADS)

    McMichael, Andrew J.; Rowland-Jones, Sarah L.

    2001-04-01

    The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

  19. Immune Responses in Parasitic Diseases

    DTIC Science & Technology

    1982-09-01

    RESPONSES IN PARASITIC DISEASES Final Scientific Report Daniel J. Stechschulte, M.D. Herbert B. Lindsley, M.D. September 1982 (July 1974 - December 1979...REPORT & PERIOD COVERED IMMUNE RESPONSES IN PARASITIC DISEASES Final Report July 1977 - Dec. 1979 6. PERFORMING ORG. REPORT NUMBER S 4 7. AUTNIOR(a) 6...DAMD 17-74-C-4136 AD_______________ IMMUNE RESPONSES IN PARASITIC DISEASES Final Scientific Report Daniel J. Stechschulte, M.D. Herbert B. Lindsley

  20. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

    PubMed Central

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  1. Murine intestinal antibody response to heterologous rotavirus infection.

    PubMed Central

    Merchant, A A; Groene, W S; Cheng, E H; Shaw, R D

    1991-01-01

    Rotavirus is the most important worldwide cause of severe gastroenteritis. Extensive efforts have been devoted to the design of a vaccine that will prevent disease, but development of a more effective vaccine strategy may require progress in the understanding of the mucosal immune response to replicating viral antigens. In this article, we report the characterization of the intestinal antibody response of a murine model to heterologous infection with the rhesus rotavirus vaccine strain. We have adapted the enzyme-linked immunospot assay to measure this response without the difficulties associated with measurement of antibodies in intestinal contents or the artifacts associated with culturing of lymphocytes. The predominant response in terms of antibody-secreting cells (ASC) is seen in the small intestine lamina propria, which can be measured within 4 days of infection, peaks 3 weeks after infection, and remains near that level for longer than 8 weeks. The magnitude of the immunoglobulin A (IgA) cell response is approximately 10 times greater than the intestinal IgG cell response, and IgM cells are rare. Virus-specific ASC constitute approximately 50% of all ASC in the gut at the peak of the virus-specific response. This response is considerably greater than responses to nonreplicating mucosal antigens measured by similar techniques. Enteral infection engenders minimal virus-specific ASC response in the spleen. Rhesus rotavirus-specific enzyme-linked immunosorbent assay and neutralization assays of serum and intestinal contents did not correlate with virus-specific ASC response. Images PMID:1761691

  2. Induction of Protective CTL Responses in Newborn Mice by a Murine Retrovirus

    NASA Astrophysics Data System (ADS)

    Sarzotti, Marcella; Robbins, Deanna S.; Hoffman, Paul M.

    1996-03-01

    The susceptibility of neonates to virus-induced disease is thought to reflect, in part, the immaturity of their immune systems. However, inoculation of newborn mice with low doses of Cas-Br-M murine leukemia virus induced a protective cytotoxic T lymphocyte (CTL) response. The inability of neonates to develop a CTL response to high doses of virus was not the result of immunological immaturity but correlated with the induction of a nonprotective type 2 cytokine response. Thus, the initial viral dose is critical in the development of protective immunity in newborns.

  3. Immune response and immunopathology during toxoplasmosis1

    PubMed Central

    Dupont, Christopher D.; Christian, David A.; Hunter, Christopher A.

    2012-01-01

    Toxoplasma gondii is a protozoan parasite of medical and veterinary significance that is able to infect any warm-blooded vertebrate host. In addition to its importance to public health, several inherent features of the biology of T. gondii have made it an important model organism to study host-pathogen interactions. One factor is the genetic tractability of the parasite, which allows studies on the microbial factors that affect virulence and allows the development of tools that facilitate immune studies. Additionally, mice are natural hosts for T. gondii, and the availability of numerous reagents to study the murine immune system makes this an ideal experimental system to understand the functions of cytokines and effector mechanisms involved in immunity to intracellular microorganisms. In this article, we will review current knowledge of the innate and adaptive immune responses required for resistance to toxoplasmosis, the events that lead to the development of immunopathology, and the natural regulatory mechanisms that limit excessive inflammation during this infection. PMID:22955326

  4. Protective effect of intranasal immunization with Neospora caninum membrane antigens against murine neosporosis established through the gastrointestinal tract

    PubMed Central

    Ferreirinha, Pedro; Dias, Joana; Correia, Alexandra; Pérez-Cabezas, Begoña; Santos, Carlos; Teixeira, Luzia; Ribeiro, Adília; Rocha, António; Vilanova, Manuel

    2014-01-01

    Neospora caninum is an Apicomplexa parasite that in the last two decades was acknowledged as the main pathogenic agent responsible for economic losses in the cattle industry. In the present study, the effectiveness of intranasal immunization with N. caninum membrane antigens plus CpG adjuvant was assessed in a murine model of intragastrically established neosporosis. Immunized mice presented a lower parasitic burden in the brain on infection with 5 × 107 tachyzoites, showing that significant protection was achieved by this immunization strategy. Intestinal IgA antibodies raised by immunization markedly agglutinated live N. caninum tachyzoites whereas previous opsonization with IgG antibodies purified from immunized mice sera reduced parasite survival within macrophage cells. Although an IgG1 : IgG2a ratio < 1 was detected in the immunized mice before and after infection, indicative of a predominant T helper type 1 immune response, no increased production of interferon-γ was detected in the spleen or mesenteric lymph nodes of the immunized mice. Altogether, these results show that mucosal immunization with N. caninum membrane proteins plus CpG adjuvant protect against intragastrically established neosporosis and indicate that parasite-specific mucosal and circulating antibodies have a protective role against this parasitic infection. PMID:24128071

  5. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection

    PubMed Central

    Stevens, Natalie E.; Hatjopolous, Antoinette; Fraser, Cara K.; Alsharifi, Mohammed; Diener, Kerrilyn R.; Hayball, John D.

    2016-01-01

    Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus. PMID:27380890

  6. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection.

    PubMed

    Stevens, Natalie E; Hatjopolous, Antoinette; Fraser, Cara K; Alsharifi, Mohammed; Diener, Kerrilyn R; Hayball, John D

    2016-07-06

    Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus.

  7. Leptin Regulation of Immune Responses.

    PubMed

    Naylor, Caitlin; Petri, William A

    2016-02-01

    Leptin is a regulatory hormone with multiple roles in the immune system. We favor the concept that leptin signaling 'licenses' various immune cells to engage in immune responses and/or to differentiate. Leptin is an inflammatory molecule that is capable of activating both adaptive and innate immunity. It can also 'enhance' immune functions, including inflammatory cytokine production in macrophages, granulocyte chemotaxis, and increased Th17 proliferation. Leptin can also 'inhibit' cells; CD4(+) T cells are inhibited from differentiating into regulatory T cells in the presence of elevated leptin, while NK cells can exhibit impaired cytotoxicity under the same circumstances. Consequently, understanding the effect of leptin signaling is important to appreciate various aspects of immune dysregulation observed in malnutrition, obesity, and autoimmunity.

  8. Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

    PubMed Central

    Chang, C-H; Chen, Y-C; Yu, Y-H; Tao, M-H; Leung, P S C; Ansari, A A; Gershwin, M E; Chuang, Y-H

    2014-01-01

    Although primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA–BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA–BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA–BSA/PBS or 2-OA–BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways. PMID:24547942

  9. Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis.

    PubMed

    Kumagai, Kenichi; Horikawa, Tatsuya; Shigematsu, Hiroaki; Matsubara, Ryota; Kitaura, Kazutaka; Eguchi, Takanori; Kobayashi, Hiroshi; Nakasone, Yasunari; Sato, Koichiro; Yamada, Hiroyuki; Suzuki, Satsuki; Hamada, Yoshiki; Suzuki, Ryuji

    2016-01-12

    Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK) T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion-induced allergic contact dermatitis.

  10. Studies of immunity and bacterial invasiveness in mice given a recombinant salmonella vector encoding murine interleukin-6.

    PubMed

    Dunstan, S J; Ramsay, A J; Strugnell, R A

    1996-07-01

    Interleukin-6 (IL-6) was expressed in Salmonella typhimurium in an attempt to increase the mucosal immune response against the bacterium. Murine IL-6 was PCR amplified from cDNA, cloned, sequenced, and found to be functionally active when expressed in S. typhimurium BRD509, the (delta)aroA (delta)aroD vaccine strain. Expression of murine IL-6 did not appear to adversely affect the growth of salmonellae, as the construct was retained in the absence of antibiotic selection and the growth rate was unaffected compared with that of the parent strain in vitro. However, IL-6 expression led to a significant reduction in bacterial invasiveness in vitro and in vivo. Splenocytes and small intestinal lamina propria lymphocytes were isolated from mice orally immunized with BRD509 expressing IL-6 (pKK233-2/IL-6), and the number of antibody-secreting cells was determined by the ELISPOT technique. No differences were observed between mice immunized with BRD509(pKK.233-2/IL-6) and those immunized with BRD509(pKK233-2) with respect to the antibody subclass-specific responses elicited despite the markedly reduced invasiveness of the former. Serum antibody responses were also examined by a kinetic enzyme-linked immunosorbent assay (ELISA), and equivalent levels of antibody response were detected in mice given BRD509(pKK233-2/IL-6) and those given BRD509(pKK233-2). The humoral immune response against bacterial lipopolysaccharides was also examined in transgenic IL-6-deficient mice given oral inocula of BRD509. Equivalent numbers of antibody-secreting cells (ELISPOTs) were observed in the spleens and laminae propriae of both IL-6-deficient (-/-) mice and control (+/+) mice harboring an intact IL-6 gene, whereas small, yet significant differences in the serum immunoglobulin A ELISA titers were observed. These data suggest that the immunoglobulin A response against Salmonella lipopolysaccharides is largely IL-6 independent.

  11. The Role of Costimulatory Molecules in the Development of Memory and Effector T Helper 2 Cells During an in vivo Immune Response to the Murine Gastrointestinal Parasite Heligmosomoides polygyrus

    DTIC Science & Technology

    2007-11-02

    of Toxoplasma gondii , chronically infected CD28-deficient mice were not able to mount a host-protective response to rechallenge with a virulent...Role of CD28 in the generation of effector and memory responses required for resistance to Toxoplasma gondii . J.Immunol. 163:3344-3353. 106...strain of T. gondii (105). This study suggested that other costimulatory molecules may substitute for CD28 during development of a primary immune

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

    PubMed

    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.

  13. Immune responses in space flight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1998-01-01

    Space flight has been shown to have profound effects on immunological parameters of humans, monkeys and rodents. These studies have been carried out by a number of different laboratories. Among the parameters affected are leukocyte blastogenesis, natural killer cell activity, leukocyte subset distribution, cytokine production - including interferons and interleukins, and macrophage maturation and activity. These changes start to occur only after a few days space flight, and some changes continue throughout long-term space flight. Antibody responses have received only very limited study, and total antibody levels have been shown to be increased after long-term space flight. Several factors could be involved in inducing these changes. These factors could include microgravity, lack of load-bearing, stress, acceleration forces, and radiation. The mechanism(s) for space flight-induced changes in immune responses remain(s) to be established. Certainly, there can be direct effects of microgravity, or other factors, on cells that play a fundamental role in immune responses. However, it is now clear that there are interactions between the immune system and other physiological systems that could play a major role. For example, changes occurring in calcium use in the musculoskeletal system induced by microgravity or lack of use could have great impact on the immune system. Most of the changes in immune responses have been observed using samples taken immediately after return from space flight. However, there have been two recent studies that have used in-flight testing. Delayed-type hypersensitivity responses to common recall antigens of astronauts and cosmonauts have been shown to be decreased when tested during space flights. Additionally, natural killer cell and blastogenic activities are inhibited in samples taken from rats during space flight. Therefore, it is now clear that events occurring during space flight itself can affect immune responses. The biological

  14. Immune responses in space flight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1998-01-01

    Space flight has been shown to have profound effects on immunological parameters of humans, monkeys and rodents. These studies have been carried out by a number of different laboratories. Among the parameters affected are leukocyte blastogenesis, natural killer cell activity, leukocyte subset distribution, cytokine production - including interferons and interleukins, and macrophage maturation and activity. These changes start to occur only after a few days space flight, and some changes continue throughout long-term space flight. Antibody responses have received only very limited study, and total antibody levels have been shown to be increased after long-term space flight. Several factors could be involved in inducing these changes. These factors could include microgravity, lack of load-bearing, stress, acceleration forces, and radiation. The mechanism(s) for space flight-induced changes in immune responses remain(s) to be established. Certainly, there can be direct effects of microgravity, or other factors, on cells that play a fundamental role in immune responses. However, it is now clear that there are interactions between the immune system and other physiological systems that could play a major role. For example, changes occurring in calcium use in the musculoskeletal system induced by microgravity or lack of use could have great impact on the immune system. Most of the changes in immune responses have been observed using samples taken immediately after return from space flight. However, there have been two recent studies that have used in-flight testing. Delayed-type hypersensitivity responses to common recall antigens of astronauts and cosmonauts have been shown to be decreased when tested during space flights. Additionally, natural killer cell and blastogenic activities are inhibited in samples taken from rats during space flight. Therefore, it is now clear that events occurring during space flight itself can affect immune responses. The biological

  15. Cytomegalovirus infection enhances the immune response to influenza.

    PubMed

    Furman, David; Jojic, Vladimir; Sharma, Shalini; Shen-Orr, Shai S; Angel, Cesar J L; Onengut-Gumuscu, Suna; Kidd, Brian A; Maecker, Holden T; Concannon, Patrick; Dekker, Cornelia L; Thomas, Paul G; Davis, Mark M

    2015-04-01

    Cytomegalovirus (CMV) is a β-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-γ compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species.

  16. Immune Response to Giardia duodenalis

    PubMed Central

    Faubert, Gaétan

    2000-01-01

    The intestinal protozoan Giardia duodenalis is a widespread opportunistic parasite of humans and animals. This parasite inhabits the upper part of the small intestine and has a direct life cycle. After ingestion of cysts, which are the infective stage, the trophozoites emerge from the cysts in the duodenum and attach to the small intestinal mucosa of the host. Since the migration of trophozoites from the lumen of the intestine into surrounding tissues is an unusual occurrence, the immune response to Giardia remains localized. The identification of antigens that play a role in acquired immunity has been difficult because of the occurrence of antigenic variation and because, Giardia being an ubiquituous organism, it is possible that the antigenic profiles of isolates from different geographic areas will vary. Innate-immunity mechanisms play a role in the control and/or severity of the infection. Both humoral and cell-mediated immune responses play a role in acquired immunity, but the mechanisms involved are unknown. A variety of serological assays have been used to detect circulating antibodies in serum. Because of the biological characteristics of the parasite and the lack of suitable antigens, the sensitivity of serological assays remains poor. On the other hand, detection of antigens in feces of infected patients has met with success. Commercial kits are available, and they are reported to be more sensitive than microscopic examination for the detection of giardiasis on a single specimen. PMID:10627490

  17. Immune responses to improving welfare

    PubMed Central

    Berghman, L. R.

    2016-01-01

    The relationship between animal welfare and the immune status of an animal has a complex nature. Indeed, the intuitive notion that “increased vigilance of the immune system is by definition better” because it is expected to better keep the animal healthy, does not hold up under scrutiny. This is mostly due to the fact that the immune system consists of 2 distinct branches, the innate and the adaptive immune system. While they are intimately intertwined and synergistic in the living organism, they are profoundly different in their costs, both in terms of performance and wellbeing. In contrast to the adaptive immune system, the action of the innate immune system has a high metabolic cost as well as undesirable behavioral consequences. When a pathogen breaches the first line of defense (often a mucosal barrier), that organism's molecular signature is recognized by resident macrophages. The macrophages respond by releasing a cocktail of pro-inflammatory cytokines (including interleukin-1 and -6) that signal the brain via multiple pathways (humoral as well as neural) of the ongoing peripheral innate immune response. The behavioral response to the release of proinflammatory cytokines, known as “sickness behavior,” includes nearly all the behavioral aspects that are symptomatic for clinical depression in humans. Hence, undesired innate immune activity, such as chronic inflammation, needs to be avoided by the industry. From an immunological standpoint, one of the most pressing poultry industry needs is the refinement of our current veterinary vaccine arsenal. The response to a vaccine, especially to a live attenuated vaccine, is often a combination of innate and adaptive immune activities, and the desired immunogenicity comes at the price of high reactogenicity. The morbidity, albeit limited and transient, caused by live vaccines against respiratory diseases and coccidiosis are good examples. Thankfully, the advent of various post-genomics technologies, such as DNA

  18. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

    Turroni, Francesca; Taverniti, Valentina; Ruas-Madiedo, Patricia; Duranti, Sabrina; Guglielmetti, Simone; Lugli, Gabriele Andrea; Gioiosa, Laura; Palanza, Paola; Margolles, Abelardo; van Sinderen, Douwe

    2014-01-01

    Here, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, with Bifidobacterium bifidum PRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure to B. bifidum PRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest that Bifidobacterium bifidum PRL2010 modulates the innate immune response of the host. PMID:24242237

  19. Murine RAW 264.7 cell line as an immune target: are we missing something?

    PubMed

    Merly, Liza; Smith, Sylvia L

    2017-04-01

    The popular murine macrophage cell line, RAW 264.7, is often used to initially screen natural products for bioactivity and to predict their potential effect in vivo or on primary cells. The cell line response is considered to reflect the potential human de novo response, and is used to evaluate the effective bioactivity of the product. Here, we compared the cytokine response of RAW 264.7 cells to shark cartilage (SC) with that of human leukocytes to determine whether the cell line response was a reliable predictor of the cytokine response one can expect from similarly stimulated human primary cells. Results not only revealed significant differences in the nature and level of TNFα produced by cells in vitro, but also showed that while the primary cell response included an upregulation in the production of IL-1β such a response was absent in RAW 264.7 cells. This suggests that had we relied on RAW 264.7 cells alone to assess the cytokine-inducing capacity of SC, the comprehensive Th1 response (shown in an earlier study) induced by SC in primary cells, consisting of release of several proinflammatory cytokines and chemokines, would not have been revealed. We conclude, therefore, that assays using only RAW 264.7 cells to initially screen for and assess immune reactivity of test products will not necessarily provide a comprehensive picture of the immunomodulatory properties of the substance under investigation, and can in fact be misleading with regard to the overall bioactive potential of the substance on an initial screen.

  20. Specific prebiotic oligosaccharides modulate the early phase of a murine vaccination response.

    PubMed

    Vos, Arjan P; Knol, Jan; Stahl, Bernd; M'rabet, Laura; Garssen, Johan

    2010-05-01

    The immune-modulatory effect of specific prebiotic oligosaccharides was shown in previous preclinical and clinical studies. To enhance the understanding of this effect, kinetic aspects of immune modulation and the correlation between microbiological and immunological parameters were investigated in a murine vaccination model. C57BL/6 mice were supplemented with short-chain galactooligosaccharides and long-chain fructooligosaccharides (ratio 9:1; Immunofortis()) in combination with pectin-derived acidic oligosaccharides. The timing of supplementation was varied around the primary (day 0) and secondary (day 21) vaccinations. Supplementation before the primary vaccination was necessary to increase delayed-type hypersensitivity responses (DTH) significantly at day 30. Supplementation after day 8 did not affect the DTH response at day 30, indicating that immune modulation occurred during the early phase. Therefore, correlation analysis of microbiological and immunological parameters was performed in a shortened experiment to focus on the early phase. At day 9 post-priming, the percentages of cecal lactobacilli were correlated to the DTH responses (p=0.01). Furthermore, the results suggested that yet unidentified factors may play a role. Additional analysis of intestinal Peyer's patch major lymphocyte populations did not show effects of supplementation. In conclusion, a specific oligosaccharide mixture was shown to exert its immune-modulatory effect during the early phase of a murine immune response. The results are consistent with a role of the microbiota and possibly other factors in oligosaccharide-induced immune modulation. Furthermore, the results demonstrate that it is critical to consider kinetic aspects of immune-modulatory and prebiotic effects in order to study their interaction in a meaningful way. Copyright 2010 Elsevier B.V. All rights reserved.

  1. Carbohydrate Mimetic Peptides Augment Carbohydrate-Reactive Immune Responses in the Absence of Immune Pathology

    PubMed Central

    Hennings, Leah; Artaud, Cecile; Jousheghany, Fariba; Monzavi-Karbassi, Behjatolah; Pashov, Anastas; Kieber-Emmons, Thomas

    2011-01-01

    Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses. PMID:24213131

  2. Sex differences in immune responses.

    PubMed

    Klein, Sabra L; Flanagan, Katie L

    2016-10-01

    Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

  3. Fetal immune response to chorioamnionitis.

    PubMed

    Kallapur, Suhas G; Presicce, Pietro; Rueda, Cesar M; Jobe, Alan H; Chougnet, Claire A

    2014-01-01

    Chorioamnionitis is a frequent cause of preterm birth and is associated with an increased risk for injury responses in the lung, gastrointestinal tract, brain, and other fetal organs. Chorioamnionitis is a polymicrobial nontraditional infectious disease because the organisms causing chorioamnionitis are generally of low virulence and colonize the amniotic fluid often for extended periods, and the host (mother and the fetus) does not have typical infection-related symptoms such as fever. In this review, we discuss the effects of chorioamnionitis in experimental animal models that mimic the human disease. Our focus is on the immune changes in multiple fetal organs and the pathogenesis of chorioamnionitis-induced injury in different fetal compartments. As chorioamnionitis disproportionately affects preterm infants, we discuss the relevant developmental context for the immune system. We also provide a clinical context for the fetal responses. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Fetal immune response to chorioamnionitis

    PubMed Central

    Kallapur, Suhas G.; Presicce, Pietro; Rueda, Cesar M.; Jobe, Alan H.; Chougnet, Claire A.

    2014-01-01

    Chorioamnionitis is a frequent cause of preterm birth and is associated with an increased risk for injury responses in the lung, GI tract, brain and other fetal organs. Chorioamnionitis is a polymicrobial non-traditional infectious disease because the organisms causing chorioamnionitis are generally of low virulence and colonize the amniotic fluid often for extended periods, and the host (mother and the fetus) does not have typical infection related symptoms such as fever. In this review, we discuss the effects of chorioamnionitis in experimental animal models that mimic the human disease. Our focus is on the immune changes in multiple fetal organs and the pathogenesis of chorioamnionitis induced injury in different fetal compartments. Since chorioamnionitis disproportionately affects preterm infants, we discuss the relevant developmental context for the immune system. We also provide a clinical context for the fetal responses. PMID:24390922

  5. Systems level immune response analysis and personalized medicine.

    PubMed

    Brodin, Petter; Valentini, Davide; Uhlin, Michael; Mattsson, Jonas; Zumla, Alimuddin; Maeurer, Markus J

    2013-04-01

    The immune system is an anatomically structured, orchestrated interaction of different cell types that communicate via a large number of receptors recognizing both soluble and cellular ligands. Recent technological advances now allow large-scale measurements for better appreciation of this complexity. Despite these advances, only a few immunological parameters are routinely measured in clinical practice. The authors believe that these measurements are insufficient to describe the immune function of individual patients and thus cannot be used to evaluate immune-mediated diseases or response to therapy. Our current knowledge of immunology comes largely from work in murine model systems where the immune system has been characterized in great detail. This impressive volume of knowledge has proven to be difficult to translate into novel therapies in humans; one reason for this is the lack of large-scale immune monitoring allowing for systems-wide analysis of the human immune system. The authors propose a systems approach to immunology, where the focus is moved from analysis of individual cell types towards more integrated studies of the entire immune system. Exercising 'systems immunology' in preclinical research, during drug development and in patients undergoing therapies affecting the immune system, will enable us to improve clinical results through personalized medicine and help to define clinically relevant patterns of immune reactivity.

  6. [Immune response to influenza vaccination].

    PubMed

    Alvarez, I; Corral, J; Arranz, A; Foruria, A; Landa, V; Lejarza, J R; Marijuán, L; Martínez, J M

    1989-01-01

    The present study investigated the level of immunity of the population against three strains of the influenza virus (A Chile/1/83 -A Philippines/2/82 and B URSS/100/83) before and three months after vaccination, and the immune response to whole virus vaccine as compared with fragmented virus vaccine. A high percentage of the population had titers greater than or equal to 1/10 before vaccination for the Chile (54%) and Philippines (65.7%) strains, while titers against the URSS strain were lower (25.4%). There was a definitive increase in antibody titer in the vaccinated population, although it was lower than expected. The overall response to both vaccines, with protecting titers greater than or equal to 1/40 after vaccination was 65.2% for the Chile strain, 74.6% for the Philippines strain, and 15% for the URSS strain. No differences in the overall immune response were found between the groups vaccinated with whole and fragmented virus.

  7. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell-directed gene therapy of murine hemophilia A.

    PubMed

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

  8. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

    PubMed Central

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

  9. Arg-Gingipain A DNA Vaccine Induces Protective Immunity against Infection by Porphyromonas gingivalis in a Murine Model

    PubMed Central

    Yonezawa, Hideo; Ishihara, Kazuyuki; Okuda, Katsuji

    2001-01-01

    Arginine-specific cysteine proteinases (RgpA and RgpB) produced by the periodontal pathogen Porphyromonas gingivalis are suspected virulence factors and are involved in interrupting host defense mechanisms as well as in penetrating and destroying periodontal connective tissues. To induce a protective immune response against P. gingivalis, we constructed an rgpA DNA vaccine. BALB/c mice were immunized intradermally by Gene Gun with plasmid DNA carrying rgpA. Antibody responses against P. gingivalis were determined by an enzyme-linked immunosorbent assay. The rgpA DNA vaccine induced high levels of serum antibodies against P. gingivalis. Sera from the rgpA DNA vaccine-immunized mice diminished the proteolytic activity of RgpA and RgpB and inhibited the binding of P. gingivalis to a type I collagen sponge. Moreover, the sera effectively reduced the hemagglutination of P. gingivalis, indicating that the hemagglutinin activity of the organism is associated with RgpA. We found with a murine abscess model that mice immunized with the rgpA DNA vaccine were resistant to an invasive P. gingivalis W50 challenge. These results suggest that the rgpA DNA vaccine induced specific antibodies against the enzyme and that this vaccine could confer protective immunity against P. gingivalis infection. PMID:11292699

  10. Silicone Oil Microdroplets Can Induce Antibody Responses Against Recombinant Murine Growth Hormone In Mice

    PubMed Central

    Chisholm, Carly Fleagle; Baker, Abby E.; Soucie, Kaitlin R.; Torres, Raul M.; Carpenter, John F.; Randolph, Theodore W.

    2016-01-01

    Therapeutic protein products can cause adverse immune responses in patients. The presence of sub-visible particles is a potential contributing factor to the immunogenicity of parenterally-administered therapeutic protein formulations. Silicone oil microdroplets, which derive from silicone oil used as a lubricating coating on barrels of prefilled glass syringes, are often found in formulations. In this study, we investigated the potential of silicone oil microdroplets to act as adjuvants to induce an immune response in mice against a recombinant murine protein. Antibody responses in mice to subcutaneous injections of formulations of recombinant murine growth hormone (rmGH) that contained silicone oil microdroplets were measured and compared to responses to oil-free rmGH formulations. When rmGH formulations containing silicone oil microdroplets were administered once every other week, anti-rmGH antibodies were not detected. In contrast, mice exhibited a small IgG1 response against rmGH when silicone oil-containing rmGH formulations were administered daily, and an anti-rmGH IgM response was observed at later time points. Our findings showed that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody responses against a recombinant self-protein. PMID:27020987

  11. Silicone Oil Microdroplets Can Induce Antibody Responses Against Recombinant Murine Growth Hormone in Mice.

    PubMed

    Chisholm, Carly Fleagle; Baker, Abby E; Soucie, Kaitlin R; Torres, Raul M; Carpenter, John F; Randolph, Theodore W

    2016-05-01

    Therapeutic protein products can cause adverse immune responses in patients. The presence of subvisible particles is a potential contributing factor to the immunogenicity of parenterally administered therapeutic protein formulations. Silicone oil microdroplets, which derive from silicone oil used as a lubricating coating on barrels of prefilled glass syringes, are often found in formulations. In this study, we investigated the potential of silicone oil microdroplets to act as adjuvants to induce an immune response in mice against a recombinant murine protein. Antibody responses in mice to subcutaneous injections of formulations of recombinant murine growth hormone (rmGH) that contained silicone oil microdroplets were measured and compared to responses to oil-free rmGH formulations. When rmGH formulations containing silicone oil microdroplets were administered once every other week, anti-rmGH antibodies were not detected. In contrast, mice exhibited a small IgG1 response against rmGH when silicone oil-containing rmGH formulations were administered daily, and an anti-rmGH IgM response was observed at later time points. Our findings showed that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody responses against a recombinant self-protein. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Effects of fenbendazole on the murine humoral immune system.

    PubMed

    Landin, Ana Marie; Frasca, Daniela; Zaias, Julia; Van der Put, Elaine; Riley, Richard L; Altman, Norman H; Blomberg, Bonnie B

    2009-05-01

    Pinworms are highly contagious parasites that have been effectively treated in laboratory rodents with fenbendazole (FBZ). Whether FBZ has any detrimental side effects that may compromise experimental results is unknown. Here we asked whether the immune systems from young and aged mice are altered under FBZ treatment. We compared control and FBZ-treated groups of young (age, 2 to 4 mo) and old (age, 22 to 24 mo) BALB/cN mice. The treated mice received a total of 4 wk (alternating-week treatment regimen) of FBZ-medicated feed. Spleen and bone marrow were collected for immunologic assays, and heart, stomach, intestines, kidneys, and liver were evaluated by histopathology. Our results indicate that FBZ treatment has significant effects on the immune systems of mice; these effects are greater in aged mice. FBZ treatment adversely affected mRNA and protein expression of E2A (a transcription factor crucial for B lymphocytes) in activated precursor B lymphocytes obtained from the bone marrow of young and old mice. These effects were reversed by 6 wk on regular feed after the end of treatment. Activated B lymphocytes from the spleens of young and old mice showed decreased function (cell proliferation, E2A mRNA and protein expression) through the last time point of FBZ treatment but recovered by 2 to 4 wk after treatment. Our findings suggest that FBZ treatment may alter sensitive immune and molecular measures as presented here, and postponing the experimental use of mice until at least 6 wk after treatment should be considered.

  13. CXCL10-Mediates Macrophage, but not Other Innate Immune Cells-Associated Inflammation in Murine Nonalcoholic Steatohepatitis

    PubMed Central

    Tomita, Kyoko; Freeman, Brittany L.; Bronk, Steven F.; LeBrasseur, Nathan K.; White, Thomas A.; Hirsova, Petra; Ibrahim, Samar H.

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) is an inflammatory lipotoxic disorder, but how inflammatory cells are recruited and activated within the liver is still unclear. We previously reported that lipotoxic hepatocytes release CXCL10-enriched extracellular vesicles, which are potently chemotactic for cells of the innate immune system. In the present study, we sought to determine the innate immune cell involved in the inflammatory response in murine NASH and the extent to which inhibition of the chemotactic ligand CXCL10 and its cognate receptor CXCR3 could attenuate liver inflammation, injury and fibrosis. C57BL/6J CXCL10−/−, CXCR3−/− and wild type (WT) mice were fed chow or high saturated fat, fructose, and cholesterol (FFC) diet. FFC-fed CXCL10−/− and WT mice displayed similar weight gain, metabolic profile, insulin resistance, and hepatic steatosis. In contrast, compared to the WT mice, FFC-fed CXCL10−/− mice had significantly attenuated liver inflammation, injury and fibrosis. Genetic deletion of CXCL10 reduced FFC-induced proinflammatory hepatic macrophage infiltration, while natural killer cells, natural killer T cells, neutrophils and dendritic cells hepatic infiltration were not significantly affected. Our results suggest that CXCL10−/− mice are protected against diet-induced NASH, in an obesity-independent manner. Macrophage-associated inflammation appears to be the key player in the CXCL10-mediated sterile inflammatory response in murine NASH. PMID:27349927

  14. Conditioning of the immune response.

    PubMed

    Ader, R; Cohen, N

    1991-10-01

    Experimental studies in humans and experimental animals document the acquisition and extinction of classically conditioned alterations of different parameters of humoral- and cell-mediated immune responses. Although the aversive effects of cyclophosphamide in a taste aversion learning paradigm has been the most frequently used model, conditioned immunomodulatory effects are not confined to this conditioning procedure, and they are not limited to cyclophosphamide or, for that matter, the use of immunomodulating drugs as unconditioned stimuli. Conditioned changes in immunologic reactivity have also been found to modulate the progression of spontaneously-developing or experimentally-induced pathophysiological processes in experimental animals. The available data on the immunoregulatory effects of conditioning indicate that the immune system, like other systems operating in the interests of homeostasis, is integrated with other physiological processes and is therefore influenced by and capable of influencing the brain.

  15. Immune Modulatory Effects of Human Chorionic Gonadotropin on Dendritic Cells Supporting Fetal Survival in Murine Pregnancy

    PubMed Central

    Dauven, Dominique; Ehrentraut, Stefanie; Langwisch, Stefanie; Zenclussen, Ana Claudia; Schumacher, Anne

    2016-01-01

    Dendritic cells (DCs) are critically involved in the determination of immunity vs. tolerance. Hence, DCs are key regulators of immune responses either favoring or disfavoring fetal survival. Several factors were proposed to modulate DC phenotype and function during pregnancy. Here, we studied whether the pregnancy hormone human chorionic gonadotropin (hCG) is involved in DC regulation. In vitro, bone marrow-derived DCs (BMDCs) were stimulated in the presence or absence of urine-purified or recombinant hCG (rhCG) preparations. Subsequently, BMDC maturation was assessed. Cytokine secretion of activated BMDCs and their capability to enforce TH1, TH2, TH17, or Treg cell differentiation was determined after rhCG treatment. Moreover, the in vivo potential of hCG-modulated BMDCs to influence pregnancy outcome, Treg cell number, and local cytokine expression was evaluated after adoptive transfer in a murine abortion-prone model before and after conception. Both hCG preparations impaired the maturation process of BMDCs. rhCG treatment did neither alter cytokine secretion by BMDCs nor their ability to drive TH1, TH2, or TH17 differentiation. rhCG-treated BMDCs augmented the number of Treg cells within the T cell population. Adoptive transfer of rhCG-treated BMDCs after conception did not influence pregnancy outcome. However, transfer of hCG-treated BMDCs prior to mating had a protective effect on pregnancy. This positive effect was accompanied by increased Treg cell numbers and decidual IL-10 and TGF-β expression. Our results unveil the importance of hCG in retaining DCs in a tolerogenic state, thereby promoting Treg cell increment and supporting fetal survival. PMID:27895621

  16. Immune responses to resistance exercise.

    PubMed

    Freidenreich, Daniel J; Volek, Jeff S

    2012-01-01

    Resistance exercise induces changes in leukocyte redistribution, phenotypical surface expression and leukocyte functionality. Several factors have been shown to alter the temporal pattern and/or magnitude of response including manipulation of acute program variables, the aging process, and nutritional supplementation. Rest period length and load can modify the temporal pattern and/or magnitude of leukocytosis post exercise. Aging diminishes both the duration and magnitude of the post exercise leukocytosis and reduces leukocyte functionality. The few studies that assessed the effects of nutritional supplements (e.g., carbohydrate, whey protein, caffeine) peri-resistance exercise showed minimal effects on leukocyte responses. Sex differences exist in the timing and magnitude of leukocyte infiltration into skeletal muscle. The immune response to resistance exercise is only a small part of the recovery paradigm. A better understanding of how acute program variables and other factors such as aging, sex and nutritional supplementation affect the immune response to resistance exercise is important in the context of improving recovery, performance and health.

  17. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    PubMed

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

  18. Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

    PubMed Central

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Background Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Methodology/Principal Findings Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Conclusions/Significance Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a

  19. Passive immunization of channel catfish (Ictalurus punctatus) against the ciliated protozoan parasite Ichthyophthirius multifiliis by use of murine monoclonal antibodies.

    PubMed Central

    Lin, T L; Clark, T G; Dickerson, H

    1996-01-01

    Fish acquire immunity against the ciliated protozoan parasite Ichthyophthirius multifiliis following sublethal infection. The immune response includes the elaboration of humoral antibodies against a class of abundant surface membrane proteins referred to as immobilization antigens (i-antigens). Antibodies against these proteins immobilize the parasite in vitro, suggesting a potential role for the i-antigens in protective immunity. To test this hypothesis, passive immunization experiments were carried out with naive channel catfish, Ictalurus punctatus, using immobilizing murine monoclonal antibodies (MAbs). Fish were completely protected against lethal challenge following intraperitoneal injection of 20 to 200 micrograms of MAb. Although fish succumbed to infection at lower doses, palliative effects were observed with as little as 2 micrograms of antibody. In experiments in which animals were challenged at various times following inoculation, an inverse relationship between parasite load and serum immobilizing activity was seen. Of seven MAbs which conferred protection, all were immunoglobulin G class antibodies. The only immobilizing MAb that failed to protect was an immunoglobulin M antibody that was absent from surface mucosa as determined by enzyme-linked immunosorbent assay. The implications of these findings for the development of a vaccine against I. multifiliis and immunity against surface pathogens of fish are discussed. PMID:8926073

  20. Eosinophils in mucosal immune responses

    PubMed Central

    Travers, J; Rothenberg, M E

    2015-01-01

    Eosinophils, multifunctional cells that contribute to both innate and adaptive immunity, are involved in the initiation, propagation and resolution of immune responses, including tissue repair. They achieve this multifunctionality by expression of a diverse set of activation receptors, including those that directly recognize pathogens and opsonized targets, and by their ability to store and release preformed cytotoxic mediators that participate in host defense, to produce a variety of de novo pleotropic mediators and cytokines and to interact directly and indirectly with diverse cell types, including adaptive and innate immunocytes and structural cells. Herein, we review the basic biology of eosinophils and then focus on new emerging concepts about their role in mucosal immune homeostasis, particularly maintenance of intestinal IgA. We review emerging data about their development and regulation and describe new concepts concerning mucosal eosinophilic diseases. We describe recently developed therapeutic strategies to modify eosinophil levels and function and provide collective insight about the beneficial and detrimental functions of these enigmatic cells. PMID:25807184

  1. Immune responses to bioengineered organs

    PubMed Central

    Ochando, Jordi; Charron, Dominique; Baptista, Pedro M.; Uygun, Basak E.

    2017-01-01

    Purpose of review Organ donation in the United States registered 9079 deceased organ donors in 2015. This high percentage of donations allowed organ transplantation in 29 851 recipients. Despite increasing numbers of transplants performed in comparison with previous years, the numbers of patients that are in need for a transplant increase every year at a higher rate. This reveals that the discrepancy between the demand and availability of organs remains fundamental problem in organ transplantation. Recent findings Development of bioengineered organs represents a promising approach to increase the pool of organs for transplantation. The technology involves obtaining complex three-dimensional scaffolds that support cellular activity and functional remodeling though tissue recellularization protocols using progenitor cells. This innovative approach integrates cross-thematic approaches from specific areas of transplant immunology, tissue engineering and stem cell biology, to potentially manufacture an unlimited source of donor organs for transplantation. Summary Although bioengineered organs are thought to escape immune recognition, the potential immune reactivity toward each of its components has not been studied in detail. Here, we summarize the host immune response toward different progenitor cells and discuss the potential implications of using nonself biological scaffolds to develop bioengineered organs. PMID:27926545

  2. EVOLUTION OF THE IMMUNE RESPONSE

    PubMed Central

    Papermaster, Ben W.; Condie, Richard M.; Finstad, Joanne; Good, Robert A.

    1964-01-01

    1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T2 and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T2. Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that

  3. TIGIT predominantly regulates the immune response via regulatory T cells.

    PubMed

    Kurtulus, Sema; Sakuishi, Kaori; Ngiow, Shin-Foong; Joller, Nicole; Tan, Dewar J; Teng, Michele W L; Smyth, Mark J; Kuchroo, Vijay K; Anderson, Ana C

    2015-11-02

    Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.

  4. TIGIT predominantly regulates the immune response via regulatory T cells

    PubMed Central

    Kurtulus, Sema; Sakuishi, Kaori; Ngiow, Shin-Foong; Joller, Nicole; Tan, Dewar J.; Teng, Michele W.L.; Smyth, Mark J.; Kuchroo, Vijay K.; Anderson, Ana C.

    2015-01-01

    Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings. PMID:26413872

  5. Surgical and immune reconstitution murine models in bone marrow research: Potential for exploring mechanisms in sepsis, trauma and allergy

    PubMed Central

    Xavier-Elsas, Pedro; Ferreira, Renato Nunes; Gaspar-Elsas, Maria Ignez C

    2017-01-01

    Bone marrow, the vital organ which maintains lifelong hemopoiesis, currently receives considerable attention, as a source of multiple cell types which may play important roles in repair at distant sites. This emerging function, distinct from, but closely related to, bone marrow roles in innate immunity and inflammation, has been characterized through a number of strategies. However, the use of surgical models in this endeavour has hitherto been limited. Surgical strategies allow the experimenter to predetermine the site, timing, severity and invasiveness of injury; to add or remove aggravating factors (such as infection and defects in immunity) in controlled ways; and to manipulate the context of repair, including reconstitution with selected immune cell subpopulations. This endows surgical models overall with great potential for exploring bone marrow responses to injury, inflammation and infection, and its roles in repair and regeneration. We review three different murine surgical models, which variously combine trauma with infection, antigenic stimulation, or immune reconstitution, thereby illuminating different aspects of the bone marrow response to systemic injury in sepsis, trauma and allergy. They are: (1) cecal ligation and puncture, a versatile model of polymicrobial sepsis; (2) egg white implant, an intriguing model of eosinophilia induced by a combination of trauma and sensitization to insoluble allergen; and (3) ectopic lung tissue transplantation, which allows us to dissect afferent and efferent mechanisms leading to accumulation of hemopoietic cells in the lungs. These models highlight the gain in analytical power provided by the association of surgical and immunological strategies. PMID:28890868

  6. IMMUNE AND NATURAL ANTIBODIES TO SYNGENEIC MURINE PLASMA CELL TUMORS

    PubMed Central

    Herberman, Ronald B.; Aoki, Tadao

    1972-01-01

    Cytotoxic antibody to a plasma cell tumor antigen was produced in syngeneic BALB mice by immunization with viable or inactivated plasma cell tumors. Antibody with the same specificity was found in the sera of normal BALB and other strains of mice. This natural antibody reacted with an antigen with characteristics indistinguishable from the previously described alloantigen, PC.1, and with viral envelope antigen, χVEA. The incidence of cytotoxic reactivity and the antibody titers reached a peak in normal BALB mice at 3–4 months of age, and were lower in 9–12-month old mice. The sera of germfree mice had lower reactivity; but when the mice were transferred to conventional conditions, their sera soon became as active as those of conventional mice. A virus common to all plasma cell tumors, which is present in latent form in some normal tissues of BALB and other PC.1 positive strains, is suggested as the cause for the PC.1 antigen and for the appearance of natural antibody to it. The considerable evidence for the close association of a virus with plasma cell tumors is presented. PMID:5033423

  7. Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer

    PubMed Central

    Ito, Fumito; Ku, Amy W.; Bucsek, Mark J.; Muhitch, Jason B.; Vardam-Kaur, Trupti; Kim, Minhyung; Fisher, Daniel T.; Camoriano, Marta; Khoury, Thaer; Skitzki, Joseph J.; Gollnick, Sandra O.; Evans, Sharon S.

    2015-01-01

    Purpose While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA) in a preclinical mouse model. Experimental Design Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma. Results Treatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity. Conclusion Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant

  8. Tilapia show immunization response against Ich

    USDA-ARS?s Scientific Manuscript database

    This study compares the immune response of Nile tilapia and red tilapia against parasite Ichthyophthirius multifiliis (Ich) using a cohabitation challenge model. Both Nile and red tilapia showed strong immune response post immunization with live Ich theronts by IP injection or immersion. Blood serum...

  9. A genetic inference on cancer immune responsiveness

    PubMed Central

    Wang, Ena; Uccellini, Lorenzo; Marincola, Francesco M.

    2012-01-01

    A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness. PMID:22754772

  10. Enhancement of survivin-specific anti-tumor immunity by adenovirus prime protein-boost immunity strategy with DDA/MPL adjuvant in a murine melanoma model.

    PubMed

    Wang, Yu-Qian; Zhang, Hai-Hong; Liu, Chen-Lu; Wu, Hui; Wang, Peng; Xia, Qiu; Zhang, Li-Xing; Li, Bo; Wu, Jia-Xin; Yu, Bin; Gu, Tie-Jun; Yu, Xiang-Hui; Kong, Wei

    2013-09-01

    As an ideal tumor antigen, survivin has been widely used for tumor immunotherapy. Nevertheless, no effective protein vaccine targeting survivin has been reported, which may be due to its poor ability to induce cellular immunity. Thus, a suitable immunoadjuvant and optimized immunization strategy can greatly enhance the cellular immune response to this protein vaccine. DDA/MPL (monophosphoryl lipid A formulated with cationic dimethyldioctadecylammonium) has been reported to enhance the antigen uptake and presentation to T cells as an adjuvant. Meanwhile, a heterologous prime-boost strategy can enhance the cellular immunity of a protein vaccine by applying different antigen-presenting systems. Here, DDA/MPL and an adenovirus prime-protein boost strategy were applied to enhance the specific anti-tumor immunity of a truncated survivin protein vaccine. Antigen-specific IFN-γ-secreting T cells were increased by 10-fold, and cytotoxic T lympohocytes (CTLs) were induced effectively when the protein vaccine was combined with the DDA/MPL adjuvant. Meanwhile, the Th1 type cellular immune response was strongly enhanced and tumor inhibition was significantly increased by 96% with the adenovirus/protein prime-boost strategy, compared to the protein homologous prime-boost strategy. Moreover, this adjuvanted heterologous prime-boost strategy combined with oxaliplatin could significantly enhance the efficiency of tumor growth inhibition through promoting the proliferation of splenocytes. Thus, our results provide a novel vaccine strategy for cancer therapy using an adenovirus prime-protein boost strategy in a murine melanoma model, and its combination with oxaliplatin may further enhance the anti-tumor efficacy while alleviating side effects of the drug.

  11. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model.

    PubMed

    Agmon-Levin, Nancy; Arango, María-Teresa; Kivity, Shaye; Katzav, Aviva; Gilburd, Boris; Blank, Miri; Tomer, Nir; Volkov, Alex; Barshack, Iris; Chapman, Joab; Shoenfeld, Yehuda

    2014-11-01

    Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events.

  12. Immune responses and vaccination against periodontal infections.

    PubMed

    Persson, G Rutger

    2005-01-01

    The infectious aetiology of periodontitis is complex and no curative treatment modality exists. Palliative therapy is available. To review the evidence that active or passive immunization against periodontitis provides immune protection. PubMed (Medline), the National Institutes of Health, the Food and Drug Administration, and the Center for Disease Control electronic databases were searched to extrapolate information on immune responses to immunization against periodontitis. Studies in non-human primate models using ligature-induced experimental periodontitis suggest that antibody responses by active immunization against Porphyromonas gingivalis can safely be induced, enhanced, and obtained over time. Immune responses to whole bacterial cell and purified protein preparations considered as vaccine candidates have been evaluated in different animal models demonstrating that there are several valid vaccine candidates. Data suggest that immunization reduces the rate and severity of bone loss. It is also, temporarily, possible to alter the composition of the subgingival microflora. Natural active immunization by therapeutic interventions results in antibody titre enhancement and potentially improves treatment outcomes. Passive immunization of humans using P. gingivalis monoclonal antibodies temporarily prevents colonization of P. gingivalis. Probiotic therapy may be an alternative approach. Regulatory and safety issues for human periodontal vaccine trials must be considered. Shared infectious aetiology between periodontitis and systemic diseases may enhance vaccine effort developments. Proof of principle that active and passive immunization can induce protective antibody responses is given. The impact of natural immunization and passive immunization in humans should be explored and may, presently, be more feasible than active immunization studies.

  13. Effects of macrocyclic trichothecene mycotoxins on the murine immune system

    SciTech Connect

    Hughes, B.J.

    1988-01-01

    The macrocyclic trichothecenes are a unique group of toxins which have some antileukemic properties. In the first study, verrucarin A and roridin A were examined. Both mycotoxins were administered intraperitoneally at an equitoxic dose of 0.35 mg/kg to CD-1 mice. Lymphocyte proliferation was studied after animals were dosed with verrucarin A. After day 2, no differences in {sup 3}H-thymidine incorporation were observed using concanavalin A (Con A), phytohemagglutinin (PHA), pokeweed mitogen (PWM), or lipopolysaccharide (LPS). On day 4, DNA synthesis induced by Con A, PHA, and PWM increased significantly. On day 7, PHA stimulation increased above controls while Con A, PWM, and LPS responses were not significantly different. In contrast, roridin A decreased PHA stimulation only on day 7. In the second study the mycotoxins roritoxin B, myrotoxin B, roridin A, verrucarin A, 16-hydroxyverrucarin A, verrucarin J, baccharinoid B12, roridin D, roridin E, baccharinoid B4, and baccharinoid B5 were investigated. In the third study lymphocytes were cultured with each of the mycotoxins for 48 hr to assess their lethality.

  14. The immune response to surgery and infection

    PubMed Central

    Słotwiński, Robert

    2014-01-01

    Surgical trauma affects both the innate and acquired immunity. The severity of immune disorders is proportional to the extent of surgical trauma and depends on a number of factors, including primarily the basic disease requiring surgical treatment (e.g. cancer), often coexisting infections and impaired nutritional status. Disorder of the immune response following surgical trauma may predispose to septic complications burdened with the highest mortality rate. Extensive surgery in cancer patients is associated with simultaneous activation of pro- and anti-inflammatory processes defined as SIRS (systemic inflammatory immune response) and CARS (compensatory anti-inflammatory immune response). However, it is generally believed that major surgical trauma is accompanied by sustained postoperative immunosuppression, which is particularly important in patients operated on for cancer, since the suppression of the immune system promotes not only septic complications, but also proliferation and tumor metastasis. This paper reviews the main features of immune response to surgical trauma and possibilities of its regulation. PMID:26155175

  15. Spaceflight and immune responses of Rhesus monkeys

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies indicates that alterations in immunological parameters occur after space flight. The objective of this project is to determine the effects of space flight on immune responses of Rhesus monkeys. The expected significance of the work is a determination of the range of immunological functions of the Rhesus monkey, a primate similar in many ways to man, affected by space flight. Changes in immune responses that could yield alterations in resistance to infection may be determined as well as the duration of alterations in immune responses. Additional information on the nature of cellular interactions for the generation of immune responses may also be obtained.

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

    PubMed

    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.

  17. Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses

    PubMed Central

    Deal, Emily M.; Lahl, Katharina; Narváez, Carlos F.; Butcher, Eugene C.; Greenberg, Harry B.

    2013-01-01

    B cell–dependent immunity to rotavirus, an important intestinal pathogen, plays a significant role in viral clearance and protects against reinfection. Human in vitro and murine in vivo models of rotavirus infection were used to delineate the role of primary plasmacytoid DCs (pDCs) in initiating B cell responses. Human pDCs were necessary and sufficient for B cell activation induced by rotavirus. Type I IFN recognition by B cells was essential for rotavirus-mediated B cell activation in vitro and murine pDCs and IFN-α/β–mediated B cell activation after in vivo intestinal rotavirus infection. Furthermore, rotavirus-specific serum and mucosal antibody responses were defective in mice lacking functional pDCs at the time of infection. These data demonstrate that optimal B cell activation and virus-specific antibody secretion following mucosal infection were a direct result of pDC-derived type I IFN. Importantly, viral shedding significantly increased in pDC-deficient mice, suggesting that pDC-dependent antibody production influences viral clearance. Thus, mucosal pDCs critically influence the course of rotavirus infection through rotavirus recognition and subsequent IFN production and display powerful adjuvant properties to initiate and enhance humoral immunity. PMID:23635775

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

    PubMed

    Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A; Gerdts, Volker

    2014-01-01

    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.

  19. Noninvasive imaging of immune responses

    PubMed Central

    Rashidian, Mohammad; Keliher, Edmund J.; Bilate, Angelina M.; Duarte, Joao N.; Wojtkiewicz, Gregory R.; Jacobsen, Johanne Tracey; Cragnolini, Juanjo; Swee, Lee Kim; Victora, Gabriel D.; Weissleder, Ralph; Ploegh, Hidde L.

    2015-01-01

    At their margins, tumors often contain neutrophils, dendritic cells, and activated macrophages, which express class II MHC and CD11b products. The interplay between stromal cells, tumor cells, and migratory cells such as lymphocytes creates opportunities for noninvasive imaging of immune responses. We developed alpaca-derived antibody fragments specific for mouse class II MHC and CD11b products, expressed on the surface of a variety of myeloid cells. We validated these reagents by flow cytometry and two-photon microscopy to obtain images at cellular resolution. To enable noninvasive imaging of the targeted cell populations, we developed a method to site-specifically label VHHs [the variable domain (VH) of a camelid heavy-chain only antibody] with 18F or 64Cu. Radiolabeled VHHs rapidly cleared the circulation (t1/2 ≈ 20 min) and clearly visualized lymphoid organs. We used VHHs to explore the possibility of imaging inflammation in both xenogeneic and syngeneic tumor models, which resulted in detection of tumors with remarkable specificity. We also imaged the infiltration of myeloid cells upon injection of complete Freund’s adjuvant. Both anti-class II MHC and anti-CD11b VHHs detected inflammation with excellent specificity. Given the ease of manufacture and labeling of VHHs, we believe that this method could transform the manner in which antitumor responses and/or infectious events may be tracked. PMID:25902531

  20. Effects of fish oil on cytokines and immune functions of mice with murine AIDS.

    PubMed

    Xi, S; Cohen, D; Chen, L H

    1998-08-01

    The effects of fish oil, which is rich in n-3 fatty acids, on cytokine levels in a murine model of acquired immune deficiency syndrome (AIDS) were studied. Thirty-two C57BL/6 female mice were divided into two dietary groups and fed either a corn oil diet or a fish oil diet. After 4 weeks, each diet group was further divided into two subgroups, and mice in one subgroup were injected i.p. with LP-BM5 murine retrovirus (MAIDS) stock. After 4 weeks, all mice were killed, blood samples were collected, and the spleens and the livers were excised. Splenocytes were isolated immediately and cultured in RPMI-1640 medium and stimulated by either lipopolysaccharide (LPS) or Concanavalin A (ConA) for 24 h. The supernatant was collected for cytokine assays. The results showed that MAIDS infection increased the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta), while fish oil partially prevented this elevation. MAIDS infection depressed interleukin-2 (IL-2) and interferon-gamma (IFNgamma), while fish oil partially prevented the depression of IL-2. In addition, MAIDS infection depressed LPS- and ConA-stimulated cell proliferation, while fish oil partially prevented the depression. The results suggest that fish oil may slow down the progression of murine AIDS by modulating levels of cytokines including TNF-alpha, IL-1beta, and IL-2.

  1. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses.

    PubMed

    Madera, Laurence; Greenshields, Anna; Coombs, Melanie R Power; Hoskin, David W

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated enhanced production of pro-inflammatory cytokines tumor necrosis factor α, interleukin-6, and CCL2 in response to lipopolysaccharide (LPS) while production of interleukin-10 remained unchanged. The increased LPS-induced production of pro-inflammatory cytokines was transient and correlated with enhanced cytokine production in response to other Toll-like receptor agonists, including peptidoglycan and flagellin. In addition, 4T1-conditioned BMDMs exhibited strengthened LPS-induced nitric oxide production and enhanced phagocytosis of Escherichia coli. 4T1-mediated augmentation of macrophage responses to LPS was partially dependent on the NFκB pathway, macrophage-colony stimulating factor, and actin polymerization, as well as the presence of 4T1-secreted extracellular vesicles. Furthermore, peritoneal macrophages obtained from 4T1 tumor-bearing mice displayed enhanced pro-inflammatory cytokine production in response to LPS. These results suggest that uptake of 4T1-secreted factors and actin-mediated ingestion of 4T1-secreted exosomes by macrophages cause a transient enhancement of innate inflammatory responses. Mammary carcinoma-mediated regulation of innate immunity may have significant implications for our understanding of host defense and cancer progression.

  2. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses

    PubMed Central

    Madera, Laurence; Greenshields, Anna; Coombs, Melanie R. Power; Hoskin, David W.

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated enhanced production of pro-inflammatory cytokines tumor necrosis factor α, interleukin-6, and CCL2 in response to lipopolysaccharide (LPS) while production of interleukin-10 remained unchanged. The increased LPS-induced production of pro-inflammatory cytokines was transient and correlated with enhanced cytokine production in response to other Toll-like receptor agonists, including peptidoglycan and flagellin. In addition, 4T1-conditioned BMDMs exhibited strengthened LPS-induced nitric oxide production and enhanced phagocytosis of Escherichia coli. 4T1-mediated augmentation of macrophage responses to LPS was partially dependent on the NFκB pathway, macrophage-colony stimulating factor, and actin polymerization, as well as the presence of 4T1-secreted extracellular vesicles. Furthermore, peritoneal macrophages obtained from 4T1 tumor-bearing mice displayed enhanced pro-inflammatory cytokine production in response to LPS. These results suggest that uptake of 4T1-secreted factors and actin-mediated ingestion of 4T1-secreted exosomes by macrophages cause a transient enhancement of innate inflammatory responses. Mammary carcinoma-mediated regulation of innate immunity may have significant implications for our understanding of host defense and cancer progression. PMID:26177198

  3. Hypothalamic neurohormones and immune responses

    PubMed Central

    Quintanar, J. Luis; Guzmán-Soto, Irene

    2013-01-01

    The aim of this review is to provide a comprehensive examination of the current literature describing the neural-immune interactions, with emphasis on the most recent findings of the effects of neurohormones on immune system. Particularly, the role of hypothalamic hormones such as Thyrotropin-releasing hormone (TRH), Corticotropin-releasing hormone (CRH) and Gonadotropin-releasing hormone (GnRH). In the past few years, interest has been raised in extrapituitary actions of these neurohormones due to their receptors have been found in many non-pituitary tissues. Also, the receptors are present in immune cells, suggesting an autocrine or paracrine role within the immune system. In general, these neurohormones have been reported to exert immunomodulatory effects on cell proliferation, immune mediators release and cell function. The implications of these findings in understanding the network of hypothalamic neuropeptides and immune system are discussed. PMID:23964208

  4. Hypothalamic neurohormones and immune responses.

    PubMed

    Quintanar, J Luis; Guzmán-Soto, Irene

    2013-01-01

    The aim of this review is to provide a comprehensive examination of the current literature describing the neural-immune interactions, with emphasis on the most recent findings of the effects of neurohormones on immune system. Particularly, the role of hypothalamic hormones such as Thyrotropin-releasing hormone (TRH), Corticotropin-releasing hormone (CRH) and Gonadotropin-releasing hormone (GnRH). In the past few years, interest has been raised in extrapituitary actions of these neurohormones due to their receptors have been found in many non-pituitary tissues. Also, the receptors are present in immune cells, suggesting an autocrine or paracrine role within the immune system. In general, these neurohormones have been reported to exert immunomodulatory effects on cell proliferation, immune mediators release and cell function. The implications of these findings in understanding the network of hypothalamic neuropeptides and immune system are discussed.

  5. CD44 Antibodies and Immune Thrombocytopenia in the Amelioration of Murine Inflammatory Arthritis

    PubMed Central

    Mott, Patrick J.; Lazarus, Alan H.

    2013-01-01

    Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP) that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7), also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics. PMID:23785450

  6. Cellular immunity in ASFV responses.

    PubMed

    Takamatsu, Haru-Hisa; Denyer, Michael S; Lacasta, Anna; Stirling, Catrina M A; Argilaguet, Jordi M; Netherton, Christopher L; Oura, Chris A L; Martins, Carlos; Rodríguez, Fernando

    2013-04-01

    African swine fever virus (ASFV) infection usually results in an acute haemorrhagic disease with a mortality rate approaching 100% in domestic pigs. However, pigs can survive infection with less-virulent isolates of ASFV and may become chronically infected. Surviving animals are resistant to challenge with homologous or, in some cases, closely related isolates of the virus indicating that pigs can develop protective immunity against ASFV. During asymptomatic, non-virulent ASFV infections natural killer cell activity increases in pigs, suggesting this cell type plays a role in ASFV immunity. Furthermore, depletion of CD8(+) lymphocytes from ASFV immune pigs demolishes protective immunity against related virulent viruses. This suggests that ASFV specific antibody alone is not sufficient for protection against ASFV infection and that there is an important role for the CD8(+) lymphocyte subset in ASFV protective immunity. These results were supported by DNA immunization studies, demonstrating a correlation between the protection afforded against lethal challenge and the detection of a large number of vaccine-induced antigen-specific CD8(+) T-cells. Peripheral blood mononuclear cells (PBMCs) from ASF immune pigs protected from clinical disease show higher proportions of ASFV specific CD4(+)CD8(high+) double positive cytotoxic T cells than PBMCs from ASF immune but clinically diseased pig. The frequency of ASFV specific IFNγ producing T cells induced by immunization correlates to the degree of protection from ASFV challenge, and this may prove to be a useful indicator of any potential cross-protection against heterologous ASFV isolates.

  7. Oral treatment with Saccharomyces cerevisiae strain UFMG 905 modulates immune responses and interferes with signal pathways involved in the activation of inflammation in a murine model of typhoid fever.

    PubMed

    Martins, Flaviano S; Elian, Samir D A; Vieira, Angélica T; Tiago, Fabiana C P; Martins, Ariane K S; Silva, Flávia C P; Souza, Ericka L S; Sousa, Lirlândia P; Araújo, Helena R C; Pimenta, Paulo F; Bonjardim, Cláudio A; Arantes, Rosa M E; Teixeira, Mauro M; Nicoli, Jacques R

    2011-04-01

    Salmonella spp. are Gram-negative, facultative, intracellular pathogens that cause several diarrheal diseases ranging from self-limiting gastroenteritis to typhoid fever. Previous results from our laboratory showed that Saccharomyces cerevisiae strain UFMG 905 isolated from 'cachaça' production presented probiotic properties due to its ability to protect against experimental infection with Salmonella enterica serovar Typhimurium. In this study, the effects of oral treatment with S. cerevisiae 905 were evaluated at the immunological level in a murine model of typhoid fever. Treatment with S. cerevisiae 905 inhibited weight loss and increased survival rate after Salmonella challenge. Immunological data demonstrated that S. cerevisiae 905 decreased levels of proinflammatory cytokines and modulated the activation of mitogen-activated protein kinases (p38 and JNK, but not ERK1/2), NF-κB and AP-1, signaling pathways which are involved in the transcriptional activation of proinflammatory mediators. Experiments in germ-free mice revealed that probiotic effects were due, at least in part, to the binding of Salmonella to the yeast. In conclusion, S. cerevisiae 905 acts as a potential new biotherapy against S. Typhimurium infection due to its ability to bind bacteria and modulate signaling pathways involved in the activation of inflammation in a murine model of typhoid fever. Copyright © 2010 Elsevier GmbH. All rights reserved.

  8. Photodynamic therapy induces an immune response against a bacterial pathogen

    PubMed Central

    Huang, Ying-Ying; Tanaka, Masamitsu; Vecchio, Daniela; Garcia-Diaz, Maria; Chang, Julie; Morimoto, Yuji; Hamblin, Michael R

    2012-01-01

    Photodynamic therapy (PDT) employs the triple combination of photosensitizers, visible light and ambient oxygen. When PDT is used for cancer, it has been observed that both arms of the host immune system (innate and adaptive) are activated. When PDT is used for infectious disease, however, it has been assumed that the direct antimicrobial PDT effect dominates. Murine arthritis caused by methicillin-resistant Staphylococcus aureus in the knee failed to respond to PDT with intravenously injected Photofrin®. PDT with intra-articular Photofrin produced a biphasic dose response that killed bacteria without destroying host neutrophils. Methylene blue was the optimum photosensitizer to kill bacteria while preserving neutrophils. We used bioluminescence imaging to noninvasively monitor murine bacterial arthritis and found that PDT with intra-articular methylene blue was not only effective, but when used before infection, could protect the mice against a subsequent bacterial challenge. The data emphasize the importance of considering the host immune response in PDT for infectious disease. PMID:22882222

  9. Effects of selenizing angelica polysaccharide and selenizing garlic polysaccharide on immune function of murine peritoneal macrophage.

    PubMed

    Gao, Zhenzhen; Liu, Kuanhui; Tian, Weijun; Wang, Hongchao; Liu, Zhenguang; Li, Youying; Li, Entao; Liu, Cui; Li, Xiuping; Hou, Ranran; Yue, Chanjuan; Wang, Deyun; Hu, Yuanliang

    2015-07-01

    The effects of two selenizing polysaccharides (sCAP2 and sGPS6) on immune function of murine peritoneal macrophages taking two non-selenizing polysaccharides (CAP and GPS) and modifier Na2SeO3 as control. In vitro test, the changes of selenizing polysaccharides, non-selenizing polysaccharides and Na2SeO3 on murine macrophages function were evaluated by phagocytosis and nitric oxide (NO) secretion tests. In vivo test, the mice were injected respectively with 0.2, 0.4 and 0.6 mg of sCAP2, sGPS6, CAP and GPS, or Na2SeO3 80 μg or normal saline 0.4 mL. The peritoneal macrophages were collected and cultured to determine the contents of TNF-α, IL-6 and IL-10 in supernatants by enzyme-linked immunosorbent assay. The results showed that sCAP2 and sGPS6 could significantly promote the phagocytosis and secretion of NO and three cytokines of macrophages in comparison with CAP and GPS. sCAP2 possessed the strongest activity. This indicates that selenylation modification can further improve the immune-enhancing activity of polysaccharide, and sCAP2 could be as a new immunopotentiator.

  10. CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia.

    PubMed

    Ma, Li; Simpson, Elisa; Li, June; Xuan, Min; Xu, Miao; Baker, Laura; Shi, Yan; Yougbaré, Issaka; Wang, Xiaozhong; Zhu, Guangheng; Chen, Pingguo; Prud'homme, Gerald J; Lazarus, Alan H; Freedman, John; Ni, Heyu

    2015-07-09

    Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (αIIbβ3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTLs) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Because steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, whereas CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tregs while decreasing CTLs. In vitro coculture studies revealed CD8(+) Tregs suppressed CD4(+) and CD19(+) proliferation, platelet-associated immunoglobulin G generation, CTL cytotoxicity, platelet apoptosis, and clearance. Furthermore, we found increased production of anti-inflammatory interleukin-10 in coculture studies and in vivo after steroid treatment. Thus, we uncovered subsets of CD8(+) Tregs and demonstrated their potent immunosuppressive and protective roles in experimentally induced thrombocytopenia. The data further elucidate mechanisms of steroid treatment and suggest therapeutic potential for CD8(+) Tregs in immune thrombocytopenia. © 2015 by The American Society of Hematology.

  11. The Immune Response to Astrovirus Infection

    PubMed Central

    Marvin, Shauna A.

    2016-01-01

    Astroviruses are one of the leading causes of pediatric gastroenteritis worldwide and are clinically importantly pathogens in the elderly and immunocompromised populations. Although the use of cell culture systems and small animal models have enhanced our understanding of astrovirus infection and pathogenesis, little is known about the immune response to astrovirus infection. Studies from humans and animals suggest that adaptive immunity is important in restricting classic and novel astrovirus infections, while studies from animal models and cell culture systems suggest that an innate immune system plays a role in limiting astrovirus replication. The relative contribution of each arm of the immune system in restricting astrovirus infection remains unknown. This review summarizes our current understanding of the immune response to astrovirus infection and highlights some of the key questions that stem from these studies. A full understanding of the immune response to astrovirus infection is required to be able to treat and control astrovirus-induced gastroenteritis. PMID:28042824

  12. Cytokines and the immune response.

    PubMed

    Van der Meide, P H; Schellekens, H

    1996-01-01

    Cytokines participate in many physiological processes including the regulation of immune and inflammatory responses. These effector molecules are produced transiently and locally controlling the amplitude and duration of the response. A variety of experiments has shown that excessive or insufficient production may significantly contribute to the pathophysiology of a range of diseases. Particularly cytokines released by CD4+ T cells at the onset of an immune response are thought to be decisive for pathological or physiological consequences. The meeting in Budapest was focussed on cytokines known to contribute to the pathophysiology of autoimmune diseases, infectious diseases and allograft rejection (e.g., IL-1, IL-4, IL-6, IL-10, IL-12, TNF-alpha and IFN-alpha, -beta, -gamma). A central role for IFN-gamma in autoimmunity was suggested by blocking experiments in vivo using monoclonal antibodies and soluble forms of the IFN-gamma receptor (IFN-gamma SR). These agents ameliorated disease development in a variety of experimental autoimmune diseases in rodents. In a mouse model for the human disease Myasthenia gravis, IFN-alpha was found to reduce both the incidence and progression of the disease. Treatment of R. aurantiacus-infected mice with anti-IL-4 monoclonal antibodies (mAbs) was reported to interfere with the regression of granulomas in spleen and liver, most likely through inadequate IL-4-mediated suppression of IFN-gamma production. In addition, it was shown that mice with disrupted IFN-gamma R genes died rapidly after infection with the BCG strain of M. bovis, whereas normal mice survived the infection. IL-12 was found to be the main inductor of IFN-gamma during the lethal Shwartzman reaction. TNF-alpha was identified as the principal cause of mortality after the second injection with LPS. In a variety of studies examining the role of cytokines in the pathogenesis of AIDS, much attention was given to the in vitro effects of HIV-1 and/or the HIV-1 viral membrane

  13. Protective host immune responses to Salmonella infection.

    PubMed

    Pham, Oanh H; McSorley, Stephen J

    2015-01-01

    Salmonella enterica serovars Typhi and Paratyphi are the causative agents of human typhoid fever. Current typhoid vaccines are ineffective and are not widely used in endemic areas. Greater understanding of host-pathogen interactions during Salmonella infection should facilitate the development of improved vaccines to combat typhoid and nontyphoidal Salmonellosis. This review will focus on our current understanding of Salmonella pathogenesis and the major host immune components that participate in immunity to Salmonella infection. In addition, recent findings regarding host immune mechanisms in response to Salmonella infection will be also discussed, providing a new perspective on the utility of improved tools to study the immune response to Salmonella infections.

  14. Protective host immune responses to Salmonella infection

    PubMed Central

    Pham, Oanh H; McSorley, Stephen J.

    2015-01-01

    Salmonella enterica serovars Typhi and Paratyphi are the causative agents of human typhoid fever. Current typhoid vaccines are ineffective and are not widely used in endemic areas. Greater understanding of host–pathogen interactions during Salmonella infection should facilitate the development of improved vaccines to combat typhoid and nontyphoidal Salmonellosis. This review will focus on our current understanding of Salmonella pathogenesis and the major host immune components that participate in immunity to Salmonella infection. In addition, recent findings regarding host immune mechanisms in response to Salmonella infection will be also discussed, providing a new perspective on the utility of improved tools to study the immune response to Salmonella infections. PMID:25598340

  15. Murine lung responses to ambient particulate matter: genomic analysis and influence on airway hyperresponsiveness.

    PubMed

    Wang, Ting; Moreno-Vinasco, Liliana; Huang, Yong; Lang, Gabriel D; Linares, Jered D; Goonewardena, Sascha N; Grabavoy, Alayna; Samet, Jonathan M; Geyh, Alison S; Breysse, Patrick N; Lussier, Yves A; Natarajan, Viswanathan; Garcia, Joe G N

    2008-11-01

    Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Epidemiologic studies have demonstrated that exposures to environmental factors such as ambient particulate matter (PM), a major air pollutant, contribute to increased asthma prevalence and exacerbations. We investigated pathophysiologic responses to Baltimore, Maryland, ambient PM (median diameter, 1.78 mum) in a murine model of asthma and attempted to identify PM-specific genomic/molecular signatures. We exposed ovalbumin (OVA)-sensitized A/J mice intratracheally to PM (20 mg/kg), and assayed both AHR and bronchoalveolar lavage (BAL) on days 1, 4, and 7 after PM exposure. Lung gene expression profiling was analyzed in OVA- and PM-challenged mice. Consistent with this murine model of asthma, we observed significant increases in airway responsiveness in OVA-treated mice, with PM exposure inducing significant changes in AHR in both naive mice and OVA-induced asthmatic mice. PM evoked eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of type 1 T helper (T(H)1) cytokines [interferon-gamma, interleukin-6 (IL-6), tumor necrosis factor-alpha] and T(H)2 cytokines (IL-4, IL-5, eotaxin) into murine airways. Furthermore, PM consistently induced expression of genes involved in innate immune responses, chemotaxis, and complement system pathways. This study is consistent with emerging epidemiologic evidence and indicates that PM exposure evokes proinflammatory and allergic molecular signatures that may directly contribute to the asthma susceptibility in naive subjects and increased severity in affected asthmatics.

  16. Human Immune Responses to Dengue Viruses.

    DTIC Science & Technology

    1983-09-01

    A-Al?l 362 HUMAN IMMUNE RESPONSES TO DENGUE YXRUSES(U) MASSACHUSETTS UNIV MEDICAL SCHOOL NORCESTER F A ENNIS SE 83" I ?-2C23 UNCLASSI FIED SE 3IRD?8...SHEET PREVIOUS EDITION MAY BE USED UNTILDTIC FORM 70A OUMNPRESIGSETSTOCK IS EXHAUSTED.DEC 83 AD IHuman Immune Responses to Dengue Viruses Annual Report...edilon may be ued Y01dxffnUICFMCASIAZIlow f~ rolit SUMMARY The purpose of this contract is to analyse the immune responses to dengue virus infections

  17. Human Immune Response to Dengue Infections.

    DTIC Science & Technology

    1987-07-30

    W5l "I± H"MN IMMUNE RESPONSE TO DENGUE INFECTIONS(U) i/il MASSACHUSETTS UNIV MEDICAL CENTER NORCESTER MR1 F R ENIS 36 JUL 87 DAMD7-86-C-6200...1 U . AD HUMAN IMMUNE RESPONSE TO DENGUE INFECTIONS ANNUAL REPORT In 00 FRANCIS A. ENNIS JULY 30, 1987 Supported by U.S. ARMY MEDICAL RESEARCH...Human Immune Response to Dengue Infections 12. PERSONAL AUTHOR(S) Ennis, Francis A. 13a. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF REPORT (Year

  18. Effects of lymphokines and immune complexes on murine placental cell growth in vitro

    SciTech Connect

    Armstrong, D.T.; Chaouat, G. )

    1989-03-01

    Isolated murine placental cells obtained at Day 16 of allogeneic gestation (C3H x DBA/2J) were cultured for 3 days alone or in coculture with irradiated mouse splenocytes at the end of which 3H-thymidine was added for an additional 18-h culture to assess cell proliferation. Placental cell proliferation was significantly enhanced at spleen cell:placental cell ratios of 10:1 and 25:1 above that observed in the absence of added spleen cells. The stimulatory effect of irradiated allogeneic (C3H plus Balb/cJ) spleen cell cultures was significantly greater (approximately 2-fold) than that of isogeneic spleen cells (C3H alone). Conditioned medium from murine spleen cells cultured with concanavalin A (ConA) to induce lymphokine production had dose-dependent inhibitory effects on proliferation when added to placental cell cultures over a range of concentrations from 10 to 40% (vol:vol). Addition of pseudo immune complexes in the form of heat-aggregated human gamma globulin (AHGG) to culture medium failed to alter placental cell proliferation over a range of concentrations from 2 to 200 micrograms/ml either in the absence or presence of ConA-conditioned medium. In contrast to late-gestational stage placental cells, cell suspensions obtained from Days 8-9 murine ectoplacental cone (EPC) outgrowths, or from earlier stage placentas (Days 12-14) responded to low concentrations of conditioned medium from ConA-stimulated splenocytes with increased proliferation. The effect was less impressive on placental cells at gestational ages later than 12 days than on earlier stage preparations. On all placental cell suspensions tested, as well as EPC cells, a clear-cut inhibition of growth was observed at high doses of conditioned medium.

  19. [Correlation between chemical carcinogenesis and immune response].

    PubMed

    Brai, M; Bonasera, L; Tolone, G

    1975-01-01

    Methylcholanthrene, in amount sufficient to induce tumors in 100% of treated animals failed to influence primary and secondary phases of antibody synthesis in mice immunized with sheep erythrocytes and human serum albumin. The early immune response in tumor bearing mice was also indistinguischable from that of normal animals, despite the presence of marked splenomegaly in the former group.

  20. Murine bone marrow IgA responses to orally administered sheep erythrocytes.

    PubMed

    Alley, C D; Kiyono, H; McGhee, J R

    1986-06-15

    Specific immunization protocols have been established for the induction of murine bone marrow IgA responses to the T cell-dependent (TD) antigen sheep red blood cells (SRBC). Systemic immunization, either i.p. or i.v., followed by a second injection, induced splenic IgM and IgG responses and a bone marrow IgM response. No significant IgA responses were observed in either lymphoid tissue compartment. Oral immunization with SRBC by gastric intubation for 2 days, followed 1 wk later by an i.p. injection of SRBC resulted in a splenic IgA plaque-forming cell (PFC) response, but did not elicit a bone marrow IgA response. Repeated daily gastric intubation of SRBC to C3H/HeN and C3H/HeJ mice led to the previously reported pattern of systemic unresponsiveness in C3H/HeN mice and good anamnestic type IgM, IgG, and IgA splenic anti-SRBC PFC responses in the C3H/HeJ strain upon parenteral challenge. Oral administration of SRBC for 14 days to C3H/HeN mice, followed by systemic SRBC challenge, resulted in diminished splenic PFC responses of all isotypes, whereas gastric intubation of SRBC for 28 days led to complete systemic unresponsiveness to antigen in C3H/HeN mice. Interestingly, the repeated oral administration of SRBC resulted in significant bone marrow IgA PFC responses upon i.p. challenge in both C3H/HeN and C3H/HeJ mouse strains. The bone marrow IgA responses were clearly dependent upon chronic oral exposure to SRBC, because gastric intubation with SRBC for 2 consecutive days/wk for 10 wk also induced bone marrow and splenic IgA anti-SRBC PFC responses in C3H/HeN mice. These results suggest that memory B cells reside in the bone marrow of orally immunized mice and can yield anamnestic-type responses to challenge with the inducing antigen. The memory cells may arise in the Peyer's patches of the gut and migrate to the bone marrow. The possibility that the bone marrow is a component of the common mucosal immune system in mammals is suggested by this study.

  1. Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages.

    PubMed

    Abu Khweek, Arwa; Fernández Dávila, Natalia S; Caution, Kyle; Akhter, Anwari; Abdulrahman, Basant A; Tazi, Mia; Hassan, Hoda; Novotny, Laura A; Bakaletz, Lauren O; Amer, Amal O

    2013-01-01

    Legionella pneumophila, the causative agent of Legionnaire's disease, replicates in human alveolar macrophages to establish infection. There is no human-to-human transmission and the main source of infection is L. pneumophila biofilms established in air conditioners, water fountains, and hospital equipments. The biofilm structure provides protection to the organism from disinfectants and antibacterial agents. L. pneumophila infection in humans is characterized by a subtle initial immune response, giving time for the organism to establish infection before the patient succumbs to pneumonia. Planktonic L. pneumophila elicits a strong immune response in murine, but not in human macrophages enabling control of the infection. Interactions between planktonic L. pneumophila and murine or human macrophages have been studied for years, yet the interface between biofilm-derived L. pneumophila and macrophages has not been explored. Here, we demonstrate that biofilm-derived L. pneumophila replicates significantly more in murine macrophages than planktonic bacteria. In contrast to planktonic L. pneumophila, biofilm-derived L. pneumophila lacks flagellin expression, do not activate caspase-1 or -7 and trigger less cell death. In addition, while planktonic L. pneumophila is promptly delivered to lysosomes for degradation, most biofilm-derived bacteria were enclosed in a vacuole that did not fuse with lysosomes in murine macrophages. This study advances our understanding of the innate immune response to biofilm-derived L. pneumophila and closely reproduces the natural mode of infection in human.

  2. Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages

    PubMed Central

    Abu Khweek, Arwa; Fernández Dávila, Natalia S.; Caution, Kyle; Akhter, Anwari; Abdulrahman, Basant A.; Tazi, Mia; Hassan, Hoda; Novotny, Laura A.; Bakaletz, Lauren O.; Amer, Amal O.

    2013-01-01

    Legionella pneumophila, the causative agent of Legionnaire's disease, replicates in human alveolar macrophages to establish infection. There is no human-to-human transmission and the main source of infection is L. pneumophila biofilms established in air conditioners, water fountains, and hospital equipments. The biofilm structure provides protection to the organism from disinfectants and antibacterial agents. L. pneumophila infection in humans is characterized by a subtle initial immune response, giving time for the organism to establish infection before the patient succumbs to pneumonia. Planktonic L. pneumophila elicits a strong immune response in murine, but not in human macrophages enabling control of the infection. Interactions between planktonic L. pneumophila and murine or human macrophages have been studied for years, yet the interface between biofilm-derived L. pneumophila and macrophages has not been explored. Here, we demonstrate that biofilm-derived L. pneumophila replicates significantly more in murine macrophages than planktonic bacteria. In contrast to planktonic L. pneumophila, biofilm-derived L. pneumophila lacks flagellin expression, do not activate caspase-1 or -7 and trigger less cell death. In addition, while planktonic L. pneumophila is promptly delivered to lysosomes for degradation, most biofilm-derived bacteria were enclosed in a vacuole that did not fuse with lysosomes in murine macrophages. This study advances our understanding of the innate immune response to biofilm-derived L. pneumophila and closely reproduces the natural mode of infection in human. PMID:23750338

  3. Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

    PubMed

    Crow, Andrew R; Song, Seng; Suppa, Sara J; Ma, Shuhua; Reilly, Michael P; Andre, Pierrette; McKenzie, Steven E; Lazarus, Alan H

    2011-01-20

    To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.

  4. Epigenetics and the Adaptive Immune Response

    PubMed Central

    Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.

    2012-01-01

    Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathogens. While the immune system benefits from the dynamic nature of the epigenome, such benefit comes at a cost – increased likelihood of disease-causing mutation. PMID:22789989

  5. Isolation and characterisation of Ebolavirus-specific recombinant antibody fragments from murine and shark immune libraries.

    PubMed

    Goodchild, Sarah A; Dooley, Helen; Schoepp, Randal J; Flajnik, Martin; Lonsdale, Stephen G

    2011-09-01

    Members of the genus Ebolavirus cause fulminating outbreaks of disease in human and non-human primate populations with a mortality rate up to 90%. To facilitate rapid detection of these pathogens in clinical and environmental samples, robust reagents capable of providing sensitive and specific detection are required. In this work recombinant antibody libraries were generated from murine (single chain variable domain fragment; scFv) and nurse shark, Ginglymostoma cirratum (IgNAR V) hosts immunised with Zaire ebolavirus. This provides the first recorded IgNAR V response against a particulate antigen in the nurse shark. Both murine scFv and shark IgNAR V libraries were panned by phage display technology to identify useful antibodies for the generation of immunological detection reagents. Two murine scFv were shown to have specificity to the Zaire ebolavirus viral matrix protein VP40. Two isolated IgNAR V were shown to bind to the viral nucleoprotein (NP) and to capture viable Zaire ebolavirus with a high degree of sensitivity. Assays developed with IgNAR V cross-reacted to Reston ebolavirus, Sudan ebolavirus and Bundibugyo ebolavirus. Despite this broad reactivity, neither of IgNAR V showed reactivity to Côte d'Ivoire ebolavirus. IgNAR V was substantially more resistant to irreversible thermal denaturation than murine scFv and monoclonal IgG in a comparative test. The demonstrable robustness of the IgNAR V domains may offer enhanced utility as immunological detection reagents in fieldable biosensor applications for use in tropical or subtropical countries where outbreaks of Ebolavirus haemorrhagic fever occur.

  6. Cellular immune response in intraventricular experimental neurocysticercosis.

    PubMed

    Moura, Vania B L; Lima, Sarah B; Matos-Silva, Hidelberto; Vinaud, Marina C; Loyola, Patricia R A N; Lino, Ruy S

    2016-03-01

    Neurocysticercosis (NCC) is considered a neglected parasitic infection of the human central nervous system. Its pathogenesis is due to the host immune response, stage of evolution and location of the parasite. The aim of this study was to evaluate the in situ and systemic immune response through cytokines dosage (IL-4, IL-10, IL-17 and IFN-γ) as well as the local inflammatory response of the experimental NCC with Taenia crassiceps. The in situ and systemic cellular and inflammatory immune response were evaluated through the cytokines quantification at 7, 30, 60 and 90 days after inoculation and histopathological analysis. All cysticerci were found within the cerebral ventricles. There was a discrete intensity of inflammatory cells of mixed immune profile, polymorphonuclear and mononuclear cells, at the beginning of the infection and predominance of mononuclear cells at the end. The systemic immune response showed a significant increase in all the analysed cytokines and predominance of the Th2 immune profile cytokines at the end of the infection. These results indicate that the location of the cysticerci may lead to ventriculomegaly. The acute phase of the infection showed a mixed Th1/Th17 profile accompanied by high levels of IL-10 while the late phase showed a Th2 immune profile.

  7. Integrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles

    PubMed Central

    Varn, Frederick S.; Andrews, Erik H.; Mullins, David W.; Cheng, Chao

    2016-01-01

    Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these results allow for a detailed and personalized assessment of the patient immune response to a tumour. When combined with routinely collected patient biopsy genomic data, this method can enable a richer understanding of the complex interplay between the host immune system and cancer. PMID:26725977

  8. Acute lethal toxicity following passive immunization for treatment of murine cryptococcosis.

    PubMed Central

    Savoy, A C; Lupan, D M; Manalo, P B; Roberts, J S; Schlageter, A M; Weinhold, L C; Kozel, T R

    1997-01-01

    Passive immunization with monoclonal antibodies (MAbs) specific for the major capsular polysaccharide of Cryptococcus neoformans alters the course of murine cryptococcosis. During studies of passive immunization for treatment of murine cryptococcosis, we noted the occurrence of an acute, lethal toxicity. Toxicity was characterized by scratching, lethargy, respiratory distress, collapse, and death within 20 to 60 min after injection of antibody. The toxic effect was observed only in mice with a cryptococcal infection and was reduced or absent in the early and late stages of disease. The clinical course and histopathology were consistent with those for shock. There was considerable variation between mouse strains in susceptibility to toxicity. Swiss Webster mice from the Charles River colony were most susceptible, followed by C3H/He, BALB/c, and C57BL/6 mice. DBA/2 mice and Swiss Webster mice from the Simonsen colony were resistant. Acute toxicity was mimicked by injection of preformed complexes of MAb and purified polysaccharide. The toxic effect was also produced by injection of MAbs into mice that were preloaded with polysaccharide. The toxic effect was not blocked by treatment of mice with chloropheniramine or anti-tumor necrosis factor alpha antibodies or by depletion of complement components via pretreatment with cobra venom factor. Toxicity was reduced by treatment of mice with high doses of epinephrine, dexamethasone, or chlorpromazine. Finally, the toxic effect was completely blocked by treatment of mice with the platelet-activating factor antagonist WEB 2170 BS or by pretreatment of mice with the liposome-encapsulated drug dichloromethylene diphosphonate, a procedure which depletes macrophages from the spleen and liver. PMID:9125564

  9. Nerve growth factor translates stress response and subsequent murine abortion via adhesion molecule-dependent pathways.

    PubMed

    Tometten, Mareike; Blois, Sandra; Kuhlmei, Arne; Stretz, Anna; Klapp, Burghard F; Arck, Petra C

    2006-04-01

    Spontaneous abortion is a frequent threat affecting 10%-25% of human pregnancies. Psychosocial stress has been suggested to be attributable for pregnancy losses by challenging the equilibrium of systems mandatory for pregnancy maintenance, including the nervous, endocrine, and immune system. Strong evidence indicates that stress-triggered abortion is mediated by adhesion molecules, i.e., intercellular adhesion molecule 1 (ICAM1) and leukocyte function associated molecule 1, now being referred to as integrin alpha L (ITGAL), which facilitate recruitment of inflammatory cells to the feto-maternal interface. The neurotrophin beta-nerve growth factor (NGFB), which has been shown to be upregulated in response to stress in multiple experimental settings including in the uterine lining (decidua) during pregnancy, increases ICAM1 expression on endothelial cells. Here, we investigated whether and how NGFB neutralization has a preventive effect on stress-triggered abortion in the murine CBA/J x DBA/2J model. We provide experimental evidence that stress exposure upregulates the frequency of abortion and the expression of uterine NGFB. Further, adhesion molecules ICAM1 and selectin platelet (SELP, formerly P-Selectin) and their ligands ITGAL and SELP ligand (SELPL, formerly P selectin glycoprotein ligand 1) respectively increase in murine deciduas in response to stress. Subsequently, decidual cytokines are biased toward a proinflammatory and abortogenic cytokine profile. Additionally, a decrease of pregnancy protective CD8alpha(+) decidual cells is present. Strikingly, all such uterine stress responses are abrogated by NGFB neutralization. Hence, NGFB acts as a proximal mediator in the hierarchical network of immune rejection by mediating an abortogenic environment comprised of classical signs of neurogenic inflammation.

  10. Adaptive immune responses to Acanthamoeba cysts.

    PubMed

    McClellan, Kathy; Howard, Kevin; Mayhew, Elizabeth; Niederkorn, Jerry; Alizadeh, Hassan

    2002-09-01

    Acanthamoeba cysts are not eliminated from the corneas of human subjects or experimentally infected animals. The persistence of Acanthamoeba cysts in the cornea indicates that either the cysts escape immunological elimination or are not recognized by the host's immunological elements. The aim of this study was to determine the immunogenicity and antigenicity of the Acanthamoeba cyst. Mice were immunized intraperitoneally and serum anti-Acanthamoeba IgG was measured by ELISA. Lymphoproliferative assay and delayed type hypersensitivity (DTH) responses to Acanthamoeba castellanii cyst and trophozoite antigens were used to determine the cell mediated immune responses against Acanthamoeba cysts. A. castellanii cysts were both immunogenic and antigenic, producing anti-Acanthamoeba serum IgG, T lymphocyte proliferation, and delayed type hypersensitivity responses. These results indicate that Acanthamoeba cysts are recognized by the immune system. The persistence of the organism in the human cornea means that these adaptive immune responses fail to kill Acanthamoeba cysts.

  11. Immune response to uv-induced tumors: transplantation immunity and lymphocyte populations exhibiting anti-tumor activity

    SciTech Connect

    Streeter, P.R.

    1985-01-01

    Ultraviolet light-induced murine skin tumors were analyzed for their ability to induce tumor-specific and cross-protective transplantation immunity in immunocompetent syngeneic mice. These studies revealed that progressor UV-tumors, like regressor UV-tumors, possess tumor-specific transplantation antigens. Cross-protective transplantation immunity to UV-tumors, however, was associated with sensitization to the serum used to culture the tumor lines rather than to cross-reactive or common determinants on UV-tumors. An analysis of the cytolytic activity of lymphocytes from the spleens of mice immunized with either regressor or progressor UV-tumors revealed a striking difference between the two immune splenocyte populations. From regressor tumor-immune animals, cytolytic T (Tc) lymphocytes with specificity for the immunizing tumor were found. However, the analysis of splenic lymphocytes from progressor tumor immune animals revealed no such effector cells. To more effectively examine those lymphocytes exhibiting cytolytic activity in vitro, T lymphocyte cloning technology was used as a means of isolating homogeneous lymphocyte populations with the effector activities described above. The mechanisms where NK cells and other nonspecific effector cells could be induced in tumor-immune animals are discussed in the context of class II restricted immune responses.

  12. Development of the granulomatous response in murine toxocariasis. Initial events.

    PubMed Central

    Kayes, S. G.; Oaks, J. A.

    1978-01-01

    The cellular evolution of the persisting, muscle-associated granuloma in murine toxocariasis (visceral larva migrans) was chronicled for 11 weeks by light and electron microscopy. The initial granuloma consisted primarily of eosinophils and appeared to develop from the acute inflammatory infiltrate. During the ensuing 48 hours, most of the eosinophils appeared to loose their granules and disintegrate. The resulting cellular debris was then taken up by newly arrived macrophages which become the predominant mononuclear cell in the lesion by 28 days of infection. By 11 weeks, the granuloma had become a fibrotically encapsulated epithelioid granuloma surrounding the inciting larva. This histologic reaction is compared with the liver granulomatous response to Toxocara and to the well-characterized schistosome egg granuloma. A possible delayed hypersensitive etiology for the Toxocara granuloma is suggested. Images Figure 3 Figure 4 Figure 13 Figure 14 Figure 5 Figure 6 Figure 7 Figure 8 Figure 1 Figure 2 Figure 9 Figure 10 Figure 11 Figure 12 PMID:717533

  13. Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection ▿

    PubMed Central

    Kline, Kimberly A.; Schwartz, Drew J.; Lewis, Warren G.; Hultgren, Scott J.; Lewis, Amanda L.

    2011-01-01

    Group B streptococcus (GBS) is a common commensal of the gastrointestinal and vaginal mucosa and a leading cause of serious infections in newborns, the elderly, and immunocompromised populations. GBS also causes infections of the urinary tract. However, little is known about host responses to GBS urinary tract infection (UTI) or GBS virulence factors that participate in UTI. Here we describe a novel murine model of GBS UTI that may explain some features of GBS urinary tract association in the human host. We observed high titers and heightened histological signs of inflammation and leukocyte recruitment in the GBS-infected kidney. However, extensive inflammation and leukocyte recruitment were not observed in the bladder, suggesting that GBS may suppress bladder inflammation during cystitis. Acute GBS infection induced the localized expression of proinflammatory cytokines interleukin-1α (IL-1α), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and IL-9, as well as IL-10, more commonly considered an anti-inflammatory cytokine. Using isogenic GBS strains with different capsule structures, we show that capsular sialic acid residues contribute to GBS urinary tract pathogenesis, while high levels of sialic acid O-acetylation attenuate GBS pathogenesis in the setting of UTI, particularly in direct competition experiments. In vitro studies demonstrated that GBS sialic acids participate in the suppression of murine polymorphonuclear leukocyte (PMN) bactericidal activities, in addition to reducing levels of IL-1α, tumor necrosis factor alpha, IL-1β, MIP-1α, and KC produced by PMNs. These studies define several basic molecular and cellular events characterizing GBS UTI in an animal model, showing that GBS participates simultaneously in the activation and suppression of host immune responses in the urinary tract. PMID:21690238

  14. Immune Response in Hepatitis B Virus Infection

    PubMed Central

    Tan, Anthony; Koh, Sarene; Bertoletti, Antonio

    2015-01-01

    Hepatitis B virus (HBV) can replicate within hepatocytes without causing direct cell damage. The host immune response is, therefore, not only essential to control the spread of virus infection, but it is also responsible for the inflammatory events causing liver pathologies. In this review, we discuss how HBV deals with host immunity and how we can harness it to achieve virus control and suppress liver damage. PMID:26134480

  15. Comparative Analysis of the Effects of Two Probiotic Bacterial Strains on Metabolism and Innate Immunity in the RAW 264.7 Murine Macrophage Cell Line.

    PubMed

    Pradhan, Biswaranjan; Guha, Dipanjan; Ray, Pratikshya; Das, Debashmita; Aich, Palok

    2016-06-01

    Probiotic and potential probiotic bacterial strains are routinely prescribed and used as supplementary therapy for a variety infectious diseases, including enteric disorders among a wide range of individuals. While there are an increasing number of studies defining the possible mechanisms of probiotic activity, a great deal remains unknown regarding the diverse modes of action attributed to these therapeutic agents. More precise information is required to support the appropriate application of probiotics. To address this objective, we selected two probiotics strains, Lactobacillus acidophilus MTCC-10307 (LA) and Bacillus clausii MTCC-8326 (BC) that are frequently prescribed for the treatment of intestinal disorders and investigated their effects on the RAW 264.7 murine macrophage cell line. Our results reveal that LA and BC are potent activators of both metabolic activity and innate immune responses in these cells. We also observed that LA and BC possessed similar activity in preventing infection simulated in vitro in murine macrophages by Salmonella typhimurium serovar enterica.

  16. Cellular immune response experiment MA-031

    NASA Technical Reports Server (NTRS)

    Criswell, B. S.

    1976-01-01

    Significant changes in phytohemagglutinin (PHA) lymphocytic responsiveness occurred in the cellular immune response of three astronauts during the 9 day flight of the Apollo Soyuz Test Project. Parameters studied were white blood cell concentrations, lymphocyte numbers, B- and T-lymphocyte distributions in peripheral blood, and lymphocyte responsiveness to PHA, pokeweed mitogen, Concanavalin A, and influenza virus antigen.

  17. Natural immunity has significant impact on immune responses against cancer.

    PubMed

    Rubin, B

    2009-03-01

    The immune system defends the host against pathogenic attacks by micro-organisms and their products. It does not react against self-components due to the relatively efficient negative selection of developing T lymphocytes in the thymus. This process does permit T cells with low avidity against self to be present in the T cell repertoire. Such cells play an important physiological role as the host needs so-called autoimmune reactions in order to eliminate dying cells or transformed tumour cells. One of the mysteries in immunology is how the host maintains beneficial autoimmune reactions and avoids pathogenic autoimmune reactions. Activation of the adaptive T lymphocytes is mediated by the low avidity interaction between T-cell antigen receptors and antigenic peptides associated with major histocompatibility complex class I or class II molecules. This interaction is strengthened by T-cell co-receptors such as CD2, CD4, CD8, CD28 and CD154, which react with ligands expressed by cells of the innate immune system. In recent years, the importance of pre-activation of the innate immune system for initiation of adaptive T-cell immune responses has been appreciated. In the present review, I will summarize our work on how natural immunity plays an important role in determining the level of beneficial autoimmune reactions against cancer.

  18. Immune response to lipoproteins in atherosclerosis.

    PubMed

    Samson, Sonia; Mundkur, Lakshmi; Kakkar, Vijay V

    2012-01-01

    Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.

  19. Initiation of adaptive immune responses by transcutaneous immunization.

    PubMed

    Warger, Tobias; Schild, Hansjörg; Rechtsteiner, Gerd

    2007-03-15

    The development of new, effective, easy-to-use and lower-cost vaccination approaches for the combat against malignant and infectious diseases is a pre-eminent need: cancer is a leading cause of morbidity in the Western World; there are numerous pathogenic diseases for which we still have no protective or therapeutic cure; and the financial limitations of developing countries to fight these diseases. In this mini-review we focus on transcutaneous immunization (TCI), a relatively new route for antigen delivery. TCI protocols appear to be particularly promising by gaining access to skin resident APC, which are highly efficient for the initiation of humoral and/or cellular immune responses. Consisting of an adjuvant as a stimulus in combination with an antigen which defines the target, TCI offers a most attractive immunization strategy to mount highly specific full-blown adaptive immune responses. As a topically applicable cell-free adjuvant/antigen mixture, TCI might be suitable to improve patient compliance, as well as feasible economically for the use in Third World countries. In addition, this non-invasive procedure might increase the safety of vaccinations by eliminating the risk of infections related to the recycling and improper disposal of needles. The dissection of antigen and adjuvant is important because it allows "free" combinations in contrast to classical immunizations which are based on application of the pathogen of interest. The most relevant ways and means to find new, effective pathogenic target antigens are "reverse vaccinology" and the direct peptide-epitope identification from MHC molecules with mass-spectrometry. Due to these efficient approaches the variety of antigenic epitopes for potential protective/therapeutic use is perpetually expanding. The most studied adjuvants in TCI approaches are cholera toxin (CT) and its less toxic relative, the heat-labile enterotoxin (LT). Both CT and LT can serve as antigen as well. In contrast to these large

  20. Humoral immune response to the antigen administered as an immune complex.

    PubMed

    Marusić, M; Marusić-Galesić, S; Pokrić, B

    1992-12-01

    Antigen (HSA) bound in immune complexes at equivalence with syngeneic anti-HSA antibodies elicit much stronger humoral immune response then soluble HSA. On the other hand, administration of immune complexes formed with xenogeneic (rabbit) anti-HSA antibodies suppressed humoral immune response against HSA, but not against rabbit IgG in mice. We suggest that immunization with antigen bound in immune complex might represent a powerful tool in enhancing humoral immune responses.

  1. Host-Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response.

    PubMed

    Brasil, Thaís Rigueti; Freire-de-Lima, Celio Geraldo; Morrot, Alexandre; Vetö Arnholdt, Andrea Cristina

    2017-01-01

    Toxoplasma gondii has successfully developed strategies to evade host's immune response and reach immune privileged sites, which remains in a controlled environment inside quiescent tissue cysts. In this review, we will approach several known mechanisms used by the parasite to modulate mainly the murine immune system at its favor. In what follows, we review recent findings revealing interference of host's cell autonomous immunity and cell signaling, gene expression, apoptosis, and production of microbicide molecules such as nitric oxide and oxygen reactive species during parasite infection. Modulation of host's metalloproteinases of extracellular matrix is also discussed. These immune evasion strategies are determinant to parasite dissemination throughout the host taking advantage of cells from the immune system to reach brain and retina, crossing crucial hosts' barriers.

  2. Host-Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response

    PubMed Central

    Brasil, Thaís Rigueti; Freire-de-Lima, Celio Geraldo; Morrot, Alexandre; Vetö Arnholdt, Andrea Cristina

    2017-01-01

    Toxoplasma gondii has successfully developed strategies to evade host’s immune response and reach immune privileged sites, which remains in a controlled environment inside quiescent tissue cysts. In this review, we will approach several known mechanisms used by the parasite to modulate mainly the murine immune system at its favor. In what follows, we review recent findings revealing interference of host’s cell autonomous immunity and cell signaling, gene expression, apoptosis, and production of microbicide molecules such as nitric oxide and oxygen reactive species during parasite infection. Modulation of host’s metalloproteinases of extracellular matrix is also discussed. These immune evasion strategies are determinant to parasite dissemination throughout the host taking advantage of cells from the immune system to reach brain and retina, crossing crucial hosts’ barriers. PMID:28955329

  3. Modulating immune responses with probiotic bacteria.

    PubMed

    Matsuzaki, T; Chin, J

    2000-02-01

    For many years, probiotic bacteria have been known to confer health benefits to the consumer. One possible mechanism for this may be the ability of probiotic bacteria to modulate immune responses. Oral administration of Lactobacillus casei strain Shirota (LcS) has been found to enhance innate immunity by stimulating the activity of splenic NK cells. Oral feeding with killed LcS was able to stimulate the production of Th1 cytokines, resulting in repressed production of IgE antibodies against Ovalbumin in experimental mice. The ability to switch mucosal immune responses towards Th1 with probiotic bacteria provides a strategy for treatment of allergic disorders. Growth of Meth A tumour cells in the lungs was also inhibited by intrapleural injection of LcS. Oral administration of other probiotic bacteria, such as Streptococcus thermophilus (St), Lactobacillus fermentum (Lf) and yeast (Y), elicited different immune responses. Mice that were prefed yeast or Lf followed by feeding with ovalbumin (OVA) responded better to vaccination with OVA than mice not given either probiotic or OVA or mice that had been prefed only OVA. However, antibody responses were significantly suppressed in response to vaccination with OVA in mice that had been prefed yeast followed by yeast and OVA as well as mice prefed Lf followed by Lf and OVA. Prefeeding St followed by OVA feeding enhanced cellular immune responses against ovalbumin. In contrast, mice prefed St followed by St + OVA were hyporesponsive against OVA. While antigen feeding alone appears to prime for an immune response, cofeeding antigen with probiotic bacteria can suppress both antibody and cellular immune responses and may provide an efficacious protocol to attenuate autoimmune diseases, such as experimental allergic encephalomyelitis, by jointly dosing with myelin basic protein and probiotic bacteria.

  4. Immune response to biologic scaffold materials.

    PubMed

    Badylak, Stephen F; Gilbert, Thomas W

    2008-04-01

    Biologic scaffold materials composed of mammalian extracellular matrix are commonly used in regenerative medicine and in surgical procedures for the reconstruction of numerous tissue and organs. These biologic materials are typically allogeneic or xenogeneic in origin and are derived from tissues such as small intestine, urinary bladder, dermis, and pericardium. The innate and acquired host immune response to these biologic materials and the effect of the immune response upon downstream remodeling events has been largely unexplored. Variables that affect the host response include manufacturing processes, the rate of scaffold degradation, and the presence of cross species antigens. This manuscript provides an overview of studies that have evaluated the immune response to biologic scaffold materials and variables that affect this response.

  5. Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency.

    PubMed

    Carmo, Marlene; Risma, Kimberly A; Arumugam, Paritha; Tiwari, Swati; Hontz, Adrianne E; Montiel-Equihua, Claudia A; Alonso-Ferrero, Maria E; Blundell, Michael P; Schambach, Axel; Baum, Christopher; Malik, Punam; Thrasher, Adrian J; Jordan, Michael B; Gaspar, H Bobby

    2015-04-01

    Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL.

  6. Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency

    PubMed Central

    Carmo, Marlene; Risma, Kimberly A; Arumugam, Paritha; Tiwari, Swati; Hontz, Adrianne E; Montiel-Equihua, Claudia A; Alonso-Ferrero, Maria E; Blundell, Michael P; Schambach, Axel; Baum, Christopher; Malik, Punam; Thrasher, Adrian J; Jordan, Michael B; Gaspar, H Bobby

    2015-01-01

    Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8+ T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8+ lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL. PMID:25523759

  7. Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.

    PubMed

    Surace, Laura; Lysenko, Veronika; Fontana, Andrea Orlando; Cecconi, Virginia; Janssen, Hans; Bicvic, Antonela; Okoniewski, Michal; Pruschy, Martin; Dummer, Reinhard; Neefjes, Jacques; Knuth, Alexander; Gupta, Anurag; van den Broek, Maries

    2015-04-21

    Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses.

  8. Cross-reactivity of anti-phosphorylcholine antibodies to neuromuscular blockers in a murine model of immunization.

    PubMed

    Mazzuco, Rosa Maria; Sato, Maria Notomi; Vasconcelos, Dewton de Moraes; Duarte, Alberto José da Silva

    2007-09-01

    Hypersensitivity reactions to curare-like neuromuscular blocking agents (NMBA) used in anesthesiology are more frequent in females and often occur at the first exposure to these drugs. To evaluate the antibody response to a hapten sharing the same allergenic epitope with NMBA in a murine model of immunization with Nitrophenylphosphorylcholine (NPPC) coupled with Keyhole Limpet Hemocyanin (KLH). BALB/c mice from both sexes were intraperitoneally immunized with NPPC-KLH with alum and boosted twice, on 7 and 14 days. The antibodies were tested for specificity to PC and for cross-reactivity to the haptens, NPPC and PC, as well as to the NMBAs. Mice immunized with NPPC-KLH produced anti-PC antibodies mainly of IgM, IgG1 and IgG3 isotypes, at similar levels in both sexes. Different affinities for the haptens were detectable between isotypes, with anti-PC IgG3 antibody reactivity mostly related to the choline portion of the NPPC hapten. When comparing among sexes, females developed greater IgG2 affinity to the hapten than males. Cross-reactivity to NMBAs was predominant among the anti-PC IgG3 antibodies, mainly in females achieving 75% of inhibition with 16 mM of suxamethonium, while other isotypes achieved up to 30% and was absent for IgE. The investigation of antibody isotypes regarding sensitization to choline-derived structures could contribute to understanding the differential ability of females to produce antibodies that are cross-reactive with NMBAs.

  9. Strain-specific Loss of Formyl Peptide Receptor 3 in the Murine Vomeronasal and Immune Systems.

    PubMed

    Stempel, Hendrik; Jung, Martin; Pérez-Gómez, Anabel; Leinders-Zufall, Trese; Zufall, Frank; Bufe, Bernd

    2016-04-29

    Formyl peptide receptor 3 (Fpr3, also known as Fpr-rs1) is a G protein-coupled receptor expressed in subsets of sensory neurons of the mouse vomeronasal organ, an olfactory substructure essential for social recognition. Fpr3 has been implicated in the sensing of infection-associated olfactory cues, but its expression pattern and function are incompletely understood. To facilitate visualization of Fpr3-expressing cells, we generated and validated two new anti-Fpr3 antibodies enabling us to analyze acute Fpr3 protein expression. Fpr3 is not only expressed in murine vomeronasal sensory neurons but also in bone marrow cells, the primary source for immune cell renewal, and in mature neutrophils. Consistent with the notion that Fpr3 functions as a pathogen sensor, Fpr3 expression in the immune system is up-regulated after stimulation with a bacterial endotoxin (lipopolysaccharide). These results strongly support a dual role for Fpr3 in both vomeronasal sensory neurons and immune cells. We also identify a large panel of mouse strains with severely altered expression and function of Fpr3, thus establishing the existence of natural Fpr3 knock-out strains. We attribute distinct Fpr3 expression in these strains to the presence or absence of a 12-nucleotide in-frame deletion (Fpr3Δ424-435). In vitro calcium imaging and immunofluorescence analyses demonstrate that the lack of four amino acids leads to an unstable, truncated, and non-functional receptor protein. The genome of at least 19 strains encodes a non-functional Fpr3 variant, whereas at least 13 other strains express an intact receptor. These results provide a foundation for understanding the in vivo function of Fpr3. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Effect of cellular mobility on immune response

    NASA Astrophysics Data System (ADS)

    Pandey, R. B.; Mannion, R.; Ruskin, H. J.

    2000-08-01

    Mobility of cell types in our HIV immune response model is subject to an intrinsic mobility and an explicit directed mobility, which is governed by Pmob. We investigate how restricting the explicit mobility, while maintaining the innate mobility of a viral-infected cell, affects the model's results. We find that increasing the explicit mobility of the immune system cells leads to viral dominance for certain levels of viral mutation. We conclude that increasing immune system cellular mobility indirectly increases the virus’ inherent mobility.

  11. Immune responses and Lassa virus infection.

    PubMed

    Russier, Marion; Pannetier, Delphine; Baize, Sylvain

    2012-11-05

    Lassa fever is a hemorrhagic fever endemic to West Africa and caused by Lassa virus, an Old World arenavirus. It may be fatal, but most patients recover from acute disease and some experience asymptomatic infection. The immune mechanisms associated with these different outcomes have not yet been fully elucidated, but considerable progress has recently been made, through the use of in vitro human models and nonhuman primates, the only relevant animal model that mimics the pathophysiology and immune responses induced in patients. We discuss here the roles of the various components of the innate and adaptive immune systems in Lassa virus infection and in the control of viral replication and pathogenesis.

  12. Human Immune Responses to Dengue Viruses.

    DTIC Science & Technology

    1984-08-01

    ND-R171 381 HUR IMMUNE RESPONSES TO DENGUE VIRUSES(U) 1/1 MASSRCHUSETTS UNIY M9DICAL SCHOOL WORCESTER F R~ ENNIS RUG 94 DRMt17-2-C-2233 UNCLASSIFIED...Responses to Dengue Viruses Annual Report 0(August 1983-July 1984) Francis A. Ennis, M.D. August 1984 Supported by U.S. Army Medical Research and...3M1- NO. SON No. Frederick, Maryland 21701-5012 61102A 61102BSI0 AA 104 11. TITLE Oxkf* Samqy Oao" Human Immune Responses to Dengue Viruses 12. PERSON

  13. Human Immune Response to Dengue Infections

    DTIC Science & Technology

    1989-07-31

    lhuman Immune Response to Dengue Infections 12. PERSONAL AUTHOR(S) Francis A. Ennis 13a. TYPE OF REPORT 13b. TIME COVERED T14. DATE OF REPORT (Year, Month...Stimulation with live dengue virus of peripheral blood mononuclear cells from a dengue 4-immune donor generated virus-specific serotype cross-reactive CD4- CD8...class I-restricted cytotoxic T lymphocytes (CL) capable of lysing dengue virus-infected autologous fibroblasts and cells pulsed with dengue I

  14. Epitopes of proteoglycans eliciting an anti-proteoglycan response in chronic immune synovitis

    SciTech Connect

    Yoo, J.U.; Kresina, T.F.; Malemud, C.J.; Goldberg, V.M.

    1987-02-01

    This study details the immune response to cartilage proteoglycan in experimental chronic IgG-induced immune synovitis. With the use of radioimmunoassay, antibodies reactive with purified rabbit proteoglycan monomer were observed in nine of nine rabbits with immune synovitis. IgG-immunized but nonsynovitic control animals with no pathology showed no antibody response. A panel of murine monoclonal antibodies with defined specificity towards rabbit proteoglycan were utilized to characterize the epitope specificity of the immune synovitis polyclonal anti-proteoglycan response. One murine monoclonal antibody, 6C11, inhibited the binding of the polyclonal antisera to proteoglycan in all nine animals with significant (>40/sup 5/) inhibition in six of nine rabbits. Further inhibition studies utilizing DEAE-cellulose-resolved proteoglycan tryptic peptides revealed that peptides poor in chondroitin sulfate were strong inhibitors of binding of the polyclonal antibodies to the proteoglycan substrate. In particular, keratan sulfate-containing tryptic peptides were most inhibitory on a per weight basis. These results indicate that, in chromic IgG-induced immune synovitis, anti-proteoglycan antibodies elicited are heterogeneous with regard to specificity, but a relatively large proportion predominantly recognized a portion of the proteoglycan molecule containing core protein and associated keratan sulfate.

  15. Gelam honey scavenges peroxynitrite during the immune response.

    PubMed

    Kassim, Mustafa; Mansor, Marzida; Suhaimi, Anwar; Ong, Gracie; Yusoff, Kamaruddin Mohd

    2012-01-01

    Monocytes and macrophages are part of the first-line defense against bacterial, fungal, and viral infections during host immune responses; they express high levels of proinflammatory cytokines and cytotoxic molecules, including nitric oxide, reactive oxygen species, and their reaction product peroxynitrite. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death. Honey, in addition to its well-known sweetening properties, is a natural antioxidant that has been used since ancient times in traditional medicine. We examined the ability of Gelam honey, derived from the Gelam tree (Melaleuca spp.), to scavenge peroxynitrite during immune responses mounted in the murine macrophage cell line RAW 264.7 when stimulated with lipopolysaccharide/interferon-γ (LPS/IFN-γ) and in LPS-treated rats. Gelam honey significantly improved the viability of LPS/IFN-γ-treated RAW 264.7 cells and inhibited nitric oxide production-similar to the effects observed with an inhibitor of inducible nitric oxide synthase (1400W). Furthermore, honey, but not 1400W, inhibited peroxynitrite production from the synthetic substrate 3-morpholinosydnonimine (SIN-1) and prevented the peroxynitrite-mediated conversion of dihydrorhodamine 123 to its fluorescent oxidation product rhodamine 123. Honey inhibited peroxynitrite synthesis in LPS-treated rats. Thus, honey may attenuate inflammatory responses that lead to cell damage and death, suggesting its therapeutic uses for several inflammatory disorders.

  16. Innate Immune Responses to AAV Vectors.

    PubMed

    Rogers, Geoffrey L; Martino, Ashley T; Aslanidi, George V; Jayandharan, Giridhara R; Srivastava, Arun; Herzog, Roland W

    2011-01-01

    Gene replacement therapy by in vivo delivery of adeno-associated virus (AAV) is attractive as a potential treatment for a variety of genetic disorders. However, while AAV has been used successfully in many models, other experiments in clinical trials and in animal models have been hampered by undesired responses from the immune system. Recent studies of AAV immunology have focused on the elimination of transgene-expressing cells by the adaptive immune system, yet the innate immune system also has a critical role, both in the initial response to the vector and in prompting a deleterious adaptive immune response. Responses to AAV vectors are primarily mediated by the TLR9-MyD88 pathway, which induces the production of pro-inflammatory cytokines by activating the NF-κB pathways and inducing type I IFN production; self-complementary AAV vectors enhance these inflammatory processes. Additionally, the alternative NF-κB pathway influences transgene expression in cells transduced by AAV. This review highlights these recent discoveries regarding innate immune responses to AAV and discusses strategies to ablate these potentially detrimental signaling pathways.

  17. Vaccination strategies for mucosal immune responses.

    PubMed

    Ogra, P L; Faden, H; Welliver, R C

    2001-04-01

    Mucosal administration of vaccines is an important approach to the induction of appropriate immune responses to microbial and other environmental antigens in systemic sites and peripheral blood as well as in most external mucosal surfaces. The development of specific antibody- or T-cell-mediated immunologic responses and the induction of mucosally induced systemic immunologic hyporesponsiveness (oral or mucosal tolerance) depend on complex sets of immunologic events, including the nature of the antigenic stimulation of specialized lymphoid structures in the host, antigen-induced activation of different populations of regulatory T cells (Th1 versus Th2), and the expression of proinflammatory and immunoregulatory cytokines. Availability of mucosal vaccines will provide a painless approach to deliver large numbers of vaccine antigens for human immunization. Currently, an average infant will receive 20 to 25 percutaneous injections for vaccination against different childhood infections by 18 months of age. It should be possible to develop for human use effective, nonliving, recombinant, replicating, transgenic, and microbial vector- or plant-based mucosal vaccines to prevent infections. Based on the experience with many dietary antigens, it is also possible to manipulate the mucosal immune system to induce systemic tolerance against environmental, dietary, and possibly other autoantigens associated with allergic and autoimmune disorders. Mucosal immunity offers new strategies to induce protective immune responses against a variety of infectious agents. Such immunization may also provide new prophylactic or therapeutic avenues in the control of autoimmune diseases in humans.

  18. Vaccination Strategies for Mucosal Immune Responses

    PubMed Central

    Ogra, Pearay L.; Faden, Howard; Welliver, Robert C.

    2001-01-01

    Mucosal administration of vaccines is an important approach to the induction of appropriate immune responses to microbial and other environmental antigens in systemic sites and peripheral blood as well as in most external mucosal surfaces. The development of specific antibody- or T-cell-mediated immunologic responses and the induction of mucosally induced systemic immunologic hyporesponsiveness (oral or mucosal tolerance) depend on complex sets of immunologic events, including the nature of the antigenic stimulation of specialized lymphoid structures in the host, antigen-induced activation of different populations of regulatory T cells (Th1 versus Th2), and the expression of proinflammatory and immunoregulatory cytokines. Availability of mucosal vaccines will provide a painless approach to deliver large numbers of vaccine antigens for human immunization. Currently, an average infant will receive 20 to 25 percutaneous injections for vaccination against different childhood infections by 18 months of age. It should be possible to develop for human use effective, nonliving, recombinant, replicating, transgenic, and microbial vector- or plant-based mucosal vaccines to prevent infections. Based on the experience with many dietary antigens, it is also possible to manipulate the mucosal immune system to induce systemic tolerance against environmental, dietary, and possibly other autoantigens associated with allergic and autoimmune disorders. Mucosal immunity offers new strategies to induce protective immune responses against a variety of infectious agents. Such immunization may also provide new prophylactic or therapeutic avenues in the control of autoimmune diseases in humans. PMID:11292646

  19. Photodynamic therapy stimulates anti-tumor immunity in a murine mastocytoma model

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Hamblin, Michael R.

    2008-02-01

    Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species that eventually cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, recognition of tumor-specific antigens, and induction of heat-shock proteins, while the three commonest cancer therapies (surgery, chemotherapy and radiotherapy) all tend to suppress the immune system. Like many other immunotherapies, the extent of the immune response after PDT tends to depend on the antigenicity of the particular tumor, or in other words, whether the tumor contains proteins with the correct characteristics to provide peptides that can bind to MHC class I molecules and provide a target for cytolytic T lymphocytes. We have described certain mouse tumors containing defined or naturally occurring tumor associated antigens that respond particularly well to PDT, and potent immune responses capable of destroying distant untreated tumors can be induced. In this report we address the induction of immunity after PDT of the DBA2 mastocytoma known as P815. This tumor was the first mouse tumor to be shown to possess a tumor-rejection antigen capable of being recognized by cytotoxic T-cells.

  20. Targeting of interleukin (IL)-17A inhibits PDL1 expression in tumor cells and induces anticancer immunity in an estrogen receptor-negative murine model of breast cancer.

    PubMed

    Ma, Yun-Feng; Chen, Chen; Li, Dongqing; Liu, Min; Lv, Zhuang-Wei; Ji, Yanhong; Xu, Jiru

    2017-01-31

    The expression of IL-17A and programmed death ligand 1 (PDL1) is increased in estrogen receptor-negative breast cancer. IL-17A promotes tumor cell survival and invasiveness and inhibits the antitumor immune response. The PDL1-PD1 (programmed death protein 1) signaling pathway promotes escape from immune surveillance in tumor cells. The pro-tumor properties of IL-17A and PDL1 in various cancers have been previously examined; however, the relationship and roles of IL-17A and PDL1 in ER-negative breast cancer have not been evaluated. Therefore, we assessed whether IL-17A promotes PDL1 expression in tumor cells and whether targeting of IL-17A could inhibit ER-negative breast cancer progression in a murine model. Our study revealed that IL-17A promoted PDL1 expression in human and mouse cells. In the murine cancer model, targeting of IL-17A inhibited PDL1 expression in the tumor microenvironment, decreased the percentage of Treg cells in tumor-infiltrating lymphocytes, and promoted CD4+ and CD8+ T cells to secrete interferon gamma. More importantly, treatment with combined anti-IL-17A and anti-PDL1 antibodies enhanced antitumor effects in favor of tumor eradication. Thus, our study established a pro-tumor role of IL-17A in promoting tumor immune escape and supports the development of a novel cytokine immunotherapy against breast cancer.

  1. Bacterial vaginosis and the cervicovaginal immune response

    PubMed Central

    Mitchell, Caroline; Marrazzo, Jeanne

    2014-01-01

    Bacterial vaginosis (BV) is a common cause of vaginal discharge in reproductive age women around the world, and is associated with several poor reproductive health outcomes, including HIV-1 acquisition. One possible mechanism for this association is the inflammatory immune response induced by BV in the cervical and vaginal mucosae. There is significant heterogeneity in reports of markers of cervicovaginal inflammation in women with bacterial vaginosis, likely due to microbial and host diversity, as well as differences in study design. In this article we review the characteristics of the mucosal immune response in BV, the potential role of lactobacilli in modulating that response, and the impact of individual BV-associated bacterial species on mucosal immunity. We focus on inflammatory markers that are proposed to increase the risk of HIV-1 acquisition. PMID:24832618

  2. Immune responses after live attenuated influenza vaccination.

    PubMed

    Mohn, Kristin G-I; Smith, Ingrid; Sjursen, Haakon; Cox, Rebecca

    2017-09-21

    Since 2003 (US) and 2012 (Europe) the live attenuated influenza vaccine (LAIV) has been used as an alternative to the traditional inactivated influenza vaccines (IIV). The immune responses elicted by LAIV mimic natural infection and have been found to provide broader clinical protection in children compared to the IIVs. However, our knowledge of the detailed immunological mechanisims induced by LAIV remain to be fully elucidated, and despite 14 years on the global market, there exists no correlate of protection. Recently, matters are further complicated by differing efficacy data from the US and Europe which are not understood. Better understanding of the immune responses after LAIV may aid in achieving the ultimate goal of a future "universal influenza vaccine". In this review we aim to cover the current understanding of the immune responses induced after LAIV.

  3. Radiation triggering immune response and inflammation.

    PubMed

    Hekim, Nezih; Cetin, Zafer; Nikitaki, Zacharenia; Cort, Aysegul; Saygili, Eyup Ilker

    2015-11-28

    Radiation therapy (RT) is a well-established but still under optimization branch of Cancer Therapy (CT). RT uses electromagnetic waves or charged particles in order to kill malignant cells, by accumulating the energy onto these cells. The issue at stake for RT, as well as for any other Cancer Therapy technique, is always to kill only cancer cells, without affecting the surrounding healthy ones. This perspective of CT is usually described under the terms "specificity" and "selectivity". Specificity and selectivity are the ideal goal, but the ideal is never entirely achieved. Thus, in addition to killing healthy cells, changes and effects are observed in the immune system after irradiation. In this review, we mainly focus on the effects of ionizing radiation on the immune system and its components like bone marrow. Additionally, we are interested in the effects and benefits of low-dose ionizing radiation on the hematopoiesis and immune response. Low dose radiation has been shown to induce biological responses like inflammatory responses, innate immune system activation and DNA repair (adaptive response). This review reveals the fact that there are many unanswered questions regarding the role of radiation as either an immune-activating (low dose) or immunosuppressive (high dose) agent.

  4. Trichinella spiralis: shaping the immune response.

    PubMed

    Ilic, Natasa; Gruden-Movsesijan, Alisa; Sofronic-Milosavljevic, Ljiljana

    2012-04-01

    The co-evolution of a wide range of helminth parasites and vertebrates represented a constant pressure on the host's immune system and a selective force for shaping the immune response. Modulation of the immune system by parasites is accomplished partly by dendritic cells. When exposed to helminth parasites or their products, dendritic cells do not become classically mature and are potent inducers of Th2 and regulatory responses. Treating animals with helminths (eggs, larvae, extracts) causes dampening or in some cases prevention of allergic or autoimmune diseases. Trichinella spiralis (T. spiralis) possess a capacity to retune the immune cell repertoire, acting as a moderator of the host response not only to itself but also to third party antigens. In this review, we will focus on the ability of T. spiralis-stimulated dendritic cells to polarize the immune response toward Th2 and regulatory mode in vitro and in vivo and also on the capacity of this parasite to modulate autoimmune disease--such as experimental autoimmune encephalomyelitis.

  5. Evaluation of immune responses and analysis of the effect of vaccination of the Leishmania major recombinant ribosomal proteins L3 or L5 in two different murine models of cutaneous leishmaniasis.

    PubMed

    Ramírez, Laura; Santos, Diego M; Souza, Ana P; Coelho, Eduardo A F; Barral, Aldina; Alonso, Carlos; Escutia, Marta R; Bonay, Pedro; de Oliveira, Camila I; Soto, Manuel

    2013-02-18

    Four new antigenic proteins located in Leishmania ribosomes have been characterized: S4, S6, L3 and L5. Recombinant versions of the four ribosomal proteins from Leishmania major were recognized by sera from human and canine patients suffering different clinical forms of leishmaniasis. The prophylactic properties of these proteins were first studied in the experimental model of cutaneous leishmaniasis caused by L. major inoculation into BALB/c mice. The administration of two of them, LmL3 or LmL5 combined with CpG-oligodeoxynucleotides (CpG-ODN) was able to protect BALB/c mice against L. major infection. Vaccinated mice showed smaller lesions and parasite burden compared to mice inoculated with vaccine diluent or vaccine adjuvant. Protection was correlated with an antigen-specific increased production of IFN-γ paralleled by a decrease of the antigen-specific IL-10 mediated response in protected mice relative to non-protected controls. Further, it was demonstrated that BALB/c mice vaccinated with recombinant LmL3 or LmL5 plus CpG-ODN were also protected against the development of cutaneous lesions following inoculation of L. braziliensis. Together, data presented here indicate that LmL3 or LmL5 ribosomal proteins combined with Th1 inducing adjuvants, may be relevant components of a vaccine against cutaneous leishmaniasis caused by distinct species.

  6. Injury-induced immune responses in Hydra.

    PubMed

    Wenger, Yvan; Buzgariu, Wanda; Reiter, Silke; Galliot, Brigitte

    2014-08-01

    The impact of injury-induced immune responses on animal regenerative processes is highly variable, positive or negative depending on the context. This likely reflects the complexity of the innate immune system that behaves as a sentinel in the transition from injury to regeneration. Early-branching invertebrates with high regenerative potential as Hydra provide a unique framework to dissect how injury-induced immune responses impact regeneration. A series of early cellular events likely require an efficient immune response after amputation, as antimicrobial defence, epithelial cell stretching for wound closure, migration of interstitial progenitors toward the wound, cell death, phagocytosis of cell debris, or reconstruction of the extracellular matrix. The analysis of the injury-induced transcriptomic modulations of 2636 genes annotated as immune genes in Hydra identified 43 genes showing an immediate/early pulse regulation in all regenerative contexts examined. These regulations point to an enhanced cytoprotection via ROS signaling (Nrf, C/EBP, p62/SQSMT1-l2), TNFR and TLR signaling (TNFR16-like, TRAF2l, TRAF5l, jun, fos-related, SIK2, ATF1/CREB, LRRC28, LRRC40, LRRK2), proteasomal activity (p62/SQSMT1-l1, Ced6/Gulf, NEDD8-conjugating enzyme Ubc12), stress proteins (CRYAB1, CRYAB2, HSP16.2, DnaJB9, HSP90a1), all potentially regulating NF-κB activity. Other genes encoding immune-annotated proteins such as NPYR4, GTPases, Swap70, the antiproliferative BTG1, enzymes involved in lipid metabolism (5-lipoxygenase, ACSF4), secreted clotting factors, secreted peptidases are also pulse regulated upon bisection. By contrast, metalloproteinases and antimicrobial peptide genes largely follow a context-dependent regulation, whereas the protease inhibitor α2macroglobulin gene exhibits a sustained up-regulation. Hence a complex immune response to injury is linked to wound healing and regeneration in Hydra. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights

  7. Damage signals in the insect immune response

    PubMed Central

    Krautz, Robert; Arefin, Badrul; Theopold, Ulrich

    2014-01-01

    Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have afflicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes. PMID:25071815

  8. Immune Responses in Parasitic Diseases.

    DTIC Science & Technology

    1982-09-01

    prepared in pure form so that quantitative radial immunodiffusion studies are feasible. The IgGl response to T. rhodesiense infection in the rat has been...sera of infected animals and definitely-separate and quantitate the 19S from 8S species by combining radial immunodiffusion techniques and sucrose

  9. CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer.

    PubMed

    K Au, Katrina; Peterson, Nichole; Truesdell, Peter; Reid-Schachter, Gillian; Khalaj, Kasra; Ren, Runhan; Francis, Julie-Ann; Graham, Charles H; Craig, Andrew W; Koti, Madhuri

    2017-06-01

    We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC. ID8 ovarian cancer cells were engineered for stable knockdown (KD) and overexpression (OX) of CXCL10. The OX and KD cell line derivatives, along with their respective vector controls, were implanted in immunocompetent C57BL/6 mice via intra-peritoneal injections. At end point, immune transcriptomic profiling of tumour tissues and multiplex cytokine profiling of ascites, was performed. Effect of CXCL10 expression on the tumour vasculature and tumour cell proliferation was evaluated by CD31 and Ki67 immunostaining, respectively. Increased CXCL10 expression led to decreased tumour burden and malignant ascites accumulation in the ID8 syngeneic murine model of HGSC. The ascites levels of IL-6 and VEGF were significantly reduced in OX mice compared to the vector controls. The OX tumours also showed reduced vasculature (CD31) and proliferative index (Ki67) compared to the control tumours. Significantly higher expression of genes associated with antigen processing, apoptosis and T cell function was observed in OX tumours compared to the controls. Reduced CXCL10 expression in tumours from KD mice led to increased ascites accumulation and disease progression compared to the controls. CXCL10 is a positive determinant of anti-tumour immune responses in HGSC TME and disease progression. These findings are foundational for future translational studies aimed at improving treatment response and survival in HGSC

  10. Immune response inhibits associative learning in insects.

    PubMed Central

    Mallon, Eamonn B; Brockmann, Axel; Schmid-Hempel, Paul

    2003-01-01

    In vertebrates, it is well established that there are many intricate interactions between the immune system and the nervous system, and vice versa. Regarding insects, until now little has been known about the link between these two systems. Here, we present behavioural evidence indicating a link between the immune system and the nervous system in insects. We show that otherwise non-infected honeybees whose immune systems are challenged by a non-pathogenic immunogenic elicitor lipopolysaccharide (LPS) have reduced abilities to associate an odour with sugar reward in a classical conditioning paradigm. The cost of an immune response therefore not only affects survival of the host, as previously shown, but also everyday behaviour and memory formation. PMID:14667337

  11. A nonequilibrium phase transition in immune response

    NASA Astrophysics Data System (ADS)

    Zhang, Wei; Qi, An-Shen

    2004-07-01

    The dynamics of immune response correlated to signal transduction in immune thymic cells (T cells) is studied. In particular, the problem of the phosphorylation of the immune-receptor tyrosine-based activation motifs (ITAM) is explored. A nonlinear model is established on the basis of experimental observations. The behaviours of the model can be well analysed using the concepts of nonequilibrium phase transitions. In addition, the Riemann-Hugoniot cusp catastrophe is demonstrated by the model. Due to the application of the theory of nonequilibrium phase transitions, the biological phenomena can be clarified more precisely. The results can also be used to further explain the signal transduction and signal discrimination of an important type of immune T cell.

  12. Human Immune Responses to Dengue Viruses.

    DTIC Science & Technology

    1986-08-01

    D-Ai8i 71S UMAN IMMUNE RESPONSES TO DENGUE VIRUSES(U) MASSACHUSETTS UNIV M DICAL CENTER WORCESTER MA F A ENNIS 81 AUG 86 DAD17-82-C-2233 UNCLSE...Classification) (U) Human Immune Responses to Dengue Viruses 12. PERSONAL AUTHOR(S) Ennis. Francis A. 13a. TYPE OF REPORT 13b. TIME COVERED 414. DATE OF...Continue on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP06 13 Virus; Dengue ; Arbovirus; Immunology 06 03 I9% ABSTRACT

  13. Human Immune Responses to Dengue Viruses.

    DTIC Science & Technology

    1985-08-01

    t-Ril 630 HuMAN IMMUNE RESPONSES TO DENGUE VIRUSES(U) 1 - MASSACHUSETTS UNIV MEDICAL SCHOOL WORCESTER F A ENNIS 01 AUGO 95 DAMDI-2-C-2233 UNCASSIFIED...Classification) (U) Human Immune Responses to Dengue Viruses 12. PERSONAL AUTHOR(S) Ennis, Francis A. 13a. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF...on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP06 13 Virus; Dengue ; Arbovirus; Immunology 06 13 19. ABSTRACT (Continue on

  14. Human Immune Response to Dengue Infections.

    DTIC Science & Technology

    1991-06-30

    DTIC AD-A240 717 AD ____ HUMAN IMMUNE RESPONSE TO DENGUE INFECTIONS ANNUAL REPORT FRANCIS A. ENNIS JUNE 30, 1991 Supported by U.S. ARMY MEDICAL...Immune Response to Dengue Infections DAMDI7-86-C-6208 6. AUTHOR(S) 61102A 1 3M161102BS13 AA Francis A. Ennis WUDA3 12059 7. PERFORMING ORGANIZATION...of NS3, respectively. We also established 16 dengue virus-specific CD8+ CD4_ T cell clones. The clone #/2.8 recognize dengue virus types 2 and 4, and

  15. Factors affecting responses to murine oncogenic viral infections.

    PubMed Central

    Harvey, J. J.; Rager-Zisman, B.; Wheelock, E. F.; Nevin, P. A.

    1980-01-01

    Silica specifically kills macrophages in vitro, and in vivo has been used as a method of determining the possible immunological or other roles of macrophages in a number of viral infections. In experiments reported here, injection of 30 or 50 mg silica i.p. increased the severity of the oncogenic effects of the murine sarcoma virus (MSV) and Friend virus (FV) in BALB/c mice. Unlike Herpes simplex and Coxsackie B-3 infections, however, passive transfer of adult macrophages to suckling mice did not protect the latter against MSV. In mice injected with silica, histological evidence of the compensatory proliferation of macrophages suggests that precursors of these cells may act as target cells for the virus and that this may override any immunosuppressive response effected by the silica. In addition, there was a considerable enhancing effect on the erythroproliferative response to both MSV and FV by injection of saline 5 h before the virus, and indeed to FV after only a simple abdominal needle puncture. We attributed this to the lymphopenic immunodepressive effects of stress, and our data may explain previously published findings of augmented oncogenic responses in mice after "normal" serum injections. Newborn BALB/c (FV-1b) mice were susceptible to N-tropic FV, but developed resistance by 29 days of age. Antithymocyte serum (ATS) but not silica injections or adult thymectomy ablated this resistance. C57BL (FV-2r) mice were completely resistant to FV; however, those receiving FV and ATS developed late-onset leukaemia histologically characteristic of that produced by the helper component of the FV complex. Images Fig. PMID:6248095

  16. Immune response from a resource allocation perspective

    PubMed Central

    Rauw, Wendy M.

    2012-01-01

    The immune system is a life history trait that can be expected to trade off against other life history traits. Whether or not a trait is considered to be a life history trait has consequences for the expectation on how it responds to natural selection and evolution; in addition, it may have consequences for the outcome of artificial selection when it is included in the breeding objective. The immune system involved in pathogen resistance comprises multiple mechanisms that define a host's defensive capacity. Immune resistance involves employing mechanisms that either prevent pathogens from invading or eliminate the pathogens when they do invade. On the other hand, tolerance involves limiting the damage that is caused by the infection. Both tolerance and resistance traits require (re)allocation of resources and carry physiological costs. Examples of trade-offs between immune function and growth, reproduction and stress response are provided in this review, in addition to consequences of selection for increased production on immune function and vice versa. Reaction norms are used to deal with questions of immune resistance vs. tolerance to pathogens that relate host health to infection intensity. In essence, selection for immune tolerance in livestock is a particular case of selection for animal robustness. Since breeding goals that include robustness traits are required in the implementation of more sustainable agricultural production systems, it is of interest to investigate whether immune tolerance is a robustness trait that is positively correlated with overall animal robustness. Considerably more research is needed to estimate the shapes of the cost functions of different immune strategies, and investigate trade-offs and cross-over benefits of selection for disease resistance and/or disease tolerance in livestock production. PMID:23413205

  17. The Innate Immune Response Against Staphylococcus aureus.

    PubMed

    Bekeredjian-Ding, Isabelle; Stein, Christoph; Uebele, Julia

    2015-12-15

    The innate immune system harbors a multitude of different receptor systems and cells that are constantly prepared to sense and eliminate invading microbial pathogens. Staphylococcus aureus enters the body on its exposed epithelial surfaces, e.g., on skin and mucosa. The initial interaction with epithelial cells is governed by Toll-like receptor (TLR)-2-mediated local production of soluble mediators, including cytokines, chemokines, and antimicrobial peptides. The overall goal is to achieve a steady state of immune mediators and colonizing bacteria. Following cell and tissue invasion clearance of bacteria depends on intracellular microbial sensors and subsequent activation of the inflammasomes. Tissue-resident mast cells and macrophages recruit neutrophils, macrophages, and NK cells. This inflammatory response supports the generation of IL-17 producing NKT, γδ T cells, and T helper cells. Local dendritic cells migrate to the lymph nodes and fine-tune the adaptive immune response. The scope of this chapter is to provide an overview on the major cell types and receptors involved in innate immune defense against S. aureus. By segregating the different stages of infection from epithelial barrier to intracellular and systemic infection, this chapter highlights the different qualities of the innate immune response to S. aureus at different stages of invasiveness.

  18. Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia.

    PubMed

    E, Shuyu; Seth, Aman; Vogel, Peter; Sommers, Matt; Ong, Taren; Pillai, Asha B

    2017-06-01

    Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp3(+) naturally occurring regulatory T cells (Tregs). This occurs via recipient iNKT- and STAT6-dependent expansion of recipient myeloid dendritic cells (MDCs) that induce contact-dependent expansion of donor Treg through PD-1/PD ligand signaling. After TLI/ATS + BMT, Gr-1(low)CD11c(+) MDCs and Gr-1(high)CD11c(neg) myeloid-derived suppressor cells (MDSCs) were enriched in GVHD target organs. We now report that the recovery of both recipient MDSCs (P < .01) and MDCs (P < .01) is significantly increased when the alkylator cyclophosphamide (CTX) is added to TLI/ATS conditioning. In a BALB/c → B6 lethal GVHD model, adoptive transfer of MDSCs from TLI/ATS/CTX-conditioned recipients is associated with significantly improved GVHD colitis and survival (P < .001), conversion of MDSCs to PD ligand-expressing MDCs, and increased donor naturally occurring Treg recovery (P < .01) compared with control treatment. Using BALB/c donors and β-thalassemic HW-80 recipients, we found significantly improved rates of engraftment and GVHD following TLI/ATS/CTX compared with TLI/ATS, lethal or sublethal total body irradiation/ATS/CTX, or CTX/ATS conditioning. These data provide preclinical support for trials of TLI/ATG/alkylator regimens for MHC-mismatched BMT for hemoglobinopathies. The data also delineate innate immune mechanisms by which TLI/ATS/CTX conditioning may augment transplantation tolerance. © 2017 by The American

  19. DNAs from Brucella strains activate efficiently murine immune system with production of cytokines, reactive oxygen and nitrogen species.

    PubMed

    Tavakoli, Zahra; Ardestani, Sussan K; Lashkarbolouki, Taghi; Kariminia, Amina; Zahraei Salehi, Taghi; Tavassoli, Nasser

    2009-09-01

    Brucellosis is an infectious disease with high impact on innate immune responses which is induced partly by its DNA. In the present study the potential differences of wild type and patients isolates versus attenuated vaccine strains in terms of cytokines, ROS and NO induction on murine splenocytes and peritoneal macrophages were investigated. This panel varied in base composition and included DNA from B. abortus, B. melitensis, B.abortus strain S19 and melitensis strain Rev1, as attenuated live vaccine. Also we included Escherichia coli DNA, calf thymus DNA (a mammalian DNA), as controls. These DNA were evaluated for their ability to stimulate IL-12, TNF-alpha, IL-10, IFN-gamma and ROS production from spleenocytes as well as NO production from peritoneal macrophages. Spleen cells were cultured in 24 well at a concentration of 106 cells/ ml with subsequent addition of 10 microg/ml of Brucella or Ecoli DNAs. These cultures were incubated at 37 degrees C with 5% CO2 for 5 days. Supernatants were harvested and cytokines, ROS and NOx were evaluated. It was observed that TNF-alpha was induced in days 1,3,5 by all Brucella strains DNAs and E. coli DNA, IL-10 only was induced in day 1, IFN- gamma was induced only in day 5 and IL-12 not induced. ROS and NOx were produced by all strains; however, we observed higher production of NOx which were stimulated by DNA of B. melitensis.

  20. Peroxiredoxin 5 modulates immune response in Drosophila

    PubMed Central

    Radyuk, Svetlana N.; Michalak, Katarzyna; Klichko, Vladimir I.; Benes, Judith; Orr, William C.

    2010-01-01

    Background Peroxiredoxins are redox-sensing enzymes with multiple cellular functions. Previously, we reported on the potent antioxidant function of Drosophila peroxiredoxin 5 (dPrx5). Studies with mammalian and human cells suggest that peroxiredoxins can modulate immune-related signaling. Methods Survivorship studies and bacteriological analysis were used to determine resistance of flies to fungal and bacterial infections. RT-PCR and immunoblot analyses determined expression of dPrx5 and immunity factors in response to bacterial challenge. Double mutants for dprx5 gene and genes comprising the Imd/Relish and dTak1/Basket branches of the immune signaling pathways were used in epistatic analysis. Results The dprx5 mutant flies were more resistant to bacterial infection than controls, while flies overexpressing dPrx5 were more susceptible. The enhanced resistance to bacteria was accompanied by rapid induction of the Imd-dependent antimicrobial peptides, phosphorylation of the JNK kinase Basket and altered transcriptional profiling of the transient response genes, puckered, ets21C and relish, while the opposite effects were observed in flies over-expressing dPrx5. Epistatic analysis of double mutants, using attacin D and Puckered as read outs of activation of the Imd and JNK pathways, implicated dPrx5 function in the control of the dTak1-JNK arm of immune signaling. Conclusions Differential effects on fly survivorship suggested a trade-off between the antioxidant and immune functions of dPrx5. Molecular and epistatic analyses identified dPrx5 as a negative regulator in the dTak1-JNK arm of immune signaling. General significance Our findings suggest that peroxiredoxins play an important modulatory role in the Drosophila immune response. PMID:20600624

  1. Identification of Immunomodulatory Signatures Induced by American Ginseng in Murine Immune Cells

    PubMed Central

    Yan, Jian; Ma, Yonghui; Zhao, Fusheng; Gu, Weikuan; Jiao, Yan

    2013-01-01

    Background. American ginseng (Panax quinquefolius, AG) has been used for more than 300 years. Some of its claimed benefits can be attributed to the immunomodulatory activities, whose molecular mechanisms are largely unknown. Methods. Murine splenic cells from adult male C57BL/6 (B6) mice were isolated and divided into 4 groups to mimic 4 basic pathophysiological states: (1) normal naïve; (2) normal activated; (3) deficient naïve; (4) deficient activated. Then, different AG extracts were added to all groups for 24 h incubation. MTT proliferation assays were performed to evaluate the phenotypic features of cells. Finally, microarray assays were carried out to identify differentially expressed genes associated with AG exposure. Real-time PCR was performed to validate the expression of selected genes. Results. Microarray data showed that most of gene expression changes were identified in the deficient naïve group, suggesting that the pathophysiological state has major impacts on transcriptomic changes associated with AG exposure. Specifically, this study revealed downregulation of interferon-γ signaling pathway in the deficient group of cells. Conclusion. Our study demonstrated that only specific groups of immune cells responded to AG intervention and immunocompromised cells were more likely regulated by AG treatment. PMID:24319490

  2. CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer.

    PubMed

    Ninalga, Christina; Loskog, Angelica; Klevenfeldt, Magdalena; Essand, Magnus; Tötterman, Thomas H

    2005-01-01

    Bacillus Calmette-Guerin (BCG) instillation is standard immunotherapy for superficial bladder carcinoma. However, many patients become refractory to BCG, giving impetus to the development of alternative therapies. CpG oligodeoxynucleotide (ODN) therapy has been shown to promote T(H)1-oriented antitumor responses in various tumor models. To investigate its therapeutic effect in bladder cancer, we used different CpG ODNs to treat C57BL/6 mice bearing the subcutaneous murine bladder tumor MB49. CpG type B ODN 1668 was superior at inhibiting tumor growth, leading to complete regression of large tumors. More importantly, CpG ODN 1668 also regressed orthotopically growing MB49 tumors for the first time. Rechallenge of CpG ODN-cured mice with MB49 showed that a majority of the mice were protected long term, demonstrating that CpG ODN therapy evokes a memory response. Adenoviral vectors (Ad) encoding CD40L, tumor necrosis factor-related activation-induced cytokine, lymphotactin, interleukin (IL) 2, and IL-15 were also investigated. AdCD40L and AdIL-15 transduction could abolish MB49 tumorigenicity, and these vectors were combined with CpG ODN 1668 to investigate any enhanced effects. No such effects were seen. All groups of mice treated with CpG ODNs, alone or in combination with adenoviral vector, exhibited increased serum concentrations of IL-12, indicative of a T(H)1 response. Our results show that CpG ODN therapy cures established subcutaneous and orthotopic bladder cancer via a T(H)1-mediated response and provides long-lasting protective immunity.

  3. Adaptive immune responses to Candida albicans infection

    PubMed Central

    Richardson, Jonathan P; Moyes, David L

    2015-01-01

    Fungal infections are becoming increasingly prevalent in the human population and contribute to morbidity and mortality in healthy and immunocompromised individuals respectively. Candida albicans is the most commonly encountered fungal pathogen of humans, and is frequently found on the mucosal surfaces of the body. Host defense against C. albicans is dependent upon a finely tuned implementation of innate and adaptive immune responses, enabling the host to neutralise the invading fungus. Central to this protection are the adaptive Th1 and Th17 cellular responses, which are considered paramount to successful immune defense against C. albicans infections, and enable tissue homeostasis to be maintained in the presence of colonising fungi. This review will highlight the recent advances in our understanding of adaptive immunity to Candida albicans infections. PMID:25607781

  4. Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis.

    PubMed

    Lewis, Eric R G; David, Victoria R; Doyle, Adina L; Rajabi, Khadijeh; Kiefer, Jeffrey A; Pirrotte, Patrick; Barker, Bridget M

    2015-10-01

    Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.

  5. Neutrophils as effector cells of T-cell-mediated, acquired immunity in murine listeriosis.

    PubMed Central

    Appelberg, R; Castro, A G; Silva, M T

    1994-01-01

    The control of the infections caused by Listeria monocytogenes, considered an example of an intracellular parasite, is thought to involve co-operation between antigen-specific T cells and activated macrophages. Here we investigated the participation of polymorphonuclear leucocytes in the mechanisms of resistance during the immune phase of the antimicrobial response to L. monocytogenes infection. We found that BALB/c mice were unable to express T-cell-mediated (acquired) immunity to this pathogen in the absence of granulocytes. We propose that neutrophils should be included in the concept of cell-mediated immunity and that their antimicrobial role is not exclusively expressed during the early phases of a primary infection. PMID:7835951

  6. Innate Immune Responses of Pulmonary Epithelial Cells to Burkholderia pseudomallei Infection

    PubMed Central

    Sim, Siew Hoon; Liu, Yichun; Wang, Dongling; Novem, Vidhya; Sivalingam, Suppiah Paramalingam; Thong, Tuck Weng; Ooi, Eng Eong; Tan, Gladys

    2009-01-01

    Background Burkholderia pseudomallei, a facultative intracellular pathogen, causes systemic infection in humans with high mortality especially when infection occurs through an infectious aerosol. Previous studies indicated that the epithelial cells in the lung are an active participant in host immunity. In this study, we aimed to investigate the innate immune responses of lung epithelial cells against B. pseudomallei. Methodology and Principal Findings Using a murine lung epithelial cell line, primary lung epithelial cells and an inhalational murine infection model, we characterized the types of innate immunity proteins and peptides produced upon B. pseudomallei infection. Among a wide panel of immune components studied, increased levels of major pro-inflammatory cytokines IL-6 and TNFα, chemokine MCP-1, and up-regulation of secretory leukocyte protease inhibitor (SLPI) and chemokine (C-C motif) ligand 20 (CCL20) were observed. Inhibition assays using specific inhibitors suggested that NF-κB and p38 MAPK pathways were responsible for these B. pseudomallei-induced antimicrobial peptides. Conclusions Our findings indicate that the respiratory epithelial cells, which form the majority of the cells lining the epithelial tract and the lung, have important roles in the innate immune response against B. pseudomallei infection. PMID:19806192

  7. Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia▿

    PubMed Central

    Shi, Xin; Zhang, Ping; Sempowski, Gregory D.; Shellito, Judd E.

    2011-01-01

    CD4+ T cells play a key role in host defense against Pneumocystis infection. To define the role of naïve CD4+ T cell production through the thymopoietic response in host defense against Pneumocystis infection, Pneumocystis murina infection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy. Pneumocystis infection caused a significant increase in the number of CCR9+ multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+ T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+ cells was increased at 5 weeks post-Pneumocystis infection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+ T cells in all tissues examined were markedly reduced following Pneumocystis infection. This deficiency of naïve and central memory CD4+ T cells was associated with delayed pulmonary clearance of Pneumocystis. Extracts of Pneumocystis resulted in an increase in the number of CCR9+ MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+ MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+ T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense against Pneumocystis infection. PMID:21343353

  8. Adaptive responses of murine osteoblasts subjected to coupled mechanical stimuli.

    PubMed

    Serrano, Jean C; Cora-Cruz, Jose; Diffoot-Carlo, Nanette; Sundaram, Paul A

    2017-09-14

    Restitution of the natural organization and orientation of cells is imperative for the construction of functional tissue scaffolds. While numerous studies have exploited mechanical methods to engineer tissues with the desired cellular architecture, fundamental knowledge is still lacking in understanding the manner in which morphological features can be modulated through coupled mechanical cues. To address this knowledge gap, the adhesion and alignment response of murine osteoblast cells under the synergistic effects of matrix rigidity and cyclic mechanical loading was investigated. This was accomplished by applying cyclic mechanical strain (1% at 0.05Hz) to MC3T3-E1 cells seeded on PDMS substrates of different elastic moduli (1.22, 1.70 and 2.04MPa). Results demonstrate that the overall cell density and expression of inactive vinculin increased on substrates subjected to cyclic stimulus in comparison to substrates under static loading. Conversely, in terms of the adhesion response, osteoblasts exhibited an increased growth of focal adhesion complexes under static substrates. Interestingly, results also elucidate that substrates of a stiffer matrix exposed to cyclic stimulus, had a significantly higher percentage of osteoblasts aligned parallel to the direction of the applied strain, as well as a higher degree of internal order with respect to the strain axis, in comparison to both cells seeded on substrates of lower stiffness under cyclic loading or under static conditions. These findings suggest the role of cyclic mechanical strain coupled with matrix rigidity in eliciting mechanosensitive adaptations in cell functions that allow for the reconstitution of the spatial and orientational assembly of cells in vivo for tissue engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A.

    PubMed

    Lai, Jesse D; Moorehead, Paul C; Sponagle, Kate; Steinitz, Katharina N; Reipert, Birgit M; Hough, Christine; Lillicrap, David

    2016-06-30

    Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naïve CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses. © 2016 by The American Society of Hematology.

  10. Murinization of Internalin Extends Its Receptor Repertoire, Altering Listeria monocytogenes Cell Tropism and Host Responses

    PubMed Central

    Tsai, Yu-Huan; Disson, Olivier; Bierne, Hélène; Lecuit, Marc

    2013-01-01

    Listeria monocytogenes (Lm) is an invasive foodborne pathogen that leads to severe central nervous system and maternal-fetal infections. Lm ability to actively cross the intestinal barrier is one of its key pathogenic properties. Lm crosses the intestinal epithelium upon the interaction of its surface protein internalin (InlA) with its host receptor E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been “murinized” to interact with mouse Ecad. Here, we demonstrate that, unexpectedly, murinized InlA (InlAm) mediates not only Ecad-dependent internalization, but also N-cadherin-dependent internalization. Consequently, InlAm-expressing Lm targets not only goblet cells expressing luminally-accessible Ecad, as does Lm in humanized mice, but also targets villous M cells, which express luminally-accessible N-cadherin. This aberrant Lm portal of entry results in enhanced innate immune responses and intestinal barrier damage, both of which are not observed in wild-type Lm-infected humanized mice. Murinization of InlA therefore not only extends the host range of Lm, but also broadens its receptor repertoire, providing Lm with artifactual pathogenic properties. These results challenge the relevance of using InlAm-expressing Lm to study human listeriosis and in vivo host responses to this human pathogen. PMID:23737746

  11. Immune Response in Mussels To Environmental Pollution.

    ERIC Educational Resources Information Center

    Pryor, Stephen C.; Facher, Evan

    1997-01-01

    Describes the use of mussels in measuring the extent of chemical contamination and its variation in different coastal regions. Presents an experiment to introduce students to immune response and the effects of environmental pollution on marine organisms. Contains 14 references. (JRH)

  12. [Modulation of immune response by bacterial lipopolysaccharides].

    PubMed

    Aldapa-Vega, Gustavo; Pastelín-Palacios, Rodolfo; Isibasi, Armando; Moreno-Eutimio, Mario A; López-Macías, Constantino

    2016-01-01

    Lipopolysaccharide (LPS) is a molecule that is profusely found on the outer membrane of Gram-negative bacteria and is also a potent stimulator of the immune response. As the main molecule on the bacterial surface, is also the most biologically active. The immune response of the host is activated by the recognition of LPS through Toll-like receptor 4 (TLR4) and this receptor-ligand interaction is closely linked to LPS structure. Microorganisms have evolved systems to control the expression and structure of LPS, producing structural variants that are used for modulating the host immune responses during infection. Examples of this include Helicobacter pylori, Francisella tularensis, Chlamydia trachomatis and Salmonella spp. High concentrations of LPS can cause fever, increased heart rate and lead to septic shock and death. However, at relatively low concentrations some LPS are highly active immunomodulators, which can induce non-specific resistance to invading microorganisms. The elucidation of the molecular and cellular mechanisms involved in the recognition of LPS and its structural variants has been fundamental to understand inflammation and is currently a pivotal field of research to understand the innate immune response, inflammation, the complex host-pathogen relationship and has important implications for the rational development of new immunomodulators and adjuvants.

  13. Adaptive immune cells temper initial innate responses.

    PubMed

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2007-10-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

  14. Adaptive immune cells temper initial innate responses

    PubMed Central

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2008-01-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25−Foxp3− or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses. PMID:17891146

  15. Immune Response in Mussels To Environmental Pollution.

    ERIC Educational Resources Information Center

    Pryor, Stephen C.; Facher, Evan

    1997-01-01

    Describes the use of mussels in measuring the extent of chemical contamination and its variation in different coastal regions. Presents an experiment to introduce students to immune response and the effects of environmental pollution on marine organisms. Contains 14 references. (JRH)

  16. [Immune response genes products in human physiology].

    PubMed

    Khaitov, R M; Alekseev, L P

    2012-09-01

    Current data on physiological role of human immune response genes' proteomic products (antigens) are discussed. The antigens are specified by a very high level of diversity that mediates a wide specter ofphysiological functions. They actually provide integrity and biological stability of human as species. These data reveal new ideas on many pathological processes as well as drafts new approaches for prophylaxis and treatment.

  17. Innate immune responses to hepatitis C virus.

    PubMed

    Schoggins, John W; Rice, Charles M

    2013-01-01

    The innate immune response provides the first line of defense against invading viral pathogens. Incoming viruses are sensed by dedicated host factors that, when triggered, initiate multiple signal transduction pathways. Activation of these pathways leads to the induction of highly orchestrated transcriptional programs designed to limit virus replication and spread. In recent years, our understanding of innate immune responses targeting hepatitis C virus (HCV) has increased substantially, largely due to the development of new systems and methodologies to study HCV-host interactions in vitro and in vivo. However, significant gaps still remain. Here, we aim to provide a comprehensive view of the innate immune response to HCV, focusing primarily on knowledge gained from cell culture models of HCV infection, as well as data from human patients infected with HCV. While some paradigms of the host response to HCV revealed in cell culture translate to human infection in vivo, others are less clear. Further insight into the similarities and differences in these systems will not only reveal directions for future studies on HCV immunity, but may also guide the development of novel strategies to control HCV and other viral infections.

  18. Innate Immune Sensing and Response to Influenza

    PubMed Central

    Pulendran, Bali; Maddur, Mohan S.

    2015-01-01

    Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocom-promised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza. PMID:25078919

  19. Humoral Immune Response to AAV.

    PubMed

    Calcedo, Roberto; Wilson, James M

    2013-10-18

    Adeno-associated virus (AAV) is a member of the family Parvoviridae that has been widely used as a vector for gene therapy because of its safety profile, its ability to transduce both dividing and non-dividing cells, and its low immunogenicity. AAV has been detected in many different tissues of several animal species but has not been associated with any disease. As a result of natural infections, antibodies to AAV can be found in many animals including humans. It has been shown that pre-existing AAV antibodies can modulate the safety and efficacy of AAV vector-mediated gene therapy by blocking vector transduction or by redirecting distribution of AAV vectors to tissues other than the target organ. This review will summarize antibody responses against natural AAV infections, as well as AAV gene therapy vectors and their impact in the clinical development of AAV vectors for gene therapy. We will also review and discuss the various methods used for AAV antibody detection and strategies to overcome neutralizing antibodies in AAV-mediated gene therapy.

  20. Imitating a stress response: a new hypothesis about the innate immune system's role in pregnancy.

    PubMed

    Schminkey, Donna L; Groer, Maureen

    2014-06-01

    Recent research challenges long-held hypotheses about mechanisms through which pregnancy induces maternal immune suppression or tolerance of the embryo/fetus. It is now understood that normal pregnancy engages the immune system and that the immune milieu changes with advancing gestation. We suggest that pregnancy mimics the innate immune system's response to stress, causing a sterile inflammatory response that is necessary for successful reproduction. The relationship between external stressors and immunomodulation in pregnancy has been acknowledged, but the specific mechanisms are still being explicated. Implantation and the first trimester are times of immune activation and intensive inflammation in the uterine environment. A period of immune quiescence during the second trimester allows for the growth and development of the maturing fetus. Labor is also an inflammatory event. The length of gestation and timing of parturition can be influenced by environmental stressors. These stressors affect pregnancy through neuroendocrine interaction with the immune system, specifically through the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-ovarian axis. Trophoblastic cells that constitute the maternal-fetal interface appear to harness the maternal immune system to promote and maximize the reproductive success of the mother and fetus. Pregnancy is a time of upregulated innate immune responses and decreased adaptive, cell-mediated responses. The inflammatory processes of pregnancy resemble an immune response to brief naturalistic stressors: there is a shift from T helper (Th) 1 to T helper (Th) 2 dominant adaptive immunity with a concomitant shift in cytokine production, decreased proliferation of T cells, and decreased cytotoxicity of natural killer (NK) cells. Inclusion of both murine and human studies, allows an exploration of insights into how trophoblasts influence the activity of the maternal innate immune system during gestation.

  1. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs.

    PubMed

    Lu, Lei; Xu, Xiaobing; Zhang, Bin; Zhang, Rongsheng; Ji, Hongzan; Wang, Xuan

    2014-02-07

    The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model. Mice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay. Combined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4⁺ cells and CD8⁺ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-γ-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-γ production and

  2. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

    PubMed Central

    2014-01-01

    Background The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model. Methods Mice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay. Results Combined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4+ cells and CD8+ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-γ-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN

  3. Pulmonary contusion primes systemic innate immunity responses.

    PubMed

    Hoth, J Jason; Martin, R S; Yoza, Barbara K; Wells, Jonathan D; Meredith, J W; McCall, Charles E

    2009-07-01

    Traumatic injury may result in an exaggerated response to subsequent immune stimuli such as nosocomial infection. This "second hit" phenomenon and molecular mechanism(s) of immune priming by traumatic lung injury, specifically, pulmonary contusion, remain unknown. We used an animal model of pulmonary contusion to determine whether the injury resulted in priming of the innate immune response and to test the hypothesis that resuscitation fluids could attenuate the primed response to a second hit. Male, 8 to 9 weeks, C57/BL6 mice with a pulmonary contusion were challenged by a second hit of intratracheal administration of the Toll-like receptor 4 agonist, lipopolysaccharide (LPS, 50 microg) 24 hours after injury (injury + LPS). Other experimental groups were injury + vehicle or LPS alone. A separate group was injured and resuscitated by 4 cc/kg of hypertonic saline (HTS) or Lactated Ringer's (LR) resuscitation before LPS challenge. Mice were killed 4 hours after LPS challenge and blood, bronchoalveolar lavage, and tissue were isolated and analyzed. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest for significant differences (*p < or = 0.05). Injury + LPS showed immune priming observed by lung injury histology and increased bronchoalveolar lavage neutrophilia, lung myeloperoxidase and serum IL-6, CXCL1, and MIP-2 levels when compared with injury + vehicle or LPS alone. After injury, resuscitation with HTS, but not Lactated Ringer's was more effective in attenuating the primed response to a second hit. Pulmonary contusion primes innate immunity for an exaggerated response to a second hit with the Toll-like receptor 4 agonist, LPS. We observed synergistic increases in inflammatory mediator expression in the blood and a more severe lung injury in injured animals challenged with LPS. This priming effect was reduced when HTS was used to resuscitate the animal after lung contusion.

  4. Pulmonary contusion primes systemic innate immunity responses

    PubMed Central

    Hoth, JJ; Martin, RS; Yoza, BK; Wells, JD; Meredith, JW; McCall, CE

    2010-01-01

    Introduction Traumatic injury may result in an exaggerated response to subsequent immune stimuli such as nosocomial infection. This “second hit” phenomenon, and molecular mechanism(s) of immune priming by traumatic lung injury, specifically pulmonary contusion, remains unknown. We used an animal model of pulmonary contusion to determine if the injury resulted in priming of the innate immune response and to test the hypothesis that resuscitation fluids could attenuate the primed response to a second hit. Methods Male, 8-9 wk, C57/BL6 mice with a pulmonary contusion were challenged by a second hit of intratracheal administration of the Toll like receptor (TLR) 4 agonist, lipopolysaccharide (LPS, 50mcg) 24hrs after injury (injury+LPS). Other experimental groups were injury+vehicle or LPS alone. A separate group were injured and resuscitated by 4cc/kg of hypertonic saline (HTS) or Lactated Ringer's (LR) resuscitation prior to LPS challenge. Mice were euthanized 4hrs after LPS challenge and blood, bronchoalveolar lavage (BAL), and tissue were isolated and analyzed. Data were analyzed using one way ANOVA with Bonferroni multiple comparison post-test for significant differences (*, p≤0.05). Results Injury+LPS showed immune priming observed by lung injury histology and increased BAL neutrophilia, lung myeloperoxidase, and serum IL-6, CXCL1 and MIP-2 levels when compared to injury+vehicle or LPS alone. After injury, resuscitation with HTS, but not LR was more effective in attenuating the primed response to a second hit. Conclusion Pulmonary contusion primes innate immunity for an exaggerated response to a second hit with the TLR4 agonist, LPS. We observed synergistic increases in inflammatory mediator expression in the blood and a more severe lung injury in injured animals challenged with LPS. This priming effect was reduced when HTS was used to resuscitate the animal after lung contusion. PMID:19590302

  5. Humoral immune responses in foetal sheep.

    PubMed Central

    Fahey, K J; Morris, B

    1978-01-01

    A total of fifty-two foetal sheep between 49 and 126 days gestation were injected with polymeric and monomeric flagellin, dinitrophenylated monomeric flagellin, chicken red blood cells, ovalbumin, ferritin, chicken gamma-globulin and the somatic antigens of Salmonella typhimurium in a variety of combinations. Immune responses were followed in these animals by taking serial blood samples from them through indwelling vascular cannulae and measuring the circulating titres of antibody. Of the antigens tested, ferritin induced immune responses in the youngest foetuses. A short time later in gestation, the majority of foetuses responded to chicken red blood cells, polymeric flagellin, monomeric flagellin and dinitrophenylated monomeric flagellin. Only older foetuses responded regularly to chicken gamma-globulin and ovalbumin. However, antibodies to all these antigens were first detected over the relatively short period of development between 64 and 82 days gestation and this made it difficult to define any precise order in the development of immune responsiveness. Of the antigens tested only the somatic antigens of S. typhimurium failed to induce a primary antibody response during foetal life. The character and magnitude of the antibody responses in foetuses changed throughout in utero development. Both the total amount of antibody produced and the duration of the response increased with foetal age. Foetuses younger than 87 days gestation did not synthesize 2-mercaptoethanol resistant antibodies or IgG1 immunoglobulin to any of the antigens tested, whereas most foetuses older than this regularly did so. PMID:711249

  6. Immune response modulation by curcumin in a latex allergy model

    PubMed Central

    Kurup, Viswanath P; Barrios, Christy S; Raju, Raghavan; Johnson, Bryon D; Levy, Michael B; Fink, Jordan N

    2007-01-01

    Background There has been a worldwide increase in allergy and asthma over the last few decades, particularly in industrially developed nations. This resulted in a renewed interest to understand the pathogenesis of allergy in recent years. The progress made in the pathogenesis of allergic disease has led to the exploration of novel alternative therapies, which include herbal medicines as well. Curcumin, present in turmeric, a frequently used spice in Asia has been shown to have anti-allergic and inflammatory potential. Methods We used a murine model of latex allergy to investigate the role of curcumin as an immunomodulator. BALB/c mice were exposed to latex allergens and developed latex allergy with a Th2 type of immune response. These animals were treated with curcumin and the immunological and inflammatory responses were evaluated. Results Animals exposed to latex showed enhanced serum IgE, latex specific IgG1, IL-4, IL-5, IL-13, eosinophils and inflammation in the lungs. Intragastric treatment of latex-sensitized mice with curcumin demonstrated a diminished Th2 response with a concurrent reduction in lung inflammation. Eosinophilia in curcumin-treated mice was markedly reduced, co-stimulatory molecule expression (CD80, CD86, and OX40L) on antigen-presenting cells was decreased, and expression of MMP-9, OAT, and TSLP genes was also attenuated. Conclusion These results suggest that curcumin has potential therapeutic value for controlling allergic responses resulting from exposure to allergens. PMID:17254346

  7. Dengue virus-specific murine T-lymphocyte proliferation: serotype specificity and response to recombinant viral proteins.

    PubMed Central

    Rothman, A L; Kurane, I; Zhang, Y M; Lai, C J; Ennis, F A

    1989-01-01

    Definition of the T-lymphocyte responses to dengue viruses should aid in the development of safe and effective vaccines and help to explain the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. In this study, we demonstrated that dengue virus-specific T lymphocytes were detected in spleen cells from dengue virus-immune mice using an in vitro proliferation assay. Following immunization with a single dose of infectious dengue virus, murine lymphocytes showed increased proliferation when incubated in the presence of viral antigens of the same serotype but not in the presence of control antigens. Depletion experiments with antibody and complement showed that the population of responding cells expressed the Thy1+ L3T4+ Lyt2- phenotype. This indicates that the predominant proliferating cells are T lymphocytes of the helper-inducer phenotype. Dengue virus-specific memory lymphocyte responses were detectable for at least 22 weeks after immunization. The response to primary infection was primarily serotype specific, with some serotype cross-reactivity present at a low level. We demonstrated that lymphocytes from mice immunized with dengue 4 virus proliferate in response to a combination of dengue 4 virus C, pre-M, E, NS1, and NS2a proteins expressed in Sf9 cells with a recombinant baculovirus, and, to a lesser extent, to the dengue 4 virus E protein alone. PMID:2786087

  8. Immune response in pemphigus and beyond: progresses and emerging concepts.

    PubMed

    Di Zenzo, Giovanni; Amber, Kyle T; Sayar, Beyza S; Müller, Eliane J; Borradori, Luca

    2016-01-01

    Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.

  9. Ovine model for studying pulmonary immune responses

    SciTech Connect

    Joel, D.D.; Chanana, A.D.

    1984-11-25

    Anatomical features of the sheep lung make it an excellent model for studying pulmonary immunity. Four specific lung segments were identified which drain exclusively to three separate lymph nodes. One of these segments, the dorsal basal segment of the right lung, is drained by the caudal mediastinal lymph node (CMLN). Cannulation of the efferent lymph duct of the CMLN along with highly localized intrabronchial instillation of antigen provides a functional unit with which to study factors involved in development of pulmonary immune responses. Following intrabronchial immunization there was an increased output of lymphoblasts and specific antibody-forming cells in efferent CMLN lymph. Continuous divergence of efferent lymph eliminated the serum antibody response but did not totally eliminate the appearance of specific antibody in fluid obtained by bronchoalveolar lavage. In these studies localized immunization of the right cranial lobe served as a control. Efferent lymphoblasts produced in response to intrabronchial antigen were labeled with /sup 125/I-iododeoxyuridine and their migrational patterns and tissue distribution compared to lymphoblasts obtained from the thoracic duct. The results indicated that pulmonary immunoblasts tend to relocate in lung tissue and reappear with a higher specific activity in pulmonary lymph than in thoracic duct lymph. The reverse was observed with labeled intestinal lymphoblasts. 35 references, 2 figures, 3 tables.

  10. Space flight, microgravity, stress, and immune responses

    NASA Astrophysics Data System (ADS)

    Sonnenfeld, G.

    1999-01-01

    Exposure of animals and humans to space flight conditions has resulted in numerous alterations in immunological parameters. Decreases in lymphocyte blastogenesis, cytokine production, and natural killer cell activity have all been reported after space flight. Alterations in leukocyte subset distribution have also been reported after flight of humans and animals in space. The relative contribution of microgravity conditions and stress to the observed results has not been established. Antiorthostatic, hypokinetic, hypodynamic, suspension of rodents and chronic head-down tilt bed-rest of humans have been used to model effects of microgravity on immune responses. After use of these models, some effects of space flight on immune responses, such as decreases in cytokine function, were observed, but others, such as alterations in leukocyte subset distribution, were not observed. These results suggest that stresses that occur during space flight could combine with microgravity conditions in inducing the changes seen in immune responses after space flight. The biological/biomedical significance of space flight induced changes in immune parameters remains to be established.

  11. Differential temperature operation of plant immune responses

    PubMed Central

    Cheng, Cheng; Gao, Xiquan; Feng, Baomin; Sheen, Jen; Shan, Libo; He, Ping

    2014-01-01

    Temperature fluctuation is a key determinant for microbial invasion and host evasion. In contrast to mammalians that maintain constant body temperature, plant temperature oscillates on a daily basis. It remains elusive how plants operate inducible defenses in response to temperature fluctuation. Here we report that ambient temperature changes lead to pronounced shifts of two distinct plant immune responses: pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). Plants preferentially activate ETI signaling at relatively low temperatures (10~23°C), whereas they switch to PTI signaling at moderately elevated temperatures (23~32°C). The Arabidopsis arp6 and hta9hta11 mutants, phenocopying plants grown at the elevated temperatures, exhibit enhanced PTI and yet reduced ETI responses. As the secretion of bacterial effectors favors low temperatures whereas bacteria multiply vigorously at elevated temperatures accompanied with increased microbe-associated molecular pattern production, our findings suggest that temperature oscillation might have driven dynamic co-evolution of distinct plant immune signaling responding to pathogen physiological changes. PMID:24067909

  12. Therapy of peritoneal murine cancer with biological response modifiers.

    PubMed

    Salup, R R; Herberman, R B; Chirigos, M A; Back, T; Wiltrout, R H

    1985-01-01

    We have used a murine renal adenocarcinoma of spontaneous origin (Renca) inplanted in the peritoneal cavity to study the therapeutic potential of biological response modifiers (BRMs) used alone or in conjunction with chemotherapy. This tumor model is therapeutically challenging since following intraperitoneal (i.p.) injection, the tumor grows progressively with hemorrhagic ascites, abdominal metastases to lymph nodes, liver, spleen, most serous membranes, and, in some animals, metastases to extra-abdominal sites (lungs). In the absence of therapy, death invariably occurs within 36 +/- 2 days. The tumor is efficiently lysed in 4 hours by peritoneal cells isolated from mice treated with BRMs. Both MVE-2 and rIL-2 significantly increased the survival time of tumor-bearing mice, but only treatment with MVE-2 led to definite cures of i.p. Renca. A single i.p. injection of MVE-2 cured 20% of the tumor-bearing mice, while repeated i.p. administration of this drug at 12 day intervals cured 70% of i.p. Renca-bearing mice. Combined therapy with doxorubicin hydrochloride and a single dose of MVE-2 cured 90% of tumor-bearing animals. The superior therapeutic efficiency of MVE-2 compared to that of the rIL-2 may be due to its ability, after i.p. inoculation, to generate and maintain high levels of cytotoxic effector cell activity for an elevated period of time within the peritoneal cell population. Additionally, MVE-2 augments effector cell activity in the liver, lungs, spleen, and blood and may therefore more efficiently interfere with metastasis formation in those compartments. The additive effects of MVE-2 and the chemotherapeutic agent suggest that more effective therapy may be achieved by the combination of immunotherapy with BRMs with chemotherapeutic drugs.

  13. Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses.

    PubMed

    Kiyotake, Ryoko; Oh-Hora, Masatsugu; Ishikawa, Eri; Miyamoto, Tomofumi; Ishibashi, Tatsuro; Yamasaki, Sho

    2015-10-16

    C-type lectin receptors (CLRs) are an emerging family of pattern recognition receptors that recognizes pathogens or damaged tissue to trigger innate immune responses. However, endogenous ligands for CLRs are not fully understood. In this study, we sought to identify an endogenous ligand(s) for human macrophage-inducible C-type lectin (hMincle). A particular fraction of lipid extracts from liver selectively activated reporter cells expressing hMincle. MS analysis determined the chemical structure of the active component as cholesterol. Purified cholesterol in plate-coated and crystalized forms activates reporter cells expressing hMincle but not murine Mincle (mMincle). Cholesterol crystals are known to activate immune cells and induce inflammatory responses through lysosomal damage. However, direct innate immune receptors for cholesterol crystals have not been identified. Murine macrophages transfected with hMincle responded to cholesterol crystals by producing pro-inflammatory cytokines. Human dendritic cells expressed a set of inflammatory genes in response to cholesterol crystals, and this was inhibited by anti-human Mincle. Importantly, other related CLRs did not bind cholesterol crystals, whereas other steroids were not recognized by hMincle. These results suggest that cholesterol crystals are an endogenous ligand for hMincle and that they activate innate immune responses. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

    PubMed Central

    Hu, Joyce K.; Crampton, Jordan C.; Cupo, Albert; Ketas, Thomas; van Gils, Marit J.; Sliepen, Kwinten; de Taeye, Steven W.; Sok, Devin; Ozorowski, Gabriel; Deresa, Isaiah; Stanfield, Robyn; Ward, Andrew B.; Burton, Dennis R.; Klasse, Per Johan; Sanders, Rogier W.; Moore, John P.

    2015-01-01

    ABSTRACT Generating neutralizing antibodies (nAbs) is a major goal of many current HIV-1 vaccine efforts. To be of practical value, these nAbs must be both potent and cross-reactive in order to be capable of preventing the transmission of the highly diverse and generally neutralization resistant (Tier-2) HIV-1 strains that are in circulation. The HIV-1 envelope glycoprotein (Env) spike is the only target for nAbs. To explore whether Tier-2 nAbs can be induced by Env proteins, we immunized conventional mice with soluble BG505 SOSIP.664 trimers that mimic the native Env spike. Here, we report that it is extremely difficult for murine B cells to recognize the Env epitopes necessary for inducing Tier-2 nAbs. Thus, while trimer-immunized mice raised Env-binding IgG Abs and had high-quality T follicular helper (Tfh) cell and germinal center (GC) responses, they did not make BG505.T332N nAbs. Epitope mapping studies showed that Ab responses in mice were specific to areas near the base of the soluble trimer. These areas are not well shielded by glycans and likely are occluded on virions, which is consistent with the lack of BG505.T332N nAbs. These data inform immunogen design and suggest that it is useful to obscure nonneutralizing epitopes presented on the base of soluble Env trimers and that the glycan shield of well-formed HIV Env trimers is virtually impenetrable for murine B cell receptors (BCRs). IMPORTANCE Human HIV vaccine efficacy trials have not generated meaningful neutralizing antibodies to circulating HIV strains. One possible hindrance has been the lack of immunogens that properly mimic the native conformation of the HIV envelope trimer protein. Here, we tested the first generation of soluble, native-like envelope trimer immunogens in a conventional mouse model. We attempted to generate neutralizing antibodies to neutralization-resistant circulating HIV strains. Various vaccine strategies failed to induce neutralizing antibodies to a neutralization

  15. Immune responses to infectious diseases in bivalves.

    PubMed

    Allam, Bassem; Raftos, David

    2015-10-01

    Many species of bivalve mollusks (phylum Mollusca, class Bivalvia) are important in fisheries and aquaculture, whilst others are critical to ecosystem structure and function. These crucial roles mean that considerable attention has been paid to the immune responses of bivalves such as oysters, clams and mussels against infectious diseases that can threaten the viability of entire populations. As with many invertebrates, bivalves have a comprehensive repertoire of immune cells, genes and proteins. Hemocytes represent the backbone of the bivalve immune system. However, it is clear that mucosal tissues at the interface with the environment also play a critical role in host defense. Bivalve immune cells express a range of pattern recognition receptors and are highly responsive to the recognition of microbe-associated molecular patterns. Their responses to infection include chemotaxis, phagolysosomal activity, encapsulation, complex intracellular signaling and transcriptional activity, apoptosis, and the induction of anti-viral states. Bivalves also express a range of inducible extracellular recognition and effector proteins, such as lectins, peptidoglycan-recognition proteins, thioester bearing proteins, lipopolysaccharide and β1,3-glucan-binding proteins, fibrinogen-related proteins (FREPs) and antimicrobial proteins. The identification of FREPs and other highly diversified gene families in bivalves leaves open the possibility that some of their responses to infection may involve a high degree of pathogen specificity and immune priming. The current review article provides a comprehensive, but not exhaustive, description of these factors and how they are regulated by infectious agents. It concludes that one of the remaining challenges is to use new "omics" technologies to understand how this diverse array of factors is integrated and controlled during infection. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Microbes and mucosal immune responses in asthma.

    PubMed

    Hansel, Trevor T; Johnston, Sebastian L; Openshaw, Peter J

    2013-03-09

    The substantial increase in the worldwide prevalence of asthma and atopy has been attributed to lifestyle changes that reduce exposure to bacteria. A recent insight is that the largely bacterial microbiome maintains a state of basal immune homoeostasis, which modulates immune responses to microbial pathogens. However, some respiratory viral infections cause bronchiolitis of infancy and childhood wheeze, and can exacerbate established asthma; whereas allergens can partly mimic infectious agents. New insights into the host’s innate sensing systems, combined with recently developed methods that characterise commensal and pathogenic microbial exposure, now allow a unified theory for how microbes cause mucosal inflammation in asthma. The respiratory mucosa provides a key microbial interface where epithelial and dendritic cells interact with a range of functionally distinct lymphocytes. Lymphoid cells then control a range of pathways, both innate and specific, which organise the host mucosal immune response. Fundamental to innate immune responses to microbes are the interactions between pathogen-associated molecular patterns and pattern recognition receptors, which are associated with production of type I interferons, proinflammatory cytokines, and the T-helper-2 cell pathway in predisposed people. These coordinated, dynamic immune responses underlie the differing asthma phenotypes, which we delineate in terms of Seven Ages of Asthma. An understanding of the role of microbes in the atopic march towards asthma, and in causing exacerbations of established asthma, provides the rationale for new specific treatments that can be assessed in clinical trials. On the basis of these new ideas, specific host biomarkers might then allow personalised treatment to become a reality for patients with asthma.

  17. The adaptive immune response in celiac disease.

    PubMed

    Qiao, Shuo-Wang; Iversen, Rasmus; Ráki, Melinda; Sollid, Ludvig M

    2012-07-01

    Compared to other human leukocyte antigen (HLA)-associated diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, fundamental aspects of the pathogenesis in celiac disease are relatively well understood. This is mostly because the causative antigen in celiac disease-cereal gluten proteins-is known and the culprit HLA molecules are well defined. This has facilitated the dissection of the disease-relevant CD4+ T cells interacting with the disease-associated HLA molecules. In addition, celiac disease has distinct antibody responses to gluten and the autoantigen transglutaminase 2, which give strong handles to understand all sides of the adaptive immune response leading to disease. Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder.

  18. Regeneration, tissue injury and the immune response

    PubMed Central

    Godwin, James W; Brockes, Jeremy P

    2006-01-01

    The involvement of the immune system in the response to tissue injury has raised the possibility that it might influence tissue, organ or appendage regeneration following injury. One hypothesis that has been discussed is that inflammatory aspects may preclude the occurrence of regeneration, but there is also evidence for more positive roles of immune components. The vertebrate eye is an immunoprivileged site where inflammatory aspects are inhibited by several immunomodulatory mechanisms. In various newt species the ocular tissues such as the lens are regenerative and it has recently been shown that the response to local injury of the lens involves activation of antigen-presenting cells which traffic to the spleen and return to displace and engulf the lens, thereby inducing regeneration from the dorsal iris. The activation of thrombin from prothrombin in the dorsal iris is one aspect of the injury response that is important in the initiation of regeneration. The possible relationships between the immune response and the regenerative response are considered with respect to phylogenetic variation of regeneration in general, and lens regeneration in particular. PMID:17005015

  19. Changing the energy of an immune response

    PubMed Central

    Delmastro-Greenwood, Meghan M; Piganelli, Jon D

    2013-01-01

    The breakdown of nutrients into the critical energy source ATP is the general purpose of cellular metabolism and is essential for sustaining life. Similarly, the immune system is composed of different cell subsets that are indispensable for defending the host against pathogens and disease. The interplay between metabolic pathways and immune cells leads to a plethora of different signaling pathways as well as cellular activities. The activation of T cells via glycolysis-mediated upregulation of surface markers, for example, is necessary for an appropriate effector response against an infection. However, tight regulation of immune cell metabolism is required for protecting the host and resuming homeostasis. An imbalance of immunological metabolic function and/or metabolic byproducts (reactive oxygen species) can oftentimes lead to diseases. In the case of cancer, overactive glucose metabolism can lead to hyperproliferation of cells and subsequent decreases in cytotoxic T cell activity, which attack and destroy the tumor. For this reason and many more, targeting metabolism in immune cells may be a novel therapeutic strategy for treatment of disease. The metabolic pathways of immune cells and the possibilities of immunometabolic therapies will be discussed. PMID:23885324

  20. In vitro immune toxicity of polybrominated diphenyl ethers on murine peritoneal macrophages: apoptosis and immune cell dysfunction.

    PubMed

    Lv, Qi-Yan; Wan, Bin; Guo, Liang-Hong; Zhao, Lixia; Yang, Yu

    2015-02-01

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants and are often detected in the environment, wildlife, and humans, presenting potential threats to ecosystem and human health. PBDEs can cause neurotoxicity, hepatotoxicity, and endocrine disruption. However, data on PBDE immunotoxicity are limited, and the toxicity mechanisms remain largely unknown. Both immune cell death and dysfunction can modulate the responses of the immune system. This study examined the toxic effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209) on the immune system by using peritoneal macrophages as the model. The macrophages were exposed to PBDEs, and cell death was determined through flow cytometry and immunochemical blot. The results showed that after 24h of exposure, BDE-47 (>5 μM) and BDE-209 (>20 μM) induced cell apoptosis, increased intracellular reactive oxygen species (ROS) formation and depleted glutathione. BDE-47 was more potent than BDE-209; the cytotoxic concentrations for BDE-47 and BDE-209 were determined to be 5 μM and 20 μM, respectively, during 24h of exposure. However, pretreatment with n-acetyl-l-cysteine (ROS scavenger) partially reversed the cytotoxic effects. Further gene expression analyses on Caspase-3,-8,-9, TNFR1, and Bax revealed that both intrinsic and extrinsic apoptotic pathways were activated. More importantly, non-cytotoxic concentrations BDE-47 (<2 μM) and BDE-209 (<10 μM) could impair macrophage accessory cell function in a concentration-dependent manner, but no effects were observed on phagocytic responses. These revealed effects of PBDEs on macrophages may shed light on the toxicity mechanisms of PBDEs and suggest the necessity of evaluating cellular functionality during the risk assessment of PBDE immunotoxicity.

  1. Dendritic Cells: A Double-Edged Sword in Immune Responses during Chagas Disease

    PubMed Central

    Gil-Jaramillo, Natalia; Motta, Flávia N.; Favali, Cecília B. F.; Bastos, Izabela M. D.; Santana, Jaime M.

    2016-01-01

    Dendritic cells (DCs) are the most important member of the antigen presenting cells group due to their ability to recognize antigen at the infection site and their high specialized antigen internalization capacity. These cells have central role in connecting the innate and adaptive immune responses against Trypanosoma cruzi, the causative agent of Chagas disease. These first line defense cells modulate host immune response depending on type, maturation level, cytokine milieu and DC receptor involved in the interactions with T. cruzi, influencing the development of the disease clinic forms. Here, we present a review of DCs–T. cruzi interactions both in human and murine models, pointing out the parasite ability to manipulate DCs activity for the purpose of evading innate immune response and assuring its own survival and persistence. PMID:27471496

  2. Murine polyomavirus virus-like particles (VLPs) as vectors for gene and immune therapy and vaccines against viral infections and cancer.

    PubMed

    Tegerstedt, Karin; Franzén, Andrea Vlastos; Andreasson, Kalle; Joneberg, Jeanna; Heidari, Shirin; Ramqvist, Torbjörn; Dalianis, Tina

    2005-01-01

    This review describes the use of murine polyomavirus "virus-like" particles (MPyV-VLPs), free from viral genes, as vectors for gene and immune therapy and as vaccines. For large-scale MPyV-VLP manufacture, VP1 is produced in a baculovirus insect cell system, E. coli or in yeast. MPyV-VLPs bind eukaryotic DNA and introduce this DNA into various cell types in vitro and in vivo. In normal and T-cell-deficient mice, this results in the production of anti-MPyV-VLP (and MPyV) antibodies. Furthermore, repeated MPyV-VLP vaccination has been shown to prevent primary MPyV infection in normal and T-cell-deficient mice, and the outgrowth of some MPyV-induced tumours in normal mice. Moreover, when inoculated with gene constructs encoding for HIV p24, MPyV-VLPs augment the antibody response to p24. In addition, MPyV-VLPs, containing fusion proteins between the VP2 or VP3 capsid protein and selected antigens, can be used as vaccines. Notably, one vaccination with MPyV-VLPs, containing a fusion protein between VP2 and the extracellular and transmembrane parts of the HER-2/neu oncogene, immunizes against outgrowth of a HER-2/neu-expressing tumour in Balb/c mice and also against the development of mammary carcinomas in BALB-neuT transgenic mice. Finally, a second polyoma VLP-vector based on murine pneumotropic virus (MPtV-VLP), which does not cross-react serologically with MPyV-VLP (and MPyV), has been developed and can be used to conduct prime boost gene and immune therapy and vaccination. In summary, MPyV-VLPs are useful vectors for gene therapy, immune therapy and as vaccines and, in combination with MPyV-VLPs, MPtV-VLPs are potentially useful as prime-boost vectors.

  3. Multiscale modeling of mucosal immune responses

    PubMed Central

    2015-01-01

    Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut

  4. Multiscale modeling of mucosal immune responses.

    PubMed

    Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep

    2015-01-01

    Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T

  5. Mesenchymal stem cells and adaptive immune responses.

    PubMed

    Cao, Wei; Cao, Kai; Cao, Jianchang; Wang, Ying; Shi, Yufang

    2015-12-01

    Over the past decade, our understanding of the regulatory role of mesenchymal stem cells (MSCs) in adaptive immune responses through both preclinical and clinical studies has dramatically expanded, providing great promise for treating various inflammatory diseases. Most studies are focused on the modulatory effects of these cells on the properties of T cell-mediated immune responses, including activation, proliferation, survival, and subset differentiation. Interestingly, the immunosuppressive function of MSCs was found to be licensed by IFN-γ and TNF-α produced by T cells and that can be further amplified by cytokines such as IL-17. However, the immunosuppressive function of MSCs can be reversed in certain situation, such as suboptimal levels of inflammatory cytokines, or in the presence of immunosuppressive molecules. Here we review the influence of MSCs on adaptive immune system, especially their bidirectional interaction in tuning the immune microenvironment and subsequently repairing damaged tissue. Understanding MSC-mediated regulation of T cells is expected to provide fundamental information for guiding appropriate applications of MSCs in clinical settings. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  6. The Memory Immune Response to Tuberculosis.

    PubMed

    Kirman, Joanna R; Henao-Tamayo, Marcela I; Agger, Else Marie

    2016-12-01

    Immunological memory is a central feature of the adaptive immune system and a prerequisite for generating effective vaccines. Understanding long-term memory responses to Mycobacterium tuberculosis will thus provide us with valuable insights that can guide us in the search for a novel vaccine against tuberculosis (TB). For many years, triggering CD4 T cells and, in particular, those secreting interferon-γ has been the goal of most TB vaccine research, and numerous data from animals and humans support the key role of this subset in protective immunity. More recently, we have learned that the memory response required for effective control of M. tuberculosis is much more complex, probably involving several phenotypically different CD4 T cell subsets as well as other cell types that are yet to be defined. Herein, we describe recent insights into memory immunity to TB in the context of both animal models and the human infection. With the increasing amount of data generated from clinical testing of novel TB vaccines, we also summarize recent knowledge of vaccine-induced memory immunity.

  7. THE EVOLUTION OF THE IMMUNE RESPONSE

    PubMed Central

    Finstad, Joanne; Good, Robert A.

    1964-01-01

    1. Studies of the immune response have been carried out in more than 1700 lampreys representing three stages in the life cycle of these animals. 2. Lampreys used in this study were unable to clear certain soluble protein antigens and bacteriophage and were unable to make antibodies to these antigens. Hemocyanin was cleared from the circulation. 3. The immune responses demonstrated in lampreys include the production of specific antibody to killed Brucella cells, the rejection of skin homografts, and the development of a delayed allergic response to old tuberculin. 4. A responsive proliferation of lymphoid cells occurred in the protovertebral arch following antigen-adjuvant stimulation. 5. Electrophoretic and immunoelectrophoretic analysis of lamprey serum revealed gamma globulin. Ultracentrifugal analysis of serum revealed proteins with sedimentation coefficients of 17S, 8S, 7S, and 3S. 6. The antibodies thus far observed in the lamprey are of relatively high molecular weight and destroyed by 2-mercaptoethanol. 7. In the lamprey it would appear that there is reflected the coordinate evolution of a primitive thymus, primitive spleen containing lymphoid foci, a family of lymphocytes in the peripheral blood and capacity for gamma globulin synthesis and expression of adaptive immunity. PMID:14238932

  8. The innate and adaptive immune response to avian influenza virus

    USDA-ARS?s Scientific Manuscript database

    Protective immunity against viruses is mediated by the early innate immune responses and later on by the adaptive immune responses. The early innate immunity is designed to contain and limit virus replication in the host, primarily through cytokine and interferon production. Most all cells are cap...

  9. MYC and HIF in shaping immune response and immune metabolism.

    PubMed

    Gnanaprakasam, J N Rashida; Sherman, John William; Wang, Ruoning

    2017-06-01

    Upon antigen stimulation, quiescent naive T cells undergo a phase of cell mass accumulation followed by cell cycle entry, clonal expansion, differentiation into functional subsets and back again to a quiescent state as they develop into memory cells. The transitions between these distinct cellular states place unique metabolic demands on energy, redox and biosynthesis. To fulfill these demands, T cells switch back and forth between their primary catabolic pathways. While quiescent naive and memory T cells largely rely on the oxidation of fatty acids and glucose, active T cells rely on glycolysis and glutaminolysis to sustain cell growth, proliferation and differentiation. Beyond several key signaling kinase cascades, the hypoxia inducible factor 1 (HIF-1) and the proto-oncogene MYC, act alone or in concert, to coordinate T cell metabolic reprogramming, cell proliferation, functional differentiation and apoptosis, enabling a robust T cell-mediated adaptive immune response. Copyright © 2017. Published by Elsevier Ltd.

  10. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis.

    PubMed

    Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta; Kolbinger, Frank; Moulin, Pierre; Brees, Dominique; Coleman, Bianca M; Mamo, Anna J; Garg, Abhishek V; Jaycox, Jillian R; Siebenlist, Ulrich; Kammüller, Michael; Gaffen, Sarah L

    2016-06-01

    Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency. © Society for Leukocyte Biology.

  11. Dengue virus infection: current concepts in immune mechanisms and lessons from murine models

    PubMed Central

    Guabiraba, Rodrigo; Ryffel, Bernhard

    2014-01-01

    Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1–4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection. PMID:24182427

  12. Analysis of cellular phenotype during in vitro immunization of murine splenocytes for generating antigen-specific immunoglobulin.

    PubMed

    Inagaki, Takashi; Yoshimi, Tatsunari; Kobayashi, Satoshi; Kawahara, Masahiro; Nagamune, Teruyuki

    2013-03-01

    Although various in vitro immunization methods to generate antigen-specific antibodies have been described, a highly effective method that can generate high-affinity immunoglobulins has not yet been reported. Herein, we analyzed a cellular phenotype during in vitro immunization of murine splenocytes for generating antigen-specific immunoglobulins. We identified a combination of T cell-dependent stimuli (IL-4, IL-5, anti-CD38 and anti-CD40 antibodies) plus lipopolysaccharides (LPS) that stimulates antigen-exposed splenocytes in vitro, followed by induction of the cells phenotypically equivalent to germinal center B cells. We also observed that LPS induced high expression levels of mRNA for activation-induced cytidine deaminase. We stimulated antigen-exposed splenocytes, followed by the accumulation of mutations in immunoglobulin genes. From the immunized splenocytes, hybridoma clones secreting antigen-specific immunoglobulins were obtained.

  13. Gut dysbiosis and neuroimmune responses to brain infection with Theiler's murine encephalomyelitis virus.

    PubMed

    Carrillo-Salinas, F J; Mestre, L; Mecha, M; Feliú, A; Del Campo, R; Villarrubia, N; Espejo, C; Montalbán, X; Álvarez-Cermeño, J C; Villar, L M; Guaza, C

    2017-03-14

    Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4(+) and CD8(+) T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4(+) and CD8(+)T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

  14. Gut dysbiosis and neuroimmune responses to brain infection with Theiler’s murine encephalomyelitis virus

    PubMed Central

    Carrillo-Salinas, F. J.; Mestre, L.; Mecha, M.; Feliú, A.; del Campo, R.; Villarrubia, N.; Espejo, C.; Montalbán, X.; Álvarez-Cermeño, J. C.; Villar, L. M.; Guaza, C.

    2017-01-01

    Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice. PMID:28290524

  15. Humoral innate immune response and disease

    PubMed Central

    Shishido, Stephanie N.; Varahan, Sriram; Yuan, Kai; Li, Xiangdong; Fleming, Sherry D.

    2012-01-01

    The humoral innate immune response consists of multiple components, including the naturally occurring antibodies (NAb), pentraxins and the complement and contact cascades. As soluble, plasma components, these innate proteins provide key elements in the prevention and control of disease. However, pathogens and cells with altered self proteins utilize multiple humoral components to evade destruction and promote pathogy. Many studies have examined the relationship between humoral immunity and autoimmune disorders. This review focuses on the interactions between the humoral components and their role in promoting the pathogenesis of bacterial and viral infections and chronic diseases such as atherosclerosis and cancer. Understanding the beneficial and detrimental aspects of the individual components and the interactions between proteins which regulate the innate and adaptive response will provide therapeutic targets for subsequent studies. PMID:22771788

  16. Evolutionary responses of innate Immunity to adaptive immunity

    USDA-ARS?s Scientific Manuscript database

    Innate immunity is present in all metazoans, whereas the evolutionarily more novel adaptive immunity is limited to jawed fishes and their descendants (gnathostomes). We observe that the organisms that possess adaptive immunity lack diversity in their innate pattern recognition receptors (PRRs), rais...

  17. Interorgan Coordination of the Murine Adaptive Response to Fasting*

    PubMed Central

    Hakvoort, Theodorus B. M.; Moerland, Perry D.; Frijters, Raoul; Sokolović, Aleksandar; Labruyère, Wilhelmina T.; Vermeulen, Jacqueline L. M.; Ver Loren van Themaat, Emiel; Breit, Timo M.; Wittink, Floyd R. A.; van Kampen, Antoine H. C.; Verhoeven, Arthur J.; Lamers, Wouter H.; Sokolović, Milka

    2011-01-01

    Starvation elicits a complex adaptive response in an organism. No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0–72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted “carbohydrate-lipid-protein” succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPARα, HNF4α, GCRα, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage. PMID:21393243

  18. Interorgan coordination of the murine adaptive response to fasting.

    PubMed

    Hakvoort, Theodorus B M; Moerland, Perry D; Frijters, Raoul; Sokolović, Aleksandar; Labruyère, Wilhelmina T; Vermeulen, Jacqueline L M; Ver Loren van Themaat, Emiel; Breit, Timo M; Wittink, Floyd R A; van Kampen, Antoine H C; Verhoeven, Arthur J; Lamers, Wouter H; Sokolović, Milka

    2011-05-06

    Starvation elicits a complex adaptive response in an organism. No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0-72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted "carbohydrate-lipid-protein" succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPARα, HNF4α, GCRα, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage.

  19. Immune responses to pertussis vaccines and disease.

    PubMed

    Edwards, Kathryn M; Berbers, Guy A M

    2014-04-01

    In this article we discuss the following: (1) acellular vaccines are immunogenic, but responses vary by vaccine; (2) pertussis antibody levels rapidly wane but promptly increase after vaccination; (3) whole-cell vaccines vary in immunogenicity and efficacy; (4) whole-cell vaccines and naturally occurring pertussis generate predominantly T-helper 1 (Th1) responses, whereas acellular vaccines generate mixed Th1/Th2 responses; (5) active transplacental transport of pertussis antibody is documented; (6) neonatal immunization with diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine has been associated with some suppression of pertussis antibody, but suppression has been seen less often with acellular vaccines; (7) memory B cells persist in both acellular vaccine- and whole cell vaccine-primed children; and (8) in acellular vaccine-primed children, T-cell responses remain elevated and do not increase with vaccine boosters, whereas in whole-cell vaccine-primed children, these responses can be increased by vaccine boosting and natural exposure. Despite these findings, challenges remain in understanding the immune response to pertussis vaccines.

  20. IL-28 elicits antitumor responses against murine fibrosarcoma.

    PubMed

    Numasaki, Muneo; Tagawa, Masatoshi; Iwata, Fumi; Suzuki, Takashi; Nakamura, Akira; Okada, Masahiro; Iwakura, Yoichiro; Aiba, Setsuya; Yamaya, Mutsuo

    2007-04-15

    IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-gamma production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-gamma and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-gamma production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-gamma. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors.

  1. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts.

    PubMed

    Onda, Masanori; Ghoreschi, Kamran; Steward-Tharp, Scott; Thomas, Craig; O'Shea, John J; Pastan, Ira H; FitzGerald, David J

    2014-07-01

    Immunogenicity remains the "Achilles' heel" of protein-based therapeutics. Anti-drug Abs produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. In this article, we report that monotherapy of mice with tofacitinib (the JAK inhibitor) quells Ab responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. Thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics.

  2. Immunization with Attenuated Equine Herpesvirus 1 Strain KyA Induces Innate Immune Responses That Protect Mice from Lethal Challenge

    PubMed Central

    Shakya, Akhalesh K.; O'Callaghan, Dennis J.

    2016-01-01

    ABSTRACT Equine herpesvirus 1 (EHV-1) is a major pathogen affecting equines worldwide. The virus causes respiratory disease, abortion, and, in some cases, neurological disease. EHV-1 strain KyA is attenuated in the mouse and equine, whereas wild-type strain RacL11 induces severe inflammation of the lung, causing infected mice to succumb at 4 to 6 days postinfection. Our previous results showed that KyA immunization protected CBA mice from pathogenic RacL11 challenge at 2 and 4 weeks postimmunization and that KyA infection elicited protective humoral and cell-mediated immune responses. To investigate the protective mechanisms of innate immune responses to KyA, KyA-immunized mice were challenged with RacL11 at various times postvaccination. KyA immunization protected mice from RacL11 challenge at 1 to 7 days postimmunization. Immunized mice lost less than 10% of their body weight and rapidly regained weight. Virus titers in the lungs of KyA-immunized mice were 1,000-fold lower at 2 days post-RacL11 challenge than virus titers in the lungs of nonimmunized mice, indicating accelerated virus clearance. Affymetrix microarray analysis revealed that gamma interferon (IFN-γ) and 16 antiviral interferon-stimulated genes (ISGs) were upregulated 3.1- to 48.2-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been immunized with KyA. Murine IFN-γ inhibited EHV-1 infection of murine alveolar macrophages and protected mice against lethal EHV-1 challenge, suggesting that IFN-γ expression is important in mediating the protection elicited by KyA immunization. These results suggest that EHV-1 KyA may be used as a live attenuated EHV-1 vaccine as well as a prophylactic agent in horses. IMPORTANCE Viral infection of cells initiates a signal cascade of events that ultimately attempts to limit viral replication and prevent infection through the expression of host antiviral proteins. In this study, we show that EHV-1 KyA immunization effectively protected CBA

  3. Experimental murine leprosy: induction of immunity and immune paralysis to Mycobacterium lepraemurium in C57BL mice.

    PubMed Central

    Closs, O

    1975-01-01

    Two series of reinfection experiments were carried out using C57BL mice. In the first series, the mice were inoculated with Mycobacterium lepraemurium (MLM) in one hind footpad and reinoculated in the contralateral footpad, two or four weeks later. Compared with normal mice of the same strain, the mice reinoculated after four weeks showed an increased local reaction to the bacilli and the bacilli did not multiply at the injection site. The responses of mice reinoculated after two weeks were intermediate to those of the other two groups. In the second series, a systemic infection was established by intraperitoneal innoculation of either a large or small dose of MLM. Twenty-two weeks later the mice were reinoculated in one of the hind footpads. Upon reinoculation, mice receiving the small intraperitoneal dose reacted more strongly than normal mice to MLM, whereas mice receiving the large dose were unable to mount any local reaction to the mycobacterium. The experiments have shown that the local reaction which develops in the C57BL strain of mice approximately four weeks after subcutaneous injection of MLM is accompanied by the onset of systemic immunity. Such systemic immunity lasted for more than 20 weeks after intraperitoneal injection of a small dose of bacilli, but was completely abolished during the course of a heavy systemic MLM infection. PMID:1104475

  4. Photodynamic therapy stimulates anti-tumor immunity in a murine model

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2007-02-01

    Cancer is a leading cause of death among modern peoples largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with the minimal toxicity. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell 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), and induction of heat-shock proteins. The induction of specific CD8+ T lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. We here report on PDT of mice bearing tumors that either do or do not express an established TAA. We utilized a BALB/c colon adenocarcinoma cell line termed CT26.CL25 retrovirally transduced to stably express β-galactosidase ( β-gal, a bacterial protein), and its non-β-gal expressing wild-type counterpart termed CT26 WT, as well as the control cell line consisting of CT26 transduced with the empty retroviral vector termed CT26-neo. All cells expressed class I MHC restriction element H-2Ld syngenic to BALB/c mice. Vascular PDT with a regimen of 1mg/kg BPD injected IV, and 120 J/cm2 of 690-nm laser light after 15 minutes successfully cured 100% of CT26.CL25 tumors but 0% of CT26-neo tumors and 0% of CT26 WT tumors. After 90 days tumor free interval the CT26.CL25 cured mice were rechallenged with CT26.CL25 tumor cells and 96% rejected the rechallenge while the CT26.CL25 cured mice did not reject a CT26 WT tumor cell challenge. Experiments with mice bearing two CT26.CL25 tumors (one

  5. Correction of age-associated deficiency in germinal center response by immunization with immune complexes.

    PubMed

    Zheng, Biao; Switzer, Kirsten; Marinova, Ekaterina; Wansley, Daniel; Han, Shuhua

    2007-08-01

    In aging, both primary and secondary antibody responses are impaired. One of the most notable changes in age-associated immune deficiency is the diminished germinal center (GC) reaction. This impaired GC response reduces antibody affinity maturation, decreases memory B cell development, and prevents the establishment of long-term antibody-forming cells in the bone marrow. It is of great importance to explore novel strategy in improving GC response in the elderly. In this study, the efficacy of immunization with immune complexes in overcoming age-associated deficiency in GC response was investigated. We show that the depressed GC response in aged mice can be significantly elevated by immunization with immune complexes. Importantly, there is a significant improvement of B cell memory response and long-lived plasma cells. Our results demonstrate that immune complex immunization may represent a novel strategy to elicit functional GC response in aging, and possibly, to overcome age-related immune deficiency in general.

  6. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses.

    PubMed

    Lin, Pei-Yi; Sun, Lishi; Thibodeaux, Suzanne R; Ludwig, Sara M; Vadlamudi, Ratna K; Hurez, Vincent J; Bahar, Rumana; Kious, Mark J; Livi, Carolina B; Wall, Shawna R; Chen, Lieping; Zhang, Bin; Shin, Tahiro; Curiel, Tyler J

    2010-09-01

    CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunopathogenic in cancers by impeding tumor-specific immunity. B7-homologue 1 (B7-H1) (CD274) is a cosignaling molecule with pleiotropic effects, including hindering antitumor immunity. In this study, we demonstrate sex-dependent, B7-H1-dependent differences in tumor immunity and response to immunotherapy in a hormone-independent cancer, murine B16 melanoma. Antitumor immunity was better in B7-H1(-/-) females versus males as a result of reduced regulatory T cell function in the B7-H1(-/-) females, and clinical response following B7-H1 blockade as tumor immunotherapy was significantly better in wild-type females than in males, owing to greater B7-H1 blockade-mediated reduction of Treg function in females. Wild-type female Tregs expressed significantly lower B7-H1 versus males but were insensitive to estrogen in vitro. Female B7-H1(-/-) Tregs were exquisitely sensitive to estrogen-mediated functional reduction in vitro, suggesting that B7-H1 effects occur before terminal Treg differentiation. Immune differences were independent of known B7-H1 ligands. Sex-dependent immune differences are seldom considered in designing immune therapy or interpreting immunotherapy treatment results. Our data demonstrate that sex is an important variable in tumor immunopathogenesis and immunotherapy responses through differential Treg function and B7-H1 signaling.

  7. Cellular immune responses towards regulatory cells.

    PubMed

    Larsen, Stine Kiær

    2016-01-01

    This thesis describes the results from two published papers identifying spontaneous cellular immune responses against the transcription factors Foxp3 and Foxo3. The tumor microenvironment is infiltrated by cells that hinder effective tumor immunity from developing. Two of these cell types, which have been linked to a bad prognosis for patients, are regulatory T cells (Treg) and tolerogenic dendritic cells (DC). Tregs inhibit effector T cells from attacking the tumor through various mechanisms, including secreted factors and cell-to-cell contact. Tregs express the transcription factor Foxp3, which is necessary for their development and suppressive activities. Tolerogenic DCs participate in creating an environment in the tumor where effector T cells become tolerant towards the tumor instead of attacking it. The transcription factor Foxo3 was recently described to be highly expressed by tolerogenic DCs and to programme their tolerogenic influence. This thesis describes for the first time the existence of spontaneous cellular immune responses against peptides derived from Foxp3 and Foxo3. We have detected the presence of cytotoxic T cells that recognise these peptides in an HLA-A2 restricted manner in cancer patients and for Foxp3 in healthy donors as well. In addition, we have demonstrated that the Foxp3- and Foxo3-specific CTLs recognize Foxp3- and Foxo3-expressing cancer cell lines and importantly, suppressive immune cells, namely Tregs and in vitro generated DCs. Cancer immunotherapy is recently emerging as an important treatment modality improving the survival of selected patients. The current progress is largely owing to targeting of the immune suppressive milieu that is dominating the tumor microenvironment. This is being done through immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies and through lymphodepleting conditioning of patients and ex vivo activation of TILs in adoptive cell transfer. Several strategies are being explored for depletion of

  8. Temporal profile of inflammatory response to fracture and hemorrhagic shock: Proposal of a novel long-term survival murine multiple trauma model.

    PubMed

    Kleber, Christian; Becker, Christopher A; Malysch, Tom; Reinhold, Jens M; Tsitsilonis, Serafeim; Duda, Georg N; Schmidt-Bleek, Katharina; Schaser, Klaus D

    2015-07-01

    Hemorrhagic shock (hS) interacts with the posttraumatic immune response and fracture healing in multiple trauma. Due to the lack of a long-term survival multiple trauma animal models, no standardized analysis of fracture healing referring the impact of multiple trauma on fracture healing was performed. We propose a new long-term survival (21 days) murine multiple trauma model combining hS (microsurgical cannulation of carotid artery, withdrawl of blood and continuously blood pressure measurement), femoral (osteotomy/external fixation) and tibial fracture (3-point bending technique/antegrade nail). The posttraumatic immune response was measured via IL-6, sIL-6R ELISA. The hS was investigated via macrohemodynamics, blood gas analysis, wet-dry lung ration and histologic analysis of the shock organs. We proposed a new murine long-term survival (21 days) multiple trauma model mimicking clinical relevant injury patterns and previously published human posttraumatic immune response. Based on blood gas analysis and histologic analysis of shock organs we characterized and standardized our murine multiple trauma model. Furthermore, we revealed hemorrhagic shock as a causative factor that triggers sIL-6R formation underscoring the fundamental pathophysiologic role of the transsignaling mechanism in multiple trauma.

  9. Staphylococcal manipulation of host immune responses

    PubMed Central

    Thammavongsa, Vilasack; Kim, Hwan Keun; Missiakas, Dominique; Schneewind, Olaf

    2015-01-01

    Staphylococcus aureus, a bacterial commensal of the human nares and skin, is a frequent cause of soft tissue and bloodstream infections. A hallmark of staphylococcal infections is their frequent recurrence, even when treated with antibiotics and surgical intervention, which demonstrates the bacterium’s ability to manipulate innate and adaptive immune responses. In this Review, we highlight how S. aureus virulence factors inhibit complement activation, block and destroy phagocytic cells and modify host B and T cell responses, and we discuss how these insights might be useful for the development of novel therapies against infections with antibiotic resistant strains such as methicillin-resistant S. aureus. PMID:26272408

  10. Human Immune Response to Dengue Infections

    DTIC Science & Technology

    1988-07-31

    Security Classification) (U) Human Immune Response to Dengue Infections 12. PERSONAL AUTHOR(S) Francis A. Ennis 13a. TYPE OF’REPORTn 13b. TIME COVERED 14...8217SUBJECT TERMS (Continue on reverse if necessary and identify by Nock rumber) FIELD GROUP SUB-GROUP RA .1, Dengue virus, T lymphopytes. 06 03 InB-GROP1.In...responses to dengue antigens in vitro to elucidate the possible role of T lymphocytes in the pathogeneeis of dengue hemorrhagic fever and dengue

  11. [Response of immune system and lymphoid tissue of respiratory and gastrointestinal organs to space flight factors].

    PubMed

    Sapin, M R; Erofeeva, L M; Grigorenko, D E

    1999-01-01

    The studies demonstrated that gamma-radiation drastically enhanced destructive processes and suppressed the mitotic activity of lymphocytes in the thymus and spleen. This resulted in the altered morphological picture of immune organs: the inversion of layers occurred in the thymus, the splenic white pulp increased by three times, lymphoid nodules with germinating centers disappeared, the marginal area became thinner. Following gamma-radiation, restorative processes in the thymus and spleen were noticeable just on day 3 and 7, respectively. However, the cell composition of murine immune organs failed to achieve control values by day 60 after exposure. Examining the responses of respiratory and digestive lymphoid tissue to acetaldehyde and drinking water organisms indicated that as the concentration of an acting agent and the time of exposure increased, there was lymphocytopoietic inhibition in the lymphoid formations whereas its small doses activated a local immune response.

  12. The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function.

    PubMed

    Falsig, Jeppe; Pörzgen, Peter; Lund, Søren; Schrattenholz, André; Leist, Marcel

    2006-02-01

    Upon injury, astrocytes assume an activated state associated with the release of inflammatory mediators. To model this, we stimulated murine primary astrocytes with a complete inflammatory cytokine mix consisting of TNF-alpha, IL-1beta and IFN-gamma. We analysed the transcriptional response of 480 genes at 4 and 16 h after stimulation on a chip designed to give a representative overview over the inflammation-relevant part of the transcriptome of macrophage-like cells. The list of the 182 genes found to be significantly regulated in astrocytes revealed an intriguing co-ordinate regulation of genes linked to the biological processes of antiviral/antimicrobial defence, antigen presentation and facilitation of leucocyte invasion. The latter group was characterized by very high up-regulations of chemokine genes. We also identified regulations of a thymidylate kinase and an interferon-regulated protein with a tetratricopeptide motive, both up to now only known from macrophages. The transcriptional regulations were confirmed on the protein level by a proteomic analysis. These findings taken together suggest that activated astrocytes in brain behave similarly in many respects to inflamed macrophages in the periphery.

  13. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma.

    PubMed

    Jovanovic, Ivan; Radosavljevic, Gordana; Mitrovic, Maja; Juranic, Vanda Lisnic; McKenzie, Andrew N J; Arsenijevic, Nebojsa; Jonjic, Stipan; Lukic, Miodrag L

    2011-07-01

    ST2 is a member of the IL-1 receptor family and IL-33 was recently identified as its natural ligand. The IL-33/ST2 pathway regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions, but the role of ST2 signaling in tumor growth and metastasis has not been investigated. We aimed to investigate whether ST2 gene deletion affects tumor appearance, growth, and metastasis, and antitumor immunity in an experimental metastatic breast cancer model. Deletion of ST2 in BALB/c mice bearing mammary carcinoma attenuated tumor growth and metastasis, which was accompanied by increased serum levels of IL-17, IFN-γ, and TNF-α and decreased IL-4. Tumor-bearing ST2-/- mice had significantly higher percentages of activated CD27high CD11bhigh NK cells, CD69+ and KLRG- NK cells and higher cytotoxic activity of splenocytes, NK cells, and CD8+ T cells in vitro. A significantly higher number of NK cells expressing IFN-γ were found in ST2-/- mice compared with WT recipients. In vivo depletion of CD8+ or NK cells revealed a key role for NK cells in enhanced antitumor immunity in ST2-/- mice. We report for the first time that suppressed breast cancer progression and metastasis in mice lacking ST2 corresponds mainly with enhanced cytotoxic activity of NK cells, and increased systemic Th1/Th17 cytokines. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Modulation of Innate Immunity by Copolymer-1 Leads to Neuroprotection in Murine HIV-1 Encephalitis

    PubMed Central

    Gorantla, Santhi; Liu, Jianuo; Wang, Tong; Holguin, Adelina; Sneller, Hannah M; Dou, Huanyu; Kipnis, Jonathan; Poluektova, Larisa; Gendelman, Howard E

    2009-01-01

    Virus-infected and immune competent mononuclear phagocytes (MP; perivascular macrophages and microglia) drive the neuropathogenesis of human immunodeficiency virus type one (HIV-1) infection. Modulation of the MP phenotype from neurodestructive to neuroprotective underlies adjunctive therapeutic strategies for human disease. We reasoned that, as Copolymer-1 (Cop-1) can induce neuroprotective activities in a number of neuroinflammatory and neurodegenerative disorders, it could directly modulate HIV-1 infected MP neurotoxic activities. We now demonstrate that, in laboratory assays, Cop-1-stimulated virus-infected human monocyte-derived macrophages protect against neuronal injury and elicit anti-retroviral activities. Severe combined immune deficient (SCID) mice were stereotactically injected with HIV-1 infected human monocyte-derived macrophages, into the basal ganglia, to induce HIV-1 encephalitis (HIVE). Cop-1 was administered subcutaneously for 7 days. In HIVE mice Cop-1 treatment led to anti-inflammatory and neuroprotective responses. Reduced micro- and astro- gliosis, and conserved NeuN/MAP-2 levels were observed in virus affected brain regions in Cop-1-treated mice. These were linked to interleukin-10 and brain-derived neurotrophic factor expression and downregulation of inducible nitric oxide synthase. The data, taken together, demonstrate that Cop-1 can modulate innate immunity and, as such, improve disease outcomes in an animal model of HIVE. PMID:18046731

  15. Erythropoietin Protects against Murine Cerebral Malaria through Actions on Host Cellular Immunity

    PubMed Central

    Wei, Xu; Li, Ying; Sun, Xiaodan; Zhu, Xiaotong; Feng, Yonghui; Liu, Jun; Jiang, Yongjun; Shang, Hong

    2014-01-01

    Cerebral malaria (CM) is associated with excessive host proinflammatory responses and endothelial activation. The hematopoietic hormone erythropoietin (EPO) possesses neuroprotective functions in animal models of ischemic-hypoxic, traumatic, and inflammatory injuries. In the Plasmodium berghei ANKA model of experimental CM (ECM), recombinant human EPO (rhEPO) has shown evident protection against ECM. To elucidate the mechanism of EPO in this ECM model, we investigated the effect of rhEPO on host cellular immune responses. We demonstrated that improved survival of mice with ECM after rhEPO treatment was associated with reduced endothelial activation and improved integrity of the blood-brain barrier. Our results revealed that rhEPO downregulated the inflammatory responses by directly inhibiting the levels and functions of splenic dendritic cells. Conversely, rhEPO treatment led to significant expansion of regulatory T cells and increased expression of the receptor cytotoxic T lymphocyte antigen 4 (CTLA-4). The data presented here provide evidence of the direct effect of rhEPO on host cellular immunity during ECM. PMID:24126529

  16. Immune-mediated modulation of breast cancer growth and metastasis by the chemokine Mig (CXCL9) in a murine model.

    PubMed

    Walser, Tonya C; Ma, Xinrong; Kundu, Namita; Dorsey, Russell; Goloubeva, Olga; Fulton, Amy M

    2007-01-01

    Current immunotherapies are limited by several factors, including the failure to recruit sufficient numbers of immune effector cells to tumors. The chemokine monokine induced by gamma-interferon (Mig; CXCL9) attracts activated T cells and natural killer (NK) cells bearing the chemokine receptor CXCR3. We investigated Mig as an immunotherapeutic agent in a syngeneic murine model of metastatic breast cancer. We transfected the highly malignant murine mammary tumor cell line 66.1 to stably express murine Mig cDNA. Immune-competent mice injected with Mig-expressing tumor cells developed smaller local tumors and fewer lung metastases, and they survived longer than mice injected with vector-control tumor cells. Mig-mediated inhibition of local tumor growth was lost in the absence of host T cells. Mig-transduced tumors had increased numbers of CD4 T cells compared with vector-control tumors, consistent with the T-cell chemoattractant property of Mig, and many tumor-infiltrating host cells expressed CXCR3. NK cells had not been examined previously as a possible effector cell in Mig-based therapies. Our studies now show that NK cells are critical to the mechanism by which Mig limits metastasis. Inhibition of angiogenesis was not implicated as a mechanism of Mig-mediated therapy in this model. These studies support the hypothesis that by manipulating the Mig-CXCR3 gradient, it is possible to direct host immune effector cells to tumors, curtailing both local tumor growth and metastasis. These studies also implicate host NK cells as an additional effector cell critical for Mig-mediated control of metastasis.

  17. C3d enhanced DNA vaccination induced humoral immune response to glycoprotein C of pseudorabies virus

    SciTech Connect

    Tong Tiezhu; Fan Huiying; Tan Yadi; Xiao Shaobo; Ling Jieyu; Chen Huanchun; Guo Aizhen . E-mail: aizhen@mail.hzau.edu.cn

    2006-09-08

    Murine C3d were utilized to enhance immunogenicity of pseudorabies virus (PrV) gC DNA vaccination. Three copies of C3d and four copies of CR2-binding domain M28{sub 4} were fused, respectively, to truncated gC gene encoding soluble glycoprotein C (sgC) in pcDNA3.1. BALB/c mice were, respectively, immunized with recombinant plasmids, blank vector, and inactivated vaccine. The antibody ELISA titer for sgC-C3d{sub 3} DNA was 49-fold more than that for sgC DNA, and the neutralizing antibody obtained 8-fold rise. Protection of mice from death after lethal PrV (316 LD{sub 5}) challenge was augmented from 25% to 100%. Furthermore, C3d fusion increased Th2-biased immune response by inducing IL-4 production. The IL-4 level for sgC-C3d{sub 3} DNA immunization approached that for the inactivated vaccine. Compared to C3d, M28 enhanced sgC DNA immunogenicity to a lesser extent. In conclusion, we demonstrated that murine C3d fusion significantly enhanced gC DNA immunity by directing Th1-biased to a balanced and more effective Th1/Th2 response.

  18. Generation of protective immune response against anthrax by oral immunization with protective antigen plant-based vaccine.

    PubMed

    Gorantala, Jyotsna; Grover, Sonam; Rahi, Amit; Chaudhary, Prerna; Rajwanshi, Ravi; Sarin, Neera Bhalla; Bhatnagar, Rakesh

    2014-04-20

    In concern with frequent recurrence of anthrax in endemic areas and inadvertent use of its spores as biological weapon, the development of an effective anthrax vaccine suitable for both human and veterinary needs is highly desirable. A simple oral delivery through expression in plant system could offer promising alternative to the current methods that rely on injectable vaccines extracted from bacterial sources. In the present study, we have expressed protective antigen (PA) gene in Indian mustard by Agrobacterium-mediated transformation and in tobacco by plastid transformation. Putative transgenic lines were verified for the presence of transgene and its expression by molecular analysis. PA expressed in transgenic lines was biologically active as evidenced by macrophage lysis assay. Intraperitoneal (i.p.) and oral immunization with plant PA in murine model indicated high serum PA specific IgG and IgA antibody titers. PA specific mucosal immune response was noted in orally immunized groups. Further, antibodies indicated lethal toxin neutralizing potential in-vitro and conferred protection against in-vivo toxin challenge. Oral immunization experiments demonstrated generation of immunoprotective response in mice. Thus, our study examines the feasibility of oral PA vaccine expressed in an edible plant system against anthrax. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

    PubMed

    Lechner, Melissa G; Karimi, Saman S; Barry-Holson, Keegan; Angell, Trevor E; Murphy, Katherine A; Church, Connor H; Ohlfest, John R; Hu, Peisheng; Epstein, Alan L

    2013-01-01

    Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.

  20. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  1. Antiviral immune responses of bats: a review.

    PubMed

    Baker, M L; Schountz, T; Wang, L-F

    2013-02-01

    Despite being the second most species-rich and abundant group of mammals, bats are also among the least studied, with a particular paucity of information in the area of bat immunology. Although bats have a long history of association with rabies, the emergence and re-emergence of a number of viruses from bats that impact human and animal health has resulted in a resurgence of interest in bat immunology. Understanding how bats coexist with viruses in the absence of disease is essential if we are to begin to develop therapeutics to target viruses in humans and susceptible livestock and companion animals. Here, we review the current status of knowledge in the field of bat antiviral immunology including both adaptive and innate mechanisms of immune defence and highlight the need for further investigations in this area. Because data in this field are so limited, our discussion is based on both scientific discoveries and theoretical predictions. It is hoped that by provoking original, speculative or even controversial ideas or theories, this review may stimulate further research in this important field. Efforts to understand the immune systems of bats have been greatly facilitated in recent years by the availability of partial genome sequences from two species of bats, a megabat, Pteropus vampyrus, and a microbat, Myotis lucifugus, allowing the rapid identification of immune genes. Although bats appear to share most features of the immune system with other mammals, several studies have reported qualitative and quantitative differences in the immune responses of bats. These observations warrant further investigation to determine whether such differences are associated with the asymptomatic nature of viral infections in bats.

  2. Immune Response among Patients Exposed to Molds

    PubMed Central

    Edmondson, David A.; Barrios, Christy S.; Brasel, Trevor L.; Straus, David C.; Kurup, Viswanath P.; Fink, Jordan N.

    2009-01-01

    Macrocyclic trichothecenes, mycotoxins produced by Stachybotrys chartarum, have been implicated in adverse reactions in individuals exposed to mold-contaminated environments. Cellular and humoral immune responses and the presence of trichothecenes were evaluated in patients with mold-related health complaints. Patients underwent history, physical examination, skin prick/puncture tests with mold extracts, immunological evaluations and their sera were analyzed for trichothecenes. T-cell proliferation, macrocyclic trichothecenes, and mold specific IgG and IgA levels were not significantly different than controls; however 70% of the patients had positive skin tests to molds. Thus, IgE mediated or other non-immune mechanisms could be the cause of their symptoms. PMID:20054481

  3. IL-1 and T Helper Immune Responses

    PubMed Central

    Santarlasci, Veronica; Cosmi, Lorenzo; Maggi, Laura; Liotta, Francesco; Annunziato, Francesco

    2013-01-01

    CD4 T cells play a critical role in mediating adaptive immunity to a variety of pathogens as well as in tumor immunity. If not adequately regulated, CD4 T cells can be also involved in autoimmunity, asthma, and allergic responses. During TCR activation in a particular cytokine milieu, naïve CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, and Th17, as defined by their pattern of cytokine production and function. IL-1, the prototypic proinflammatory cytokine, has been shown to influence growth and differentiation of immunocompetent lymphocytes. The differential expression of IL-1RI on human CD4 T cell subsets confers distinct capacities to acquire specific effector functions. In this review, we summarize the role of IL-1 on CD4 T cells, in terms of differentiation, activation, and maintenance or survival. PMID:23874332

  4. Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response

    PubMed Central

    Sampson, James F.; Hasegawa, Eiichi; Mulki, Lama; Suryawanshi, Amol; Jiang, Shuhong; Chen, Wei-Sheng; Rabinovich, Gabriel A.; Connor, Kip M.; Panjwani, Noorjahan

    2015-01-01

    Galectins have emerged as potent immunoregulatory agents that control chronic inflammation through distinct mechanisms. Here, we report that treatment with Galectin-8 (Gal-8), a tandem-repeat member of the galectin family, reduces retinal pathology and prevents photoreceptor cell damage in a murine model of experimental autoimmune uveitis. Gal-8 treatment increased the number of regulatory T cells (Treg) in both the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of Treg cells in the dLN and retina of Gal-8 treated animals expressed the inhibitory coreceptor cytotoxic T lymphocyte antigen (CTLA)-4, the immunosuppressive cytokine IL-10, and the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were primarily inducible Treg cells that lack the expression of neuropilin-1. In addition, Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type (TH) 1 and TH17 cells. The effect of Gal-8 on T cell differentiation and/or function was specific for tissues undergoing an active immune response, as Gal-8 treatment had no effect on T cell populations in the spleen. Given the need for rational therapies for managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only for treating retinal autoimmune diseases, but also for other TH1- and TH17-mediated inflammatory disorders. PMID:26126176

  5. Spaceflight and Development of Immune Responses

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1996-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. The number of flight experiments has been small, and the full breadth of immunological alterations occurring after space flight remains to be established. Among the major effects on immune responses after space flight that have been reported are: alterations in lymphocyte blastogenesis and natural killer cell activity, alterations in production of cytokines, changes in leukocyte sub-population distribution, and decreases in the ability of bone marrow cells to respond to colony stimulating factors. Changes have been reported in immunological parameters of both humans and rodents. The significance of these alterations in relation to resistance to infection remains to be established. The objective of the studies contained in this project was to determine the effects of space flight on immune responses of pregnant rats and their offspring. The hypothesis was that space flight and the attendant period of microgravity will result in alteration of immunological parameters of both the pregnant rats as well as their offspring carried in utero during the flight. The parameters tested included: production of cytokines, composition of leukocyte sub- populations, response of bone marrow/liver cells to granulocyte/monocyte colony stimulating factor, and leukocyte blastogenesis. Changes in immune responses that could yield alterations in resistance to infection were determined. This yielded useful information for planning studies that could contribute to crew health. Additional information that could eventually prove useful to determine the potential for establishment of a permanent colony in space was obtained.

  6. Transfer of protective immunity in murine histoplasmosis by a CD4+ T-cell clone.

    PubMed

    Allendoerfer, R; Magee, D M; Deepe, G S; Graybill, J R

    1993-02-01

    We have reported that a murine Histoplasma capsulatum-reactive CD4+ T-cell line and clones thereof did not adoptively transfer protection against H. capsulatum infection in normal or cyclophosphamide-treated C57BL/6 mice. One explanation for the results was that the T cells failed to traffic to lymphoid organs in these animals. In this study, we have sought to determine whether one of these clones, 2.3H3, could mediate protection in nude (C57BL/10) or irradiated (5 Gy) heterozygous nude (nu/+) C57BL/6 mice. Mice were inoculated intravenously with 10(7) resting 2.3H3 cells or with an equal number of cells of the ovalbumin-reactive clone 1S6; 2 h later, the mice were challenged intranasally with 5 x 10(6) yeast cells. By day 5 of infection, lungs, livers, and spleens of nude and irradiated nu/+ mice given 2.3H3 contained significantly fewer (P < 0.05) CFU than the same organs from mice inoculated with 1S6. This effect was specific for H. capsulatum, since 2.3H3 did not reduce the number of Coccidioides immitis CFU in lungs, livers, and spleens of irradiated nu/+ mice. By day 10, the amounts of H. capsulatum CFU in lungs, livers, or spleens of nude and irradiated nu/+ mice inoculated with 2.3H3 were smaller than those in 1S6-inoculated mice, but these differences did not reach statistical significance (P > 0.05). The mortality rate of mice inoculated with 2.3H3 and that of mice inoculated with 1S6 were similar. Histopathological examination of tissues from 2.3H3- and 1S6-inoculated mice demonstrated the presence of granulomatous inflammation in organs from both groups. Tissues from 2.3H3-treated mice contained fewer yeasts per high-power field than tissues from 1S6-treated mice. Thus, irradiated or nude mice are permissive for the expression of protective immunity by a CD4+ T-cell clone. Although the protective capacity of T cells in these animals is transient, these animals will be useful for differentiating protective from nonprotective T-cell clones.

  7. [Types of immune response in advanced suppurative peritonitis].

    PubMed

    Borisov, A G; Savchenko, A A; Cherdantsev, D V; Zdzitovetsky, D E; Pervova, O V; Kudryavtsev, I V; Belenyuk, V D; Shapkina, V A

    to assess types of immune response in patients with advanced suppurative peritonitis and course of disease. We examined 79 patients with acute surgical abdominal diseases and injuries complicated by advanced suppurative peritonitis. Blood immunological parameters were estimated using flowing cytometry and enzyme immunoassay. It was concluded that functional parameters of immune system are very various in patients with advanced suppurative peritonitis. Cluster analysis defined 4 immune types which are determined by different state of congenital and acquired immunity. Immunodeficient and unreactive immune types are unfavorable. Immune types with activation of congenital and acquired immunity are the most favourable. This stratification personifies diagnosis and treatment of immune disorders in patients with advanced suppurative peritonitis.

  8. Polychlorinated Biphenyls (PCB 101, 153, and 180) Impair Murine Macrophage Responsiveness to Lipopolysaccharide: Involvement of NF-κB Pathway.

    PubMed

    Santoro, Anna; Ferrante, Maria C; Di Guida, Francesca; Pirozzi, Claudio; Lama, Adriano; Simeoli, Raffaele; Clausi, Maria T; Monnolo, Anna; Mollica, Maria Pina; Mattace Raso, Giuseppina; Meli, Rosaria

    2015-09-01

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are persistent organic pollutants, associated with a range of adverse health effects, including interference with the immune system. In this study, we investigate the capability of NDL-PCBs 101, 153, and 180, 3 of the 6 NDL-PCBs defined as indicators, to impair the immune response in lipopolysaccharide (LPS)-activated J774A.1 and primary murine macrophages. Our results clearly demonstrate that the exposure of J774A.1 and primary macrophages to NDL-PCB 153 or 180 or all NDL-PCBs mixtures causes a significant reduction in LPS-induced cytokine/chemokine synthesis, such as tumor necrosis factor-α and interleukin-6, together with monocyte chemoattractant protein-1, involved in cell recruitment. Moreover, PCBs were found to suppress LPS-stimulated NO production, and to reduce cyclooxygenase-2 and inducible nitric oxide synthase expression in J774A.1 and primary macrophages. At mechanistic level, PCBs significantly counteract the LPS-driven toll-like receptor (TLR) 4 and CD14 upregulation, therefore inhibiting downstream nuclear factor-κB (NF-κB) activation in J774A.1. Furthermore, PCBs determine a significant loss of macrophage endocytic capacity, a prerequisite for efficient antigen presentation. Taken together, these data indicate that NDL-PCBs reduce macrophage responsiveness, particularly when they are combined at concentrations per se inactive, impairing the capability to orchestrate a proper immune response to an infectious stimulus, disrupting TLR4/NF-κB pathway.

  9. Dectin-1 is required for miR155 upregulation in murine macrophages in response to Candida albicans.

    PubMed

    Agustinho, Daniel Paiva; de Oliveira, Marco Antônio; Tavares, Aldo Henrique; Derengowski, Lorena; Stolz, Valentina; Guilhelmelli, Fernanda; Mortari, Márcia Renata; Kuchler, Karl; Silva-Pereira, Ildinete

    2017-01-02

    The commensal fungal pathogen Candida albicans is a leading cause of lethal systemic infections in immunocompromised patients. One of the main mechanisms of host immune evasion and virulence by this pathogen is the switch from yeast form to hyphal growth morphologies. Micro RNAs (miRNAs), a small regulatory non-coding RNA, has been identified as an important part of the immune response to a wide variety of pathogens. In general, miRNAs act by modulating the intensity of inflammatory responses. miRNAs act by base-paring binding to specific sequences of target mRNAs, generally causing their silencing through mRNA degradation or translational repression. To study the impact of C. albicans cell morphology upon host miRNA expression, we investigated the differential modulation of 9 different immune response-related miRNAs in primary murine bone marrow-derived macrophages (BMDMs) exposed to either yeasts or hyphal forms of Candida albicans. Here, we show that the different growth morphologies induce distinct miRNA expression patterns in BMDMs. Interestingly, our data suggest that the C-Type lectin receptor Dectin-1 is a major PRR that orchestrates miR155 upregulation in a Syk-dependent manner. Our results suggest that PRR-mediating signaling events are key drivers of miRNA-mediated gene regulation during fungal pathogenesis.

  10. Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG.

    PubMed

    Song, Seng; Crow, Andrew R; Freedman, John; Lazarus, Alan H

    2003-05-01

    Intravenous immunoglobulin (IVIG) is used to treat immune thrombocytopenia resulting from a variety of autoimmune and nonautoimmune diseases such as idiopathic thrombocytopenic purpura (ITP), heparin-induced thrombocytopenia, and posttransfusion purpura. IVIG is a limited resource and although considered safe, may nevertheless carry some risk of transferring disease. Its high cost makes monoclonal antibodies, capable of mimicking the clinical effects of IVIG, highly desirable. We show here, using a murine model of ITP, that selected monoclonal antibodies can protect against thrombocytopenia. SCID mice were pretreated with 1 of 21 monoclonal antibodies before induction of thrombocytopenia by antiplatelet antibody. Four antibodies reacted with the CD24 antigen on erythrocytes. Two antibodies were of the IgM class, and although one IgM antibody caused a minimal degree of anemia (P <.05), neither antibody ameliorated immune thrombocytopenia. One of 2 anti-CD24 antibodies of the IgG class ameliorated immune thrombocytopenia and blocked reticuloendothelial system function at the same doses that protected against thrombocytopenia. Some antibodies reactive with other circulating cell types also protected against immune-mediated thrombocytopenia while no antibody without a distinct target antigen in the mice was protective. Protective monoclonal antibodies significantly prevented thrombocytopenia at down to a 1000-fold lower dose (200 microg/kg) as compared with standard IVIG treatment (2 g/kg). It is concluded that monoclonal IgG with specificity for a circulating cellular target antigen may provide an alternative therapeutic approach to treating immune thrombocytopenia.

  11. Roles of Toll-like receptors in innate immune responses.

    PubMed

    Takeda, K; Akira, S

    2001-09-01

    Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.

  12. Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery.

    PubMed

    Heidegger, Simon; Gössl, Dorothée; Schmidt, Alexandra; Niedermayer, Stefan; Argyo, Christian; Endres, Stefan; Bein, Thomas; Bourquin, Carole

    2016-01-14

    Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.

  13. Human Immune Responses to Dengue Viruses.

    DTIC Science & Technology

    1986-07-01

    AD-AISI 652 NUMAN IMMUNE RESPONSES TO DENGUE YIRUSES(U) / MASSACHUSETTS UNJY MEDICAL CENTER WORCESTER "A F A ENNIS 61 JUL 86 DRMDI?-82-C-2233...A S. PAGE COUNT Ie ..U rO l-9SJulyl (vw = T 21 Virus; Dengue ; Arbovirus; Immunology -- 4b he,. SAaaY~d the Interaction between the peripheral blood...lymphocytes (PBL) of non- 10m.0 deors ad dengue virus-Infected cells, which results in Interferon (113) production. AutelepMu mecyts@ or the Zpstein

  14. Monitoring Regulatory Immune Responses in Tumor Immunotherapy Clinical Trials

    PubMed Central

    Olson, Brian M.; McNeel, Douglas G.

    2013-01-01

    While immune monitoring of tumor immunotherapy often focuses on the generation of productive Th1-type inflammatory immune responses, the importance of regulatory immune responses is often overlooked, despite the well-documented effects of regulatory immune responses in suppressing anti-tumor immunity. In a variety of malignancies, the frequency of regulatory cell populations has been shown to correlate with disease progression and a poor prognosis, further emphasizing the importance of characterizing the effects of immunotherapy on these populations. This review focuses on the role of suppressive immune populations (regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) in inhibiting anti-tumor immunity, how these populations have been used in the immune monitoring of clinical trials, the prognostic value of these responses, and how the monitoring of these regulatory responses can be improved in the future. PMID:23653893

  15. Immune Response of Amebiasis and Immune Evasion by Entamoeba histolytica

    PubMed Central

    Nakada-Tsukui, Kumiko; Nozaki, Tomoyoshi

    2016-01-01

    Entamoeba histolytica is a protozoan parasite and the causative agent of amebiasis. It is estimated approximately 1% of humans are infected with E. histolytica, resulting in an estimate of 100,000 deaths annually. Clinical manifestations of amebic infection range widely from asymptomatic to severe symptoms, including dysentery and extra-intestinal abscesses. Like other infectious diseases, it is assumed that only ~20% of infected individuals develop symptoms, and genetic factors of both the parasite and humans as well as the environmental factors, e.g., microbiota, determine outcome of infection. There are multiple essential steps in amebic infection: degradation of and invasion into the mucosal layer, adherence to the intestinal epithelium, invasion into the tissues, and dissemination to other organs. While the mechanisms of invasion and destruction of the host tissues by the amebae during infection have been elucidated at the molecular levels, it remains largely uncharacterized how the parasite survive in the host by evading and attacking host immune system. Recently, the strategies for immune evasion by the parasite have been unraveled, including immunomodulation to suppress IFN-γ production, elimination of immune cells and soluble immune mediators, and metabolic alterations against reactive oxygen and nitrogen species to fend off the attack from immune system. In this review, we summarized the latest knowledge on immune reaction and immune evasion during amebiasis. PMID:27242782

  16. Immune Response of Amebiasis and Immune Evasion by Entamoeba histolytica.

    PubMed

    Nakada-Tsukui, Kumiko; Nozaki, Tomoyoshi

    2016-01-01

    Entamoeba histolytica is a protozoan parasite and the causative agent of amebiasis. It is estimated approximately 1% of humans are infected with E. histolytica, resulting in an estimate of 100,000 deaths annually. Clinical manifestations of amebic infection range widely from asymptomatic to severe symptoms, including dysentery and extra-intestinal abscesses. Like other infectious diseases, it is assumed that only ~20% of infected individuals develop symptoms, and genetic factors of both the parasite and humans as well as the environmental factors, e.g., microbiota, determine outcome of infection. There are multiple essential steps in amebic infection: degradation of and invasion into the mucosal layer, adherence to the intestinal epithelium, invasion into the tissues, and dissemination to other organs. While the mechanisms of invasion and destruction of the host tissues by the amebae during infection have been elucidated at the molecular levels, it remains largely uncharacterized how the parasite survive in the host by evading and attacking host immune system. Recently, the strategies for immune evasion by the parasite have been unraveled, including immunomodulation to suppress IFN-γ production, elimination of immune cells and soluble immune mediators, and metabolic alterations against reactive oxygen and nitrogen species to fend off the attack from immune system. In this review, we summarized the latest knowledge on immune reaction and immune evasion during amebiasis.

  17. Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

    PubMed Central

    Sriram, Uma; Haldar, Bijayesh; Cenna, Jonathan M.; Gofman, Larisa; Potula, Raghava

    2015-01-01

    Methamphetamine (METH) is a highly addictive psychostimulant that not only affects the brain and cognitive functions but also greatly impacts the host immune system, rendering the body susceptible to infections and exacerbating the severity of disease. Although there is gathering evidence about METH abuse and increased incidence of HIV and other viral infections, not much is known about the effects on the immune system in a chronic viral infection setting. We have used the lymphocytic choriomeningitis virus (LCMV) chronic mouse model of viral infection in a chronic METH environment and demonstrate that METH significantly increases CD3 marker on splenocytes and programmed death-1 (PD-1) expression on T cells, a cell surface signaling molecule known to inhibit T cell function and cause exhaustion in a lymphoid organ. Many of these METH effects were more pronounced during early stage of infection, which are gradually attenuated during later stages of infection. An essential cytokine for T-lymphocyte homeostasis, Interleukin-2 (IL-2) in serum was prominently reduced in METH-exposed infected mice. In addition, the serum pro-inflammatory (TNF, IL12 p70, IL1β, IL-6, and KC-GRO) and Th2 (IL-2, IL-10, and IL-4) cytokine profiles were also altered in the presence of METH. Interestingly CXCR3, an inflammatory chemokine receptor, showed significant increase in the METH treated LCMV infected mice. Similarly, compared to only infected mice, epidermal growth factor receptor (EGFR) in METH exposed LCMV infected mice were up regulated. Collectively, our data suggest that METH alters systemic, peripheral immune responses and modulates key markers on T cells involved in pathogenesis of chronic viral infection. PMID:26322025

  18. Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis.

    PubMed

    Izmailova, Elena S; Paz, Nancy; Alencar, Herlen; Chun, Miyoung; Schopf, Lisa; Hepperle, Michael; Lane, Joan H; Harriman, Geraldine; Xu, Yajun; Ocain, Timothy; Weissleder, Ralph; Mahmood, Umar; Healy, Aileen M; Jaffee, Bruce

    2007-01-01

    The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis. ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints. Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints. Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.

  19. Elastin receptor (S-gal) occupancy by elastin peptides modulates T-cell response during murine emphysema.

    PubMed

    Meghraoui-Kheddar, Aïda; Pierre, Alexandre; Sellami, Mehdi; Audonnet, Sandra; Lemaire, Flora; Le Naour, Richard

    2017-09-01

    Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production because of excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex that includes the elastin-binding protein spliced-galactosidase (S-gal). In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP-treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T-helper (Th) and T-cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the valine-glycine-valine-alanine-proline-glycine (VGVAPG) elastin peptide, and, 21 days after treatment, local and systemic T-lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4(+) and CD8(+) T cells expressing the cytokines IFN-γ or IL-17a and the transcription factors T-box expressed in T cells or retinoic acid-related orphan receptor-γt (RORγt) without effects on IL-4 and Gata-binding protein 3 to DNA sequence [A/T]GATA[A/G] expression. These effects were maximized when each T-cell subpopulation was challenged ex vivo with EP, and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that, during murine emphysema, EP-S-gal interactions contribute to a Th-1 and Th-17 proinflammatory T-cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response. Copyright © 2017 the American Physiological Society.

  20. Dissociation of Innate Immune Responses in Microglia Infected with Listeria monocytogenes

    PubMed Central

    Frande-Cabanes, Elisabet; Fernandez-Prieto, Lorena; Calderon-Gonzalez, Ricardo; Rodríguez-Del Río, Estela; Yañez-Diaz, Sonsoles; López-Fanarraga, Monica; Alvarez-Domínguez, Carmen

    2014-01-01

    Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)-regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)-inducible genes. The bacterial gene actA was required in microglia to induce TNF-regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF-α and monocyte chemotactic protein-1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF-mediated responses to preserve brain integrity. GLIA 2014;62:233–246 PMID:24311463

  1. Immunospecific responses to bacterial elongation factor Tu during Burkholderia infection and immunization.

    PubMed

    Nieves, Wildaliz; Heang, Julie; Asakrah, Saja; Höner zu Bentrup, Kerstin; Roy, Chad J; Morici, Lisa A

    2010-12-17

    Burkholderia pseudomallei is the etiological agent of melioidosis, a disease endemic in parts of Southeast Asia and Northern Australia. Currently there is no licensed vaccine against infection with this biological threat agent. In this study, we employed an immunoproteomic approach and identified bacterial Elongation factor-Tu (EF-Tu) as a potential vaccine antigen. EF-Tu is membrane-associated, secreted in outer membrane vesicles (OMVs), and immunogenic during Burkholderia infection in the murine model of melioidosis. Active immunization with EF-Tu induced antigen-specific antibody and cell-mediated immune responses in mice. Mucosal immunization with EF-Tu also reduced lung bacterial loads in mice challenged with aerosolized B. thailandensis. Our data support the utility of EF-Tu as a novel vaccine immunogen against bacterial infection.

  2. Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss

    PubMed Central

    Deshet-Unger, Naamit; Hiram-Bab, Sahar; Haim-Ohana, Yasmin; Mittelman, Moshe; Gabet, Yankel; Neumann, Drorit

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy, characterized by osteolytic lesions and monoclonal immunoglobulins. The anemia, accompanying the disease is often treated with recombinant human EPO. Diverse non-erythropoietic effects of EPO have led us to question its combined action on the immune system and bone in the 5T33MM mouse model. EPO administration to MM mice attenuated disease progression as demonstrated by a decrease in serum MM IgG2b, splenic CD138 expressing cells, IL-6 and RORγτ transcripts in bone marrow (BM). IFN-γ transcript levels and macrophages (F4/80+CD11b+) in the BM both increased ~1.5 fold in the EPO-treated MM mice. In-vitro, EPO stimulated phagocytosis of 5T33MM cells (+30%) by BM-derived macrophages. In contrast, high-resolution microCT analysis of distal femurs revealed EPO-associated bone loss in both healthy and 5T33MM mice. EPO significantly increased expression of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in healthy mice, but not in MM mice, likely due to antagonizing effects on MM progression. Thus, in MM, EPO may act as a double-edged-sword stimulating immune response, while accelerating bone resorption, possibly via direct action on BM macrophages. This study supports a prudent approach of treating anemia in MM patients, aiming to maintain EPO-associated anti-MM effects, while considering bone damage. PMID:27481313

  3. Multi-parameter flow cytometric analysis of uterine immune cell fluctuations over the murine estrous cycle.

    PubMed

    Diener, Kerrilyn R; Robertson, Sarah A; Hayball, John D; Lousberg, Erin L

    2016-02-01

    Investigating immune cell populations within various reproductive tissues commonly utilises flow cytometric methods. With advances in fluorophore technology and equipment capabilities, multiple cell types from a single tissue sample can be identified by using different combinations of cell surface markers to distinguish specific cell populations. Here a protocol optimized for mouse uterine tissue was used to show the proportional changes in dendritic cells, monocyte/macrophages, T and B cells, NK and NK T cells, and the granulocytes, neutrophils and eosinophils at each of the four stages of the estrous cycle. Importantly, we demonstrate that use of anti-SiglecF or assessment of FSC/SSC plots could be used to differentiate monocyte/macrophage and eosinophil populations that otherwise cannot be distinguished by use of the common combination of antibodies against F4/80 and CD11b. Our results clearly indicate that within the uterus a dynamic population of immune cells resides, with many cell types reaching peak abundance at estrus and metestrus phases of the cycle, consistent with their importance in the response to paternal antigens and/or pathogens encountered after insemination.

  4. Immune responses to coiled coil supramolecular biomaterials.

    PubMed

    Rudra, Jai S; Tripathi, Pulak K; Hildeman, David A; Jung, Jangwook P; Collier, Joel H

    2010-11-01

    Self-assembly has been increasingly utilized in recent years to create peptide-based biomaterials for 3D cell culture, tissue engineering, and regenerative medicine, but the molecular determinants of these materials' immunogenicity have remained largely unexplored. In this study, a set of molecules that self-assembled through coiled coil oligomerization was designed and synthesized, and immune responses against them were investigated in mice. Experimental groups spanned a range of oligomerization behaviors and included a peptide from the coiled coil region of mouse fibrin that did not form supramolecular structures, an engineered version of this peptide that formed coiled coil bundles, and a peptide-PEG-peptide triblock bioconjugate that formed coiled coil multimers and supramolecular aggregates. In mice, the native peptide and engineered peptide did not produce any detectable antibody response, and none of the materials elicited detectable peptide-specific T cell responses, as evidenced by the absence of IL-2 and interferon-gamma in cultures of peptide-challenged splenocytes or draining lymph node cells. However, specific antibody responses were elevated in mice injected with the multimerizing peptide-PEG-peptide. Minimal changes in secondary structure were observed between the engineered peptide and the triblock peptide-PEG-peptide, making it possible that the triblock's multimerization was responsible for this antibody response.

  5. Precision Immunization: NASA Studies Immune Response to Flu Vaccine

    NASA Image and Video Library

    NASA Human Research Program Twins Study investigator Emmanuel Mignot, M.D., Ph.D, known for discovering the cause of narcolepsy is related to the immune system, is studying twin astronauts Scott an...

  6. Neuroendocrine and Immune System Responses with Spaceflights

    NASA Technical Reports Server (NTRS)

    Tipton, Charles M.; Greenleaf, John E.; Jackson, Catherine G. R.

    1996-01-01

    Despite the fact that the first human was in space during 1961 and individuals have existed in a microgravity environment for more than a year, there are limited spaceflight data available on the responses of the neuroendocrine and immune systems. Because of mutual interactions between these respective integrative systems, it is inappropriate to assume that the responses of one have no impact on functions of the other. Blood and plasma volume consistently decrease with spaceflight; hence, blood endocrine and immune constituents will be modified by both gravitational and measurement influences. The majority of the in-flight data relates to endocrine responses that influence fluids and electrolytes during the first month in space. Adrenocorticotropin (ACTH), aldo-sterone. and anti-diuretic hormone (ADH) appear to be elevated with little change in the atrial natriuretic peptides (ANP). Flight results longer than 60 d show increased ADH variability with elevations in angiotensin and cortisol. Although post-flight results are influenced by reentry and recovery events, ACTH and ADH appear to be consistently elevated with variable results being reported for the other hormones. Limited in-flight data on insulin and growth hormone levels suggest they are not elevated to counteract the loss in muscle mass. Post-flight results from short- and long-term flights indicate that thyroxine and insulin are increased while growth hormone exhibits minimal change. In-flight parathyroid hormone (PTH) levels are variable for several weeks after which they remain elevated. Post-flight PTH was increased on missions that lasted either 7 or 237 d, whereas calcitonin concentrations were increased after 1 wk but decreased after longer flights. Leukocytes are elevated in flights of various durations because of an increase in neutrophils. The majority of post-flight data indicates immunoglobulin concentrations are not significantly changed from pre-flight measurements. However, the numbers of T

  7. Neuroendocrine and Immune System Responses with Spaceflights

    NASA Technical Reports Server (NTRS)

    Tipton, Charles M.; Greenleaf, John E.; Jackson, Catherine G. R.

    1996-01-01

    Despite the fact that the first human was in space during 1961 and individuals have existed in a microgravity environment for more than a year, there are limited spaceflight data available on the responses of the neuroendocrine and immune systems. Because of mutual interactions between these respective integrative systems, it is inappropriate to assume that the responses of one have no impact on functions of the other. Blood and plasma volume consistently decrease with spaceflight; hence, blood endocrine and immune constituents will be modified by both gravitational and measurement influences. The majority of the in-flight data relates to endocrine responses that influence fluids and electrolytes during the first month in space. Adrenocorticotropin (ACTH), aldo-sterone. and anti-diuretic hormone (ADH) appear to be elevated with little change in the atrial natriuretic peptides (ANP). Flight results longer than 60 d show increased ADH variability with elevations in angiotensin and cortisol. Although post-flight results are influenced by reentry and recovery events, ACTH and ADH appear to be consistently elevated with variable results being reported for the other hormones. Limited in-flight data on insulin and growth hormone levels suggest they are not elevated to counteract the loss in muscle mass. Post-flight results from short- and long-term flights indicate that thyroxine and insulin are increased while growth hormone exhibits minimal change. In-flight parathyroid hormone (PTH) levels are variable for several weeks after which they remain elevated. Post-flight PTH was increased on missions that lasted either 7 or 237 d, whereas calcitonin concentrations were increased after 1 wk but decreased after longer flights. Leukocytes are elevated in flights of various durations because of an increase in neutrophils. The majority of post-flight data indicates immunoglobulin concentrations are not significantly changed from pre-flight measurements. However, the numbers of T

  8. Effects of fly ash inhalation on murine immune function: changes in macrophage-mediated activities

    SciTech Connect

    Zarkower, A.; Eskew, M.L.; Scheuchenzuber, W.J.; Graham, J.A.

    1982-10-01

    Mice were exposed to fly ash particles (<2.1 ..mu..m diameter) by inhalation for variable amounts of time at concentrations ranging from 535 to 2221 ..mu..g/m/sup 3/. This fine fraction was approximately 32% by weight of the total dust generated. The effects of these exposures were assessed on macrophage-mediated functions. Phagocytosis of bacterial cells by the alveolar macrophages was depressed in the fly ash-exposed animals as was the ability to enhance T-cell mitogenesis. Fly ash exposure failed to produce a significant change in the cellular immune response (delayed-type hypersensitivity reaction) to antigenic challenge in the lungs of sensitized animals.

  9. Impact of nutrition on immune function and the inflammatory response

    USDA-ARS?s Scientific Manuscript database

    The review utilizes data on three micronutrients (vitamin A, zinc and iron), anthropometrically defined undernutrition (stunting, wasting and underweight) and obesity to evaluate the effect on immune function, recovery of immune function in response to nutritional interventions, related health outco...

  10. Anti-tumor immunity induced by CDR3-based DNA vaccination in a murine B-cell lymphoma model.

    PubMed

    Rinaldi, Monica; Fioretti, Daniela; Iurescia, Sandra; Signori, Emanuela; Pierimarchi, Pasquale; Seripa, Davide; Tonon, Giancarlo; Fazio, Vito Michele

    2008-05-30

    The idiotypic structure present on B-cell neoplasms is a tumor-specific antigen and an attractive target for immunotherapy. Here, the tumor protective effects recruited by CDR3-based DNA vaccines in the poorly immunogenic, highly aggressive 38C13 murine B-cell lymphoma model were evaluated. The regions belonging to the idiotypic V(H) and V(L) CDR3 sequences were chosen for the design of two synthetic mini-genes and arranged in high-level expression plasmids. Syngeneic C3H/HeN mice were immunized by intramuscular electroporation with pV(H)CDR3-IL-2 and pV(L)CDR3-IL-2 naked DNAs. This approach provided protection in about 60% of animals challenged with a 2-fold lethal dose of tumor cells, as opposed to non-survivors in control groups. Furthermore, a long-term survival was induced in these mice since they were still alive and tumor-free 4 months following tumor challenge. Analysis of the humoral immunity revealed the presence of antibodies reactive with the peptides encompassing the CDR3 sequences in the sera of vaccinated mice. Moreover, immune sera specifically reacted with the parental 38C13 tumor cells in flow cytometry assays, indicating that such immunization elicited anti-idiotypic antibodies. These findings provide a basis for exploring the use of CDR3-based DNA vaccines against B-cell lymphoma.

  11. Effects of anti-schistosomal chemotherapy on immune responses, protection and immunity. II. Concomitant immunity and immunization with irradiated cercariae

    SciTech Connect

    Tawfik, A.F.; Colley, D.G.

    1986-01-01

    Resistance of mice to challenge infections of Schistosoma mansoni was evaluated before and after elimination of their primary, established S. mansoni infections with the chemotherapeutic drug praziquantel. Mice treated after either 10 or 20 weeks of primary infection were challenged 6 or 10 weeks after treatment. Mice infected for for 10 weeks prior to treatment expressed progressively less resistance 6 and 10 weeks after treatment. By 10 weeks after treatment significant levels of protection were no longer observed. Resistance waned more slowly if mice were treated 20 weeks after infection, and there was still significant expression of resistance to challenge 10 weeks after treatment. A separate set of experiments evaluated the use of highly irradiated cercariae as a vaccine in mice that had been previously infected with S. mansoni and cured with praziquantel. It was observed that effective immunizations were possible in previously infected mice. These studies demonstrate that established resistance waned after treatment and the rate of loss of protection was dependent upon the duration of infection prior to treatment. Furthermore, the irradiated cercarial vaccine studies indicate that in the murine model induction of immunological resistance was feasible following chemotherapeutic treatment of infected populations.

  12. Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas.

    PubMed

    Hamilton, Melisa J; Bosiljcic, Momir; Lepard, Nancy E; Halvorsen, Elizabeth C; Ho, Victor W; Banáth, Judit P; Krystal, Gerald; Bennewith, Kevin L

    2014-01-01

    Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immune-suppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b(+)Gr1(+)F4/80(-)Ly6C(mid)Ly6G(+) MDSCs ("Gr1(+) cells") and mature CD11b(+)Gr1(-)F4/80(+) cells ("F4/80(+) cells") in metastatic target organs. ATRA triggered the differentiation of Gr1(+) cells into F4/80(+) cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80(+)Ly6C(-)Ly6G(-) mature macrophages (Ms) were up to 30-fold more potent immune suppressors than Gr1(+) cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80(+) cells and Gr1(+) cells used different reactive oxygen species (ROS)-mediated mechanisms of immunosuppression ex vivo, with F4/80(+) cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of Ms, reveal that Ms can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune responses. Our findings also caution against using ATRA to modulate myeloid cell differentiation and function to treat breast cancer metastases in the lung, and support the development of therapeutic strategies to enhance antitumor immunity by targeting myeloid cells as a collective group.

  13. Alpha-tocopherol transfer protein gene inhibition enhances the acquired immune response during malaria infection in mice.

    PubMed

    Herbas, Maria Shirley; Natama, Magloire Hamtandi; Suzuki, Hiroshi

    2014-03-01

    Immune response to malaria infection is complex and seems to be regulated by innate and adaptive immune response as well as environmental factors such as host genetics and nutritional status. Previously, we have reported that α-tocopherol transfer protein knockout (α-ttp(Δ)) mice, showing low concentrations of α-tocopherol in circulation, infected with Plasmodium berghei NK65 survived significantly longer as compared with the wild-type mice. In addition, Plasmodium yoelii XL-17, a lethal strain, showed non-lethal virulence in α-ttp(Δ) mice. Thus, we hypothesized that the ability of the α-ttp(Δ) mice to control P. yoelli XL-17 proliferation may allow them to build an efficient immune response against murine malaria infection. On 15 days after infection with P. yoelli XL-17, α-ttp(Δ) mice were challenged to infection with P. berghei NK65. Results indicated that α-ttp(Δ) mice infected with P. yoelli XL-17 built a protective immunity against P. berghei NK65 associated to extremely low levels of parasitemia, a controlled inflammatory response, and a robust antibody response. Moreover, the importance of α-tocopherol for parasite proliferation was remarkable. The results suggest that inhibition of α-tocopherol transfer protein activity is effective for the enhancement of acquired immunity in murine malaria infection.

  14. Somatostatin modulates mast cell-induced responses in murine spinal neurons and satellite cells.

    PubMed

    Van Op den bosch, Joeri; Van Nassauw, Luc; Van Marck, Eric; Timmermans, Jean-Pierre

    2009-08-01

    The course of intestinal inflammatory responses is tightly coordinated by the extensive communication between the immune system and the enteric nervous system, among which the bidirectional mast cell-neuron interaction within the intestinal wall plays a prominent role. Recent research suggests that somatostatin (SOM) is able to inhibit this self-reinforcing network by simultaneously suppressing the inflammatory activities of both neurons and mast cells. Therefore, we assessed the modulatory effects of SOM on both the short-term and long-term effects induced by the main mast cell mediators histamine (HIS) and 5-HT on spinal sensory neurons. Short-term incubation of dorsal root ganglion cultures with HIS and 5-HT induced neuronal CGRP-release and calcium-mediated activation of both neurons and nonneuronal cells, both of which effects were significantly reduced by SOM. In addition, SOM was also able to suppress the increased neuronal expression of pro- and anti-inflammatory peptides induced by long-term exposure to HIS and 5-HT. Immunocytochemical and molecular-biological experiments revealed the possible involvement of somatostatin receptor 1 (SSTR1) and SSTR2A in these profound SOM-dependent effects. These data, combined with the increased expression of pro- and anti-inflammatory peptides and several SSTRs in murine dorsal root ganglia following intestinal inflammation, reveal that intestinal inflammation not only induces the onset of proinflammatory cascades but simultaneously triggers endogenous systems destined to prevent excessive tissue damage. Moreover, these data provide for the first time functional evidence that SOM is able to directly modulate intestinal inflammatory responses by interference with the coordinating mast cell-neuron communication.

  15. Intrinsic differences in donor CD4 T cell IL-2 production influence severity of parent-into-F1 murine lupus by skewing the immune response either towards help for B cells and a sustained autoantibody response or towards help for CD8 T cells and a down regulatory Th1 response

    PubMed Central

    Soloviova, Kateryna; Puliaiev, Maksym; Haas, Mark; Dalgard, Clifton L.; Schaefer, Brian C.; Via, Charles S.

    2015-01-01

    Using the parent-into-F1 model of induced lupus and (C57Bl/6xDBA2) F1 mice as hosts, we compared the inherent lupus-inducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, non-lupus prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway characterized by IL-2/IFN-g expression, help for CD8 CTL, skewing of DC subsets towards CD8a DC, coupled with reduced CD4Tfh cells and transient B cell help. By contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway characterized by poor IL-2/IFN-g expression, poor help for CD8 CTL, skewing of DC subsets towards pDC coupled with greater CD4 Tfh cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IκBα and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and towards help for CTL may be beneficial. PMID:26320249

  16. Virus-like particle (VLP) lymphatic trafficking and immune response generation after immunization by different routes.

    PubMed

    Cubas, Rafael; Zhang, Sheng; Kwon, Sunkuk; Sevick-Muraca, Eva M; Li, Min; Chen, Changyi; Yao, Qizhi

    2009-01-01

    Virus-like particles (VLPs) have gained increasing interest for their use as vaccines due to their repetitive antigenic structure that is capable of efficiently activating the immune system. The efficacy of VLP immunization may lie in its ability to traffic into draining lymph nodes while activating antigen-presenting cells to initiate the orchestration of signals required for the development of a robust immune response. Currently, there is no comprehensive study showing the correlation of different VLP vaccination routes to immune outcome. In this study, we took an optical imaging approach to directly visualize the trafficking of simian-human immunodeficiency (SHIV) VLPs after immunization by commonly used routes and analyzed the corresponding humoral and cellular immune responses generated. We found that VLPs can easily enter the subcapsular sinus of draining lymph nodes with quantitative differences in the number of lymph node involvement depending on the immunization route used. Intradermal immunization led to the largest level of lymph node involvement for the longest period of time, which correlated with the strongest humoral and cellular immune responses. Flow cytometry analysis from extracted splenocytes showed that intradermal immunization led to the largest population of germinal center and activated B cells, which translated into higher antibody levels and antigen-specific cytotoxic T lymphocyte responses. Our results indicate that VLPs traffic into lymph nodes upon immunization and can be directly visualized by optical imaging techniques. Intradermal immunization showed improved responses and might be a preferable delivery route to use for viral and cancer immunotherapeutic studies involving VLPs.

  17. Reversal of age-associated decline in immune response to Pnu-imune vaccine by supplementation with the steroid hormone dehydroepiandrosterone.

    PubMed Central

    Garg, M; Bondada, S

    1993-01-01

    Recently, we reported that murine antibody responses to the 23-valent pneumococcal polysaccharide (Pnu-Imune) vaccine declined with age. Here we present data to support the concept that age-associated immune defects are not only due to intrinsic defects in immune cells but are also due to extrinsic factors emanating from the neuroendocrine system. We found that supplementation with dehydroepiandrosterone, a steroid hormone known to be reduced in the aged, corrects the immune deficiency of aged mice and significantly enhanced their splenic immune responses to the Pnu-Imune vaccine. PMID:8478117

  18. Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation1

    PubMed Central

    Keppel, Molly P.; Yang, Liping; Cooper, Megan A.

    2013-01-01

    Several recent studies have demonstrated that innate immune NK cells exhibit memory-like properties with enhanced non-specific and specific recall responses. Cytokine activation alone of murine NK cells induces the differentiation of memory-like cells that are more likely to produce IFN-γ, a key NK cell cytokine important for activation of the immune response. Using an adoptive co-transfer system, we first show that cytokine-induced memory-like responses are NK intrinsic. However, engraftment of donor NK cells in NK-competent hosts is poor due to homeostatic control mechanisms. Therefore, we utilized alymphoid Rag- and common gamma chain (γc)-deficient mice as recipients and observed homeostatic expansion of co-transferred cytokine-activated and control donor NK cells. Despite proliferation of all cells, NK cells derived from those cells originally activated by cytokines retained an intrinsic enhanced capacity to produce IFN-γ when re-stimulated in vitro with cytokines or target cells. These NK cell memory-like responses persisted for at least 4 weeks in alymphoid hosts and 12 weeks in NK-competent hosts. These findings indicate that memory-like NK cells can readily self-renew and maintain enhanced function in a lymphopenic host for at least a month. PMID:23530145

  19. Ability of Brucella abortus rough vaccine strains to elicit DC and innate immunity in lung using a murine respiratory model.

    PubMed

    Surendran, Naveen; Zimmerman, Kurt; Seleem, Mohamed N; Sriranganathan, Nammalwar; Boyle, Stephen M; Hiltbold, Elizabeth M; Lawler, Heather; Heid, Bettina; Witonsky, Sharon G

    2010-10-08

    Brucella abortus strains RB51 and RB51SOD are live attenuated vaccine strains which protect mice against virulent B. abortus strain 2308 intraperitoneal challenge. By comparison, limited information is available on how Brucella vaccines stimulate pulmonary immunity against respiratory infection, another route of exposure in humans. Therefore, in this study, we assessed the ability of intranasally delivered vaccine strains RB51 and RB51SOD to induce innate immunity. Based on parameters assessed, rough strain RB51 induces a better innate immune response in lung versus strain RB51SOD. Additional studies to further delineate strain RB51's ability to stimulate DC and adaptive immunity are warranted.

  20. Ontogeny of the Bovine Immune Response 1

    PubMed Central

    Schultz, R. D.; Dunne, H. W.; Heist, C. E.

    1973-01-01

    The ontogenesis of the bovine immune response was studied in three embryos (<40 days) and 106 fetuses of various ages. In the absence of overt antigenic stimulation, fetuses had lymphoid development of the thymus at 42 days of gestation, the spleen was structurally present at 55 days, and certain peripheral lymph nodes were present at 60 days. Mesenteric lymph nodes were structurally present by 100 days of gestation, and lymphoid tissue of the gastrointestinal tract, particularly the lower ileum, was observed in histologic sections of a 175-day fetus with a bacterial infection. Pyroninophilic cells, plasma cells, and germinal centers were present in lymph node sections of antigenically stimulated fetuses. Lymphoid tissue developed more rapidly in fetuses with bacteria, viral antigens, or apparent maternal red-blood-cell antigens than in the normal fetus. Thymic and splenic indices reached maximal values in the 205- to 220-day fetal age group. Immunoglobulin M (IgM)-containing cells were first observed, by immunofluorescence, in a single fetus at 59 days of gestation. Immunoglobulin G (IgG)-containing cells were observed at 145 days of gestation in one fetus with a bacterial and viral infection. IgM-containing cells were observed in 36 fetuses and IgM and IgG cells were present in seven fetuses. Spleen, lymph nodes, thymus, bone marrow, and liver of one fetus from a dam with lymphosarcoma had immunoglobulin-containing cells. Hemal lymph nodes, blood (buffy coat), Peyer patches, and heart and lung sections from fetuses with immunoglobulin-containing cells in spleen or lymph node did not have immunoglobulin-containing cells. Antigens of the virus of bovine virus diarrhea-mucosal disease (BVD) were detected in one fetus, and antigens of infectious bovine rhinotracheitis (IBR) virus were detected in three fetuses; however, viruses were not isolated in primary bovine embryonic kidney cells. Two of the three fetuses with IBR virus antigens had neutralizing serum antibody

  1. Local Immune Response in Helicobacter pylori Infection

    PubMed Central

    Kivrak Salim, Derya; Sahin, Mehmet; Köksoy, Sadi; Adanir, Haydar; Süleymanlar, Inci

    2016-01-01

    Abstract There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori–infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC). In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines—interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32—in H pylori–infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients. We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori–infected NGM group. This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients. PMID:27196487

  2. Immune response in the turtle (Chrysemys picta)

    PubMed Central

    Coe, J. E.

    1972-01-01

    The immune response of painted turtles (Chrysemys picta) to four purified protein antigens was evaluated by radioimmunoelectrophoresis. Specific antibody production was consistently detected and antigen binding was related to four immunoglobulin (Ig) precipitin lines (called Ig1, 2, 3, 4) in turtle serum. Antibody activity was detected first in the Ig1 or Ig2 and then later in the course of immunization in Ig3 and Ig4. Ig1 was about 19S in size, was not detectable after reduction and alkylation, and was the only Ig absent from turtle lymph. Ig3 and Ig4 were about 7S in size and Ig2 appeared slightly heavier by sucrose density gradient and Sephadex G-200 analysis. Haemagglutinins produced after primary inoculation were routinely sensitive to mild reduction and alkylation although antigen-binding capacity was still detectable. However, mercaptoethanol-resistant haemagglutinins were found in sera from turtles after booster injections of antigen. The electrophoretically slowest gamma globulin in turtle serum did not develop specific antigen-binding capacity, but did bind Fe59 and presumably represents a transferrin-like protein. ImagesFIG. 1FIG. 2FIG. 4 PMID:4114647

  3. Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response

    PubMed Central

    Bajgar, Adam; Kucerova, Katerina; Jonatova, Lucie; Tomcala, Ales; Schneedorferova, Ivana; Okrouhlik, Jan; Dolezal, Tomas

    2015-01-01

    Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune response. To combat the invasion, the host must produce specialized immune cells (lamellocytes) that destroy the parasitoid egg. We show that a significant portion of nutrients are allocated to differentiating lamellocytes when they would otherwise be used for development. This systemic metabolic switch is mediated by extracellular adenosine released from immune cells. The switch is crucial for an effective immune response. Preventing adenosine transport from immune cells or blocking adenosine receptor precludes the metabolic switch and the deceleration of development, dramatically reducing host resistance. Adenosine thus serves as a signal that the “selfish” immune cells send during infection to secure more energy at the expense of other tissues. PMID:25915062

  4. The immune response and its therapeutic modulation in bronchiectasis.

    PubMed

    Daheshia, Massoud; Prahl, James D; Carmichael, Jacob J; Parrish, John S; Seda, Gilbert

    2012-01-01

    Bronchiectasis (BC) is a chronic pulmonary disease with tremendous morbidity and significant mortality. As pathogen infection has been advocated as a triggering insult in the development of BC, a central role for the immune response in this process seems obvious. Inflammatory cells are present in both the airways as well as the lung parenchyma, and multiple mediators of immune cells including proteases and cytokines or their humoral products are increased locally or in the periphery. Interestingly, a defect in the immune system or suppression of immune response during conditions such as immunodeficiency may well predispose one to the devastating effects of BC. Thus, the outcome of an active immune response as detrimental or protective in the pathogenesis of BC may be dependent on the state of the patient's immunity, the severity of infection, and the magnitude of immune response. Here we reassess the function of the innate and acquired immunity in BC, the major sites of immune response, and the nature of the bioactive mediators. Furthermore, the potential link(s) between an ongoing immune response and structural alterations accompanying the disease and the success of therapies that can modulate the nature and extent of immune response in BC are elaborated upon.

  5. Transplantation of syngeneic transfected cells to probe the in vivo immune response to viral proteins

    SciTech Connect

    Nakayama, Hiroyuki; Shibata, Motohiro; Wohlenberg, C.; Rooney, J.F.; Notkins, A.L. )

    1991-01-01

    BALB/3T3 cells were transfected with the glycoprotein D (gD) gene of herpes simplex virus (HSV) and a cell line expressing gD on the cell surface was isolated. In vitro, {sup 51}Cr release tests showed that the transfected cells were destroyed by anti-HSV antibody in the presence of complement. To investigate in vivo immune response, the gD-transfected cells were transplanted into the footpads of syngeneic HSV-immunized or unimmunized BALB/c mice. In unimmunized mice, transfected cells remained intact for 7 days or longer, and the site of injection showed only slight lymphocyte infiltration. In contrast, in immunized mice, transfected cells elicited massive lymphocyte infiltration and were mostly destroyed by day 4. Analysis of infiltrating cells revealed that they were mainly Thy1{sup +} and CD8{sup +} lymphocytes along with small numbers of CD5{sup +}, CD4{sup +}, and B lymphocytes. These studies show that transfected murine cells expressing gD can be used to study the in vivo immune response to single viral proteins and they argue that the immune response contributes to the pathogenesis of HSV infection.

  6. Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs).

    PubMed

    Spekker, K; Leineweber, M; Degrandi, D; Ince, V; Brunder, S; Schmidt, S K; Stuhlsatz, S; Howard, J C; Schares, G; Degistirici, O; Meisel, R; Sorg, R V; Seissler, J; Hemphill, A; Pfeffer, K; Däubener, W

    2013-06-01

    Mesenchymal stromal cells (MSCs) have a multilineage differentiation potential and provide immunosuppressive and antimicrobial functions. Murine as well as human MSCs restrict the proliferation of T cells. However, species-specific differences in the underlying molecular mechanisms have been described. Here, we analyzed the antiparasitic effector mechanisms active in murine MSCs. Murine MSCs, in contrast to human MSCs, could not restrict the growth of a highly virulent strain of Toxoplasma gondii (BK) after stimulation with IFN-γ. However, the growth of a type II strain of T. gondii (ME49) was strongly inhibited by IFN-γ-activated murine MSCs. Immunity-related GTPases (IRGs) as well as guanylate-binding proteins (GBPs) contributed to this antiparasitic effect. Further analysis showed that IFN-γ-activated mMSCs also inhibit the growth of Neospora caninum, a parasite belonging to the apicomplexan group as well. Detailed studies with murine IFN-γ-activated MSC indicated an involvement in IRGs like Irga6, Irgb6 and Irgd in the inhibition of N. caninum. Additional data showed that, furthermore, GBPs like mGBP1 and mGBP2 could have played a role in the anti-N. caninum effect of murine MSCs. These data underline that MSCs, in addition to their regenerative and immunosuppressive activity, function as antiparasitic effector cells as well. However, IRGs are not present in the human genome, indicating a species-specific difference in anti-T. gondii and anti-N. caninum effect between human and murine MSCs.

  7. Cell-autonomous stress responses in innate immunity.

    PubMed

    Moretti, Julien; Blander, J Magarian

    2017-01-01

    The innate immune response of phagocytes to microbes has long been known to depend on the core signaling cascades downstream of pattern recognition receptors (PRRs), which lead to expression and production of inflammatory cytokines that counteract infection and induce adaptive immunity. Cell-autonomous responses have recently emerged as important mechanisms of innate immunity. Either IFN-inducible or constitutive, these processes aim to guarantee cell homeostasis but have also been shown to modulate innate immune response to microbes and production of inflammatory cytokines. Among these constitutive cell-autonomous responses, autophagy is prominent and its role in innate immunity has been well characterized. Other stress responses, such as metabolic stress, the ER stress/unfolded protein response, mitochondrial stress, or the DNA damage response, seem to also be involved in innate immunity, although the precise mechanisms by which they regulate the innate immune response are not yet defined. Of importance, these distinct constitutive cell-autonomous responses appear to be interconnected and can also be modulated by microbes and PRRs, which add further complexity to the interplay between innate immune signaling and cell-autonomous responses in the mediation of an efficient innate immune response.

  8. Donor dendritic cell–derived exosomes promote allograft-targeting immune response

    PubMed Central

    Rojas-Canales, Darling M.; Divito, Sherrie J.; Shufesky, William J.; Stolz, Donna Beer; Erdos, Geza; Sullivan, Mara L.G.; Gibson, Gregory A.; Larregina, Adriana T.; Morelli, Adrian E.

    2016-01-01

    The immune response against transplanted allografts is one of the most potent reactions mounted by the immune system. The acute rejection response has been attributed to donor dendritic cells (DCs), which migrate to recipient lymphoid tissues and directly activate alloreactive T cells against donor MHC molecules. Here, using a murine heart transplant model, we determined that only a small number of donor DCs reach lymphoid tissues and investigated how this limited population of donor DCs efficiently initiates the alloreactive T cell response that causes acute rejection. In our mouse model, efficient passage of donor MHC molecules to recipient conventional DCs (cDCs) was dependent on the transfer of extracellular vesicles (EVs) from donor DCs that migrated from the graft to lymphoid tissues. These EVs shared characteristics with exosomes and were internalized or remained attached to the recipient cDCs. Recipient cDCs that acquired exosomes became activated and triggered full activation of alloreactive T cells. Depletion of recipient cDCs after cardiac transplantation drastically decreased presentation of donor MHC molecules to directly alloreactive T cells and delayed graft rejection in mice. These findings support a key role for transfer of donor EVs in the generation of allograft-targeting immune responses and suggest that interrupting this process has potential to dampen the immune response to allografts. PMID:27348586

  9. Human anti-murine antibody responses in ovarian cancer patients undergoing radioimmunotherapy with the murine monoclonal antibody OC-125

    SciTech Connect

    Muto, M.G.; Finkler, N.J.; Kassis, A.I.; Lepisto, E.M.; Knapp, R.C. )

    1990-08-01

    Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-dose intraperitoneal radioimmunotherapy (RIT) with the murine monoclonal antibody OC-125. Sera of patients receiving escalating doses of OC-125 F(ab')2 (10-70 mg) radiolabeled with 18 to 141 mCi of iodine-131 were assayed for HAMA by a protein A-based radioimmunoassay. Overall, 70% of patients (16/23) developed HAMA within 10 to 46 days (median = 29) postinfusion, with peak values (23 +/- 6 to 325 +/- 10 micrograms/ml) at 32 to 102 days (median = 38). HAMA was undetectable prior to infusion in all cases and persisted up to 76 weeks. Of patients receiving a dose of 123 mCi or less, 80% (16/20) developed HAMA, whereas in the 140-mCi group, none of the three patients had detectable levels. Two patients in the 140-mCi group demonstrated dose-limiting bone marrow toxicity (severe thrombocytopenia and neutropenia). It is concluded that a single intraperitoneal dose of monoclonal antibody leads to a high incidence of HAMA production. The results also suggest that the likelihood of HAMA formation in patients who either had undergone recent chemotherapy or had received the highest dose of the radioimmunoconjugate is reduced. These observations may be of significance in designing multiple-dose therapy trials as HAMA has been demonstrated to decrease antibody-to-tumor binding and may potentially increase renal, hepatic, and hematologic toxicity associated with radioimmunotherapy.

  10. Meeting report VLPNPV: Session 3: Immune responses.

    PubMed

    Morrison, Trudy G

    2014-01-01

    Virus-like particles (VLPs) and nano-particles (NP) are increasingly considered for both prophylactic and therapeutic vaccines for a wide variety of human and animal diseases. Indeed, 2 VLPs have already been licensed for use in humans, the human papilloma virus vaccine and the hepatitis B virus vaccine. (1) Reflecting this increased interest, a second international conference with a specific focus on VLPs and NP was held at the Salk Institute for Biological Studies in La Jolla, California, in June 2014. Approximately 100 attendees, hailing from many nations, came from academic institutions, research institutes, and biotech companies. A wide variety of topics were discussed, ranging from development and characterization of specific VLP and NP vaccine candidates to methods of production of these particles. Session three was focused on the general question of immune responses to VLPs.

  11. Natural selection on immune responsiveness in blue tits Parus caeruleus.

    PubMed

    Råberg, Lars; Stjernman, Martin

    2003-07-01

    What is the form of natural selection on immune responsiveness? For a population at evolutionary equilibrium, there are two different scenarios. First, it is generally assumed that immune defense has both benefits and costs. If variation in immune responsiveness is due to variation in how individuals trade off these costs and benefits, one would expect immune responsiveness to be subject to stabilizing selection. Second, it is well known that an individual's immune responsiveness is often dependent on its overall condition. If immune responsiveness is condition-dependent, one would expect immune responsiveness to be under positive directional selection. We would therefore expect that the form of natural selection on immune responsiveness depends on the relative magnitude of these two sources of variation: variation in how individuals trade off the costs and benefits of defense, and variation in condition. We measured primary and secondary antibody responsiveness to diphtheria-tetanus vaccine in blue tits during winter and investigated the relationship between responsiveness and survival to the following breeding season. We use responsiveness to these antigens as measures of an individual's ability or propensity to mount an antibody response in case of an infection. Interestingly, different measures of responsiveness were subject to different selective regimes: primary responsiveness to diphtheria was subject to stabilizing selection, whereas secondary responsiveness to tetanus was subject to positive directional selection. In contrast, there was no significant selection on primary responsiveness to tetanus or secondary responsiveness to diphtheria. The finding of stabilizing selection on a measure of responsiveness is evidence that immune defense can incur fitness costs; a central but little-tested assumption of theories of the ecology and evolution of immunological defense. The finding of directional selection on a measure of responsiveness is consistent with the

  12. Immune response of pregnant cows to bovine rotavirus immunization.

    PubMed

    Saif, L J; Smith, K L; Landmeier, B J; Bohl, E H; Theil, K W; Todhunter, D A

    1984-01-01

    Fifteen pregnant Holstein cows were freely assigned to 3 experimental groups (5 cows in each group). Cows in group I were inoculated IM and intramammarily (IMm) with Ohio Agricultural Research and Development Center (OARDC) tissue culture-propagated modified-live Nebraska calf diarrhea bovine rotavirus with added adjuvant (OARDC vaccine-immunized cows). Group II cows were given IM injections of a commercial modified-live rotavirus-coronavirus vaccine (commercial vaccine-immunized cows), and the remaining 5 cows were noninoculated controls (group III). Rotavirus antibody in colostrum and milk was mainly associated with immunoglobulin (Ig)G1, and less so with IgG2, IgA, and IgM, as analyzed by the enzyme-linked immunosorbent assay (ELISA), using monospecific anti-bovine IgG1, IgG2, IgM, and IgA sera. In serum, the rotavirus antibody was distributed almost equally between IgG1 and IgG2. The same relationships appeared in both immunized and nonvaccinated cows. All OARDC vaccine-injected cows had virus-neutralization (VN) and ELISA IgG1 rotavirus antibody titers in serum and mammary secretions at significantly increased levels (at least 100-fold; P less than 0.05) compared with the titers in groups II (commercial vaccine-immunized cows) and III (controls). Serum, colostrum, and milk antibody titers from these latter 2 groups did not differ statistically. The ELISA IgG2, IgA, and IgM rotavirus antibody titers also were significantly greater in mammary secretions from OARDC vaccine-immunized cows than in groups II and III cows. There was a high correlation between ELISA IgG1 and VN rotavirus antibody titers for all samples tested (r = 0.97, P less than 0.001), but ELISA IgG1 antibody titers were consistently higher than VN titers. The ELISA IgG1 and VN antibody titers of milk samples collected from cows 30 days after parturition were higher from the OARDC vaccine-immunized cows (ELISA IgG1, geometric mean titer (GMT) = 3,511; VN GMT = 1,689) than were titers from the

  13. Chemical agents and the immune response.

    PubMed Central

    Luster, M I; Rosenthal, G J

    1993-01-01

    Our desire to understand the potential adverse human health effects of environmental chemical exposure has coincided with an increased understanding of the immune system and an appreciation of its complex regulatory network. This has spawned a broad interest in the area of immunotoxicology within the scientific community as well as certain concerns in the public sector regarding chemical-induced hypersensitivity and immunosuppression. The incidence of alleged human sensitization to chemicals has increased, in part, due to the fact that chemical companies are moving to larger and/or different markets. It has been estimated that 35 million Americans suffer from allergic disease, of which 2-5% are from occupational exposure. Although there is not yet a clear understanding of dose-response relationships or disease predisposition, there are many well-defined examples (isocyanates, anhydrides) of chemical sensitizers in humans and experimental animals. Evidence that chemicals suppress immune responses in humans is considerably less well established, although there is a public perception that chemicals generally cause immunosuppression. This perception has been fueled by highly publicized legal cases and scientific controversies within the academic and industrial communities. As a consequence of these public and scientific concerns, many of the regulatory agencies are developing immunotoxicity testing guidelines. At the present, however, there are limitations on adequate human methodology and data that allow the extrapolation of animal data to assess human risk. The potential for human immunosuppression remains of concern, however, because of a large database generated from animal studies that demonstrates immunosuppression as well as reports of immunosuppression in humans inadvertently (e.g., halogenated aromatic hydrocarbons) or occupationally (asbestos, benzene) exposed to xenobiotics.(ABSTRACT TRUNCATED AT 250 WORDS) Images FIGURE 1. PMID:8354170

  14. Population-expression models of immune response

    NASA Astrophysics Data System (ADS)

    Stromberg, Sean P.; Antia, Rustom; Nemenman, Ilya

    2013-06-01

    The immune response to a pathogen has two basic features. The first is the expansion of a few pathogen-specific cells to form a population large enough to control the pathogen. The second is the process of differentiation of cells from an initial naive phenotype to an effector phenotype which controls the pathogen, and subsequently to a memory phenotype that is maintained and responsible for long-term protection. The expansion and the differentiation have been considered largely independently. Changes in cell populations are typically described using ecologically based ordinary differential equation models. In contrast, differentiation of single cells is studied within systems biology and is frequently modeled by considering changes in gene and protein expression in individual cells. Recent advances in experimental systems biology make available for the first time data to allow the coupling of population and high dimensional expression data of immune cells during infections. Here we describe and develop population-expression models which integrate these two processes into systems biology on the multicellular level. When translated into mathematical equations, these models result in non-conservative, non-local advection-diffusion equations. We describe situations where the population-expression approach can make correct inference from data while previous modeling approaches based on common simplifying assumptions would fail. We also explore how model reduction techniques can be used to build population-expression models, minimizing the complexity of the model while keeping the essential features of the system. While we consider problems in immunology in this paper, we expect population-expression models to be more broadly applicable.

  15. Fetal immune response following prematurely ruptured membranes.

    PubMed

    Cederqvist, L L; Francis, L C; Zervoudakis, I A; Becker, C G; Litwin, S D

    1976-10-01

    Concentrations of immunoglobulins (Ig)A1, and IgA2, IgD, IgE, IgG, and IgM have been determined in cord blood, amniotic fluid, and maternal serum in a group of patients with a history of prematurely ruptured membranes (PRM) prior to the onset of labor and in a control group of patients undergoing normal delivery and without a history of infection during pregnancy. IgA and IgD were determined by sensitive hemagglutination-inhibition tests; IgG and IgM, by radial immunodiffusion; IgE, by a radioimmunoassay. There was evidence for an immune response in 10 of 16 cases of PRM: five of 16 had increased IgA but normal IgM; three of 16 had increased IgA and IgM; two of 16 had high IgM and normal IgA in cord blood. In patients with significantly increased levels of either IgA or IgM or both, there was a decreased level of IgD. These changes are most likely the result of the immune response to ascending infection from the maternal genitals. The sensitive testing method employed could demonstrate the presence of IgD in 53 per cent of normal cord blood samples and 72 per cent of amniotic fluid samples obtained at term. IgE was found in all normal cord blood and amniotic fluid samples tested. By concentrating the amniotic fluid up to 180-fold, IgM was demonstrated in all normal samples tested. The potential importance of IgA determinations in cord blood in addition to IgM determination for detection of intrauterine infections is stressed.

  16. The innate immune response to adjuvants dictates the adaptive immune response to autoantigens.

    PubMed

    Staykova, Maria A; Liñares, David; Fordham, Susan A; Paridaen, Judith T; Willenborg, David O

    2008-06-01

    To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant. In BN and PVG rats, there were numerous inflammatory lesions with prominent involvement of microglia and, to a lesser extent, perivascular macrophages. These data suggest that different levels of activation of the innate immune system by different adjuvants determine whether EAE will or will not develop. Accordingly, the widely accepted scale of susceptibility to EAE development (Lewis > PVG > BN) should be revised because it does not take into account the important contribution of the composition of the adjuvant to the quality and quantity of the innate immune response and, consequently, to the generation and extent of the pathogenic T-cell-mediated, that is, adaptive, autoimmune disease.

  17. Immune Responses to HCV and Other Hepatitis Viruses

    PubMed Central

    Park, Su-Hyung; Rehermann, Barbara

    2014-01-01

    Summary Five human hepatitis viruses cause most acute and chronic liver disease worldwide. Over the past 25 years hepatitis C virus (HCV) in particular has received much interest because of its ability to persist in most immunocompetent adults and the lack of a protective vaccine. Here we examine innate and adaptive immune responses to HCV infection. Although HCV activates an innate immune response, it employs an elaborate set of mechanisms to evade interferon (IFN)-based antiviral immunity. By comparing innate and adaptive immune responses to HCV with those to hepatitis A and B viruses, we suggest that prolonged innate immune activation impairs the development of successful adaptive immune responses. Comparative immunology furthermore provides insights into the maintenance of immune protection. We conclude by discussing prospects for an HCV vaccine and future research needs for the hepatitis viruses. PMID:24439265

  18. Essential oil of clove (Eugenia caryophyllata) augments the humoral immune response but decreases cell mediated immunity.

    PubMed

    Halder, Sumita; Mehta, Ashish K; Mediratta, Pramod K; Sharma, Krishna K

    2011-08-01

    The present study was undertaken to explore the effect of the essential oil isolated from the buds of Eugenia caryophyllata on some immunological parameters. Humoral immunity was assessed by measuring the hemagglutination titre to sheep red blood cells and delayed type hypersensitivity was assessed by measuring foot pad thickness. Clove oil administration produced a significant increase in the primary as well as secondary humoral immune response. In addition, it also produced a significant decrease in foot pad thickness compared with the control group. Thus, these results suggest that clove oil can modulate the immune response by augmenting humoral immunity and decreasing cell mediated immunity.

  19. Time of appearance and distribution of cells capable of secondary immune response following primary immunization

    PubMed Central

    Vischer, T. L.; Stastny, P.

    1967-01-01

    Immunological memory was studied by measurement of tritiated thymidine incorporation in tissue culture. After primary immunization with keyhole limpet haemocyanin (KLH) secondary responsiveness could be detected as early as the 2nd day after immunization with Freund's adjuvant into the footpads and on the 4th day after injection of KLH intravenously. In each case immunological memory developed first in the area of the injection, that is, the popliteal lymph nodes after footpad immunization and the spleen after intravenous injection. The secondary response could also be detected in the lymphoid cells of the blood. Cell suspensions enriched in small lymphocytes showed a similar reactivity. Cells from the thymus, however, did not develop immunological memory. Rabbits immunized with BSA showed a relatively weaker response which was clearly detectable only when Freund's adjuvant was used for immunization. The results suggest that a response essentially of a secondary type may play an important role in what is usually considered the primary immune response. PMID:6027423

  20. Staphylococcus aureus strategies to evade the host acquired immune response.

    PubMed

    Goldmann, Oliver; Medina, Eva

    2017-09-15

    Staphylococcus aureus poses a significant public-health problem. Infection caused by S. aureus can manifest as acute or long-lasting persistent diseases that are often refractory to antibiotic and are associated with significant morbidity and mortality. To develop more effective strategies for preventing or treating these infections, it is crucial to understand why the immune response is incapable to eradicate the bacterium. When S. aureus first infect the host, there is a robust activation of the host innate immune responses. Generally, S. aureus can survive this initial interaction due to the expression of a wide array of virulence factors that interfere with the host innate immune defenses. After this initial interaction the acquired immune response is the arm of the host defenses that will try to clear the pathogen. However, S. aureus is capable of maintaining infection in the host even in the presence of a robust antigen-specific immune response. Thus, understanding the mechanisms underlying the ability of S. aureus to escape immune surveillance by the acquired immune response will help uncover potentially important targets for the development of immune-based adjunctive therapies and more efficient vaccines. There are several lines of evidence that lead us to believe that S. aureus can directly or indirectly disable the acquired immune response. This review will discuss the different immune evasion strategies used by S. aureus to modulate the different components of the acquired immune defenses. Copyright © 2017 Elsevier GmbH. All rights reserved.

  1. Obligatory role of gamma interferon in T cell-replacing factor- dependent, antigen-specific murine B cell responses

    PubMed Central

    1985-01-01

    The role of gamma interferon (IFN-gamma) in T cell-replacing factor (TRF) activity for antigen-specific plaque-forming cell (PFC) responses in vitro was studied using antibodies to murine IFN-gamma (Mu IFN- gamma). TRF activity was present in supernatants (Sn) of Con A- or mixed leukocyte reaction-stimulated murine spleen cells as well as in an IL-2-rich fraction of phytohemagglutinin-stimulated human peripheral blood lymphocyte Sn and in the Sn of the Gibbon T lymphoma MLA-144. The human TRF was highly active with cells from nu/nu mice and normal mice but not with cells from animals with the xid immunologic defect, similar to the activity of murine TRF. Antibodies to IFN-gamma consisted of hyper-immune rabbit antisera, IFN-gamma affinity-purified rabbit immunoglobulin and an interspecies hybridoma specific for Mu IFN- gamma. The results show that the activities of all preparations of TRF are markedly diminished or abrogated by antibody to Mu IFN-gamma but not by antibodies to human IFN-gamma (Hu IFN-gamma), nor by normal rabbit sera or purified rabbit Ig. The degree of inhibition was dose dependent and was quantitatively reversed by the addition to the cultures of recombinant-derived Mu IFN-gamma (Mu rIFN-gamma) but not Hu rIFN-gamma. This reversal was fully antigen specific and thus not attributable to polyclonal B cell activation by IFN-gamma, which is inactive alone in the TRF assay. Kinetic analysis shows that IFN-gamma must act by 24-48 h to produce PFC responses at 4 d. Together, the data demonstrate that IFN-gamma is a necessary mediator for TRF effects and that IFN-gamma is induced by TRF from T-depleted murine spleen cells in sufficient quantity to support large antibody responses. The source of this IFN-gamma may be the potent natural killer cells that are induced in cultures stimulated with TRF. PMID:2580939

  2. Boosting BCG with inert spores improves immunogenicity and induces specific IL-17 responses in a murine model of bovine tuberculosis.

    PubMed

    Garcia-Pelayo, M Carmen; Kaveh, Daryan A; Sibly, Laura; Webb, Paul R; Bull, Naomi C; Cutting, Simon M; Hogarth, Philip J

    2016-05-01

    Tuberculosis (TB) remains a global pandemic, in both animals and man, and novel vaccines are urgently required. Heterologous prime-boost of BCG represents a promising strategy for improved TB vaccines, with respiratory delivery the most efficacious to date. Such an approach may be an ideal vaccination strategy against bovine TB (bTB), but respiratory vaccination presents a technical challenge in cattle. Inert bacterial spores represent an attractive vaccine vehicle. Therefore we evaluated whether parenterally administered spores are efficacious when used as a BCG boost in a murine model of immunity against Mycobacterium bovis. Here we report the use of heat-killed, TB10.4 adsorbed, Bacillus subtilis spores delivered via subcutaneous injection to boost immunity primed by BCG. We demonstrate that this approach improves the immunogenicity of BCG. Interestingly, this associated with substantial boosting of IL-17 responses; considered to be important in protective immunity against TB. These data demonstrate that parenteral delivery of spores represents a promising vaccine vehicle for boosting BCG, and identifies potential for optimisation for use as a vaccine for bovine TB.

  3. Mycobacterium-Induced Potentiation of Type 1 Immune Responses and Protection against Malaria Are Host Specific

    PubMed Central

    Page, Kathleen R.; Jedlicka, Anne E.; Fakheri, Benjamin; Noland, Gregory S.; Kesavan, Anup K.; Scott, Alan L.; Kumar, Nirbhay; Manabe, Yukari C.

    2005-01-01

    Malaria and tuberculosis are endemic in many regions of the world, and coinfection with the two pathogens is common. In this study, we examined the effects of long- and short-term infection with Mycobacterium tuberculosis on the course of a lethal form of murine malaria in resistant (C57BL/6) and susceptible (BALB/c) mice. C57BL/6 mice coinfected with M. tuberculosis CDC1551 and Plasmodium yoelii 17XL had a lower peak parasitemia and increased survival compared to mice infected with P. yoelii 17XL alone. Splenic microarray analysis demonstrated potentiation of type 1 immune responses in coinfected C57BL/6 mice, which was especially prominent 5 days after infection with P. yoelii 17XL. Splenocytes from coinfected C57BL/6 mice produced higher levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha than splenocytes from mice infected with either pathogen alone. Interestingly, mycobacterium-induced protection against lethal P. yoelii is mouse strain specific. BALB/c mice were significantly more susceptible than C57BL/6 mice to infection with P. yoelii 17XL and were not protected against lethal malaria by coinfection with M. tuberculosis. In addition, M. tuberculosis did not augment IFN-γ responses in BALB/c mice subsequently infected with P. yoelii 17XL. These data indicate that M. tuberculosis-induced potentiation of type 1 immune responses is associated with protection against lethal murine malaria. PMID:16299335

  4. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.

    PubMed

    Crow, A R; Song, S; Semple, J W; Freedman, J; Lazarus, A H

    2001-12-01

    Although the mechanism of action of intravenous immunoglobulin (IVIg) in treating antibody-dependent thrombocytopenia remains unclear, most studies have suggested that IVIg blocks the function of Fc receptors in the reticuloendothelial system (RES) and/or the protective effect may be due to the presence of variable region-reactive (anti-idiotype) antibodies within IVIg. We evaluated the effect of IVIg on platelet counts in a murine model of passively induced immune thrombocytopenia (PIT). Although IVIg was unable to neutralize the binding of two platelet-specific monoclonal antibodies to their target antigens either in vivo or in vitro, it was able to prevent PIT as well as ameliorate pre-established PIT mediated by these antibodies. IVIg adsorbed against the antibody used to induce thrombocytopenia or endogenous murine immunoglobulin also protected against PIT, indicating that antibodies with anti-idiotype activity present in IVIg are not necessary for its effective treatment of PIT. IVIg significantly blocked the ability of the RES to clear antibody-sensitized red blood cells. F(ab')2 fragments of IVIg, which are unable to block the RES but retain the idiotypic regions, were ineffective at protecting mice from PIT. Our data suggest that IVIg exerts its rapid effect by inhibiting RES function and that anti-idiotype interactions are not required.

  5. Evaluation of zinc salt based fixatives for preserving antigenic determinants for immunohistochemical demonstration of murine immune system cell markers.

    PubMed

    Hicks, D J; Johnson, L; Mitchell, S M; Gough, J; Cooley, W A; La Ragione, R M; Spencer, Y I; Wangoo, A

    2006-01-01

    Conventional aldehyde based fixatives produce good morphological preservation. However, owing to their cross-linking mechanism of action, epitope loss may occur during fixation compromising the tissue for subsequent immunohistochemical (IHC) analysis. IHC is an important tool for characterizing antigen, cytokine and cytomorphological markers. The increasing use of mouse models for study of pathogenesis has highlighted the need to investigate alternative fixatives. In the study reported here, tissue samples from RIII mice with immune mediated lesions, Mycobacterium bovis infected mice, and uninfected control mice were fixed in either zinc salt fixative or buffered formalin, then tested for IHC using a panel of antibodies (CD3, CD4, CD8, CD45, CD54, F4/80, Interferon-gamma and MIP2). Zinc salt fixation preserved processing-sensitive murine cell markers (CD4, CD8 and CD54) and improved the intensity of immunolabeling for CD45, F4/80 and CD3. Buffered formalin failed to preserve any of the processing-sensitive murine epitopes for demonstration by subsequent IHC.

  6. Tumor escape from immune response: mechanisms and targets of activity.

    PubMed

    Gabrilovich, Dmitry; Pisarev, Vladimir

    2003-10-01

    Immune system plays an important role in control of tumor progression. Effective antitumor immune response depends on close interaction of several elements of immune system. They include antigen-presenting cells, different subsets of T cells, B cells and NK cells. However, tumor cells developed a number of mechanisms to escape recognition and elimination by immune system. In this review we will discuss these mechanisms and address possible approaches to correct them.

  7. Opioid peptides and innate immune response in mollusc.

    PubMed

    Liu, Dong-Wu

    2008-01-01

    The nervous and the immune systems can exchange information through opioid peptides. Furthermore, some opioid peptides can function as endogenous messengers of the immune system, and participate in an important part in the regulation of the various components of the immune response. Since the capacity of immunocytes to release and respond to opioid neuropeptide messengers is not restricted to mammalian organisms, recent studies have indicated that invertebrate models have been particularly useful to understand the mechanisms of the immune response. Moreover, the immunocytes of molluscs resemble cells of the vertebrate monocyte/macrophage lineage and are activated by similar substances, which control the main immune responses, i.e. phagocytosis, chemotaxis, and cytotoxicity. Recently, Mytilus edulis has been the subject of recent studies to determine whether the relationship between the immune and nervous systems seen in vertebrates also exists in invertebrates. The focus of this review is to describe how the opioid peptides participate in immune processes in molluscs.

  8. GENETIC CONTROL OF THE IMMUNE RESPONSE

    PubMed Central

    McDevitt, Hugh O.; Deak, Beverly D.; Shreffler, Donald C.; Klein, Jan; Stimpfling, Jack H.; Snell, George D.

    1972-01-01

    Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2y, was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus. PMID:4554451

  9. Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

    PubMed Central

    Holladay, S D; Smialowicz, R J

    2000-01-01

    Fetal and early postnatal life represent critical periods in vertebrate immune system development. Disruption of such development by perinatal immunotoxic chemical exposure has been widely described in experimental animal models. The resultant inhibited postnatal immune responses in such animals are often more dramatic and persistent than those after exposure during adult life. Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate postnatal aberrant immune responses (e.g., hypersensitivity disorders and autoimmune disease) in genetically predisposed rodents. Limited information is available regarding the possibility of inhibited postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The multifactorial nature of hypersensitivity and autoimmune responses will further complicate the elucidation of possible relationships between chemical exposure during ontogeny of the human immune system and immune-mediated disease later in life. Taken together, however, the available animal data suggest the potential for altered postnatal immune function in humans exposed to immunotoxicants (e.g., environmental chemicals and therapeutic agents) during fetal and/or early postnatal life. PMID:10852846

  10. Spaceflight and immune responses of rhesus monkeys

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald; Morton, Darla S.; Swiggett, Jeanene P.; Hakenewerth, Anne M.; Fowler, Nina A.

    1995-01-01

    The effects of restraint on immunological parameters was determined in an 18 day ARRT (adult rhesus restraint test). The monkeys were restrained for 18 days in the experimental station for the orbiting primate (ESOP), the chair of choice for Space Shuttle experiments. Several immunological parameters were determined using peripheral blood, bone marrow, and lymph node specimens from the monkeys. The parameters included: response of bone marrow cells to GM-CSF (granulocyte-macrophage colony stimulating factor), leukocyte subset distribution, and production of IFN-a (interferon-alpha) and IFN-gamma (interferon-gamma). The only parameter changed after 18 days of restraint was the percentage of CD8+ T cells. No other immunological parameters showed changes due to restraint. Handling and changes in housing prior to the restraint period did apparently result in some restraint-independent immunological changes. Handling must be kept to a minimum and the animals allowed time to recover prior to flight. All experiments must be carefully controlled. Restraint does not appear to be a major issue regarding the effects of space flight on immune responses.

  11. Spaceflight and Immune Responses of Rhesus Monkeys

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1997-01-01

    In the grant period, we perfected techniques for determination of interleukin production and leukocyte subset analysis of rhesus monkeys. These results are outlined in detail in publication number 2, appended to this report. Additionally, we participated in the ARRT restraint test to determine if restraint conditions for flight in the Space Shuttle could contribute to any effects of space flight on immune responses. All immunological parameters listed in the methods section were tested. Evaluation of the data suggests that the restraint conditions had minimal effects on the results observed, but handling of the monkeys could have had some effect. These results are outlined in detail in manuscript number 3, appended to this report. Additionally, to help us develop our rhesus monkey immunology studies, we carried out preliminary studies in mice to determine the effects of stressors on immunological parameters. We were able to show that there were gender-based differences in the response of immunological parameters to a stressor. These results are outlined in detail in manuscript number 4, appended to this report.

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

    PubMed

    Skyberg, Jerod A; Thornburg, Theresa; Rollins, Maryclare; Huarte, Eduardo; Jutila, Mark A; Pascual, David W

    2011-01-01

    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.

  13. Oral administration of an Enoki mushroom protein FVE activates innate and adaptive immunity and induces anti-tumor activity against murine hepatocellular carcinoma.

    PubMed

    Chang, Hui-Hsin; Hsieh, Kuang-Yang; Yeh, Chen-Hao; Tu, Yuan-Ping; Sheu, Fuu

    2010-02-01

    FVE is a documented immunomodulatory protein purified from Enoki mushroom (Flammulina velutipes) and known as an activator for human T lymphocytes. This present study was aimed to investigate the anti-tumor effect and the related mechanisms of oral administration of FVE using a murine hepatoma model. Oral administration of FVE (10mg/kg) significantly increased the life span and inhibited the tumor size of BNL 1MEA.7R.1 (BNL) hepatoma-bearing mice. Tumor-bearing mice receiving oral FVE treatment had the highest tumoricidal capacity of peritoneal macrophages and tumor-specific splenocytes against BNL hepatoma cells. In addition, in vivo neutralization of interferon-gamma (IFN-gamma) demonstrated a significant decrease of FVE-induced anti-tumor effect (P<0.05). The expression levels of major histocompatibility complex (MHC) class I and II molecules and costimulatory molecule CD80 on peripheral blood mononuclear cells obtained from the FVE-treated mice were upregulated as compared with those of the PBS-treated mice. Furthermore, immunohistochemical staining showed a strong inhibition of tumor growth and angiogenesis in hepatoma tissues after oral administration of FVE. Taken together, oral administration of FVE displayed anti-tumor activity through activating both innate and adaptive immunity of the host to prime a cytotoxic immune response and IFN-gamma played a key role in the anti-tumor efficacy of FVE. Copyright 2009 Elsevier B.V. All rights reserved.

  14. Intratumoural GM-CSF microspheres and CTLA-4 blockade enhance the antitumour immunity induced by thermal ablation in a subcutaneous murine hepatoma model.

    PubMed

    Chen, Zubing; Shen, Shiqiang; Peng, Baogang; Tao, Jianpin

    2009-08-01

    We evaluated the effect of a new antitumour immunity regimen that included microwave ablation, intratumoural microspheres encapsulating granulocyte-macrophage colony stimulating factor (GM-CSF), and blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). C57BL6 mice with an established subcutaneous Hepa 1-6 hepatoma underwent microwave ablation, followed by intratumoural injection of GM-CSF microspheres, and intraperitoneal injection of anti-CTLA-4 antibodies. The therapeutic effects were evaluated by tumour growth, survival analysis, and cytotoxicity of T lymphocytes against Hepa 1-6. The co-administration of microwave thermal ablation, GM-CSF microspheres, and anti-CTLA-4 rejected tumour rechallenge in 90% of treated mice in a subcutaneous murine Hepa 1-6 model, and cured established distant tumour in 50% of the treated mice. This antitumour immune response was tumour-specific and mediated by natural killer (NK), CD4+, and CD8+ T cells. Microwave ablation, followed by intratumoural GM-CSF microspheres, and anti-CTLA-4 antibodies results in the local eradication of tumours, rejection of tumours following rechallenge, and cures established distant tumours, suggesting that this is a promising regimen and one that is readily applicable in the clinic.

  15. Maternal antibodies reduce costs of an immune response during development.

    PubMed

    Grindstaff, Jennifer L

    2008-03-01

    Young vertebrates are dependent primarily on innate immunity and maternally derived antibodies for immune defense. This reliance on innate immunity and the associated inflammatory response often leads to reduced growth rates after antigenic challenge. However, if offspring have maternal antibodies that recognize an antigen, these antibodies should block stimulation of the inflammatory response and reduce growth suppression. To determine whether maternal and/or offspring antigen exposure affect antibody transmission and offspring growth, female Japanese quail (Coturnix japonica) and their newly hatched chicks were immunized. Mothers were immunized with lipopolysaccharide (LPS), killed avian reovirus vaccine (AR), or were given a control, phosphate-buffered saline, injection. Within each family, one-third of offspring were immunized with LPS, one-third were immunized with AR, and one-third were given the control treatment. Maternal immunization significantly affected the specific types of antibodies that were transmitted. In general, immunization depressed offspring growth. However, offspring immunized with the same antigen as their mother exhibited elevated growth in comparison to siblings immunized with a different antigen. This suggests that the growth suppressive effects of antigen exposure during development can be partially ameliorated by the presence of maternal antibodies, but in the absence of specific maternal antibodies, offspring are dependent on more costly innate immune defenses. Together, the results suggest that the local disease environment of mothers prior to reproduction significantly affects maternal antibody transmission and these maternal antibodies may allow offspring to partially maintain growth during infection in addition to providing passive humoral immune defense.

  16. Immune function trade-offs in response to parasite threats.

    PubMed

    Kirschman, Lucas J; Quade, Adam H; Zera, Anthony J; Warne, Robin W

    2017-04-01

    Immune function is often involved in physiological trade-offs because of the energetic costs of maintaining constitutive immunity and mounting responses to infection. However, immune function is a collection of discrete immunity factors and animals should allocate towards factors that combat the parasite threat with the highest fitness cost. For example, animals on dispersal fronts of expanding population may be released from density-dependent diseases. The costs of immunity, however, and life history trade-offs in general, are often context dependent. Trade-offs are often most apparent under conditions of unusually limited resources or when animals are particularly stressed, because the stress response can shift priorities. In this study we tested how humoral and cellular immune factors vary between phenotypes of a wing dimorphic cricket and how physiological stress influences these immune factors. We measured constitutive lysozyme activity, a humoral immune factor, and encapsulation response, a cellular immune factor. We also stressed the crickets with a sham predator in a full factorial design. We found that immune strategy could be explained by the selective pressures encountered by each morph and that stress decreased encapsulation, but not lysozyme activity. These results suggest a possible trade-off between humoral and cellular immunity. Given limited resources and the expense of immune factors, parasite pressures could play a key factor in maintaining insect polyphenism via disruptive selection.

  17. Protective efficacy of Mycobacterium indicus pranii against tuberculosis and underlying local lung immune responses in guinea pig model.

    PubMed

    Gupta, Ankan; Ahmad, F J; Ahmad, Faiz; Gupta, U D; Natarajan, M; Katoch, V M; Bhaskar, Sangeeta

    2012-09-21

    Tuberculosis kills two million people each year. As the current vaccine BCG fails to prevent adult cases of TB, an improved vaccine and/or vaccination strategy is urgently needed to combat TB. Previously we reported the higher protective efficacy of Mycobacterium indicus pranii (MIP), formerly known as Mycobacterium w (M.w) as compared to BCG in murine model of TB. In this study we further evaluated the protective efficacy of MIP in guinea pig model of TB. Modulation of post infection immune response was analyzed in the lungs of MIP immunized and control groups. We found reduced bacterial loads, improved pathology and organized granulomatous response at different post infection time points in the MIP-immunized group as compared to the BCG-immunized group. Combined results suggest that MIP-immunization results in heightened protective Th1 response as compared to BCG group, early after infection with M.tb and a balanced Th1 versus immunosuppressive response at late chronic stage of infection. The study demonstrates the higher antigen presenting cells function both inside the granuloma as well as in the single cell suspension of the lung in the MIP-immunized group. We further demonstrate that live MIP is safe to use in vivo as we observed quick clearance of MIP from the body and no untoward reaction was found. Aerosol route of immunization provided higher protection. Further this study provides evidence that MIP-immunization gives significantly better long term protection as compared to BCG against TB.

  18. APRIL:TACI axis is dispensable for the immune response to rabies vaccination.

    PubMed

    Haley, Shannon L; Tzvetkov, Evgeni P; Lytle, Andrew G; Alugupalli, Kishore R; Plummer, Joseph R; McGettigan, James P

    2017-08-01

    There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent

  19. Nasal immunization with major epitope-containing ApxIIA toxin fragment induces protective immunity against challenge infection with Actinobacillus pleuropneumoniae in a murine model.

    PubMed

    Seo, Ki-Weon; Kim, Sae-Hae; Park, Jisang; Son, Youngok; Yoo, Han Sang; Lee, Kyung-Yeol; Jang, Yong-Suk

    2013-01-15

    Actinobacillus pleuropneumoniae is an infective agent that leads to porcine pleuropneumonia, a disease that causes severe economic losses in the swine industry. Based on the fact that the respiratory tract is the primary site for bacterial infection, it has been suggested that bacterial exclusion in the respiratory tract through mucosal immune induction is the most effective disease prevention strategy. ApxIIA is a vaccine candidate against A. pleuropneumoniae infection, and fragment #5 (aa. 439-801) of ApxIIA contains the major epitopes for effective vaccination. In this study, we used mice to verify the efficacy of intranasal immunization with fragment #5 in the induction of protective immunity against nasal challenge with A. pleuropneumoniae and compared its efficacy with that of subcutaneous immunization. Intranasal immunization of the fragment induced significantly higher systemic and mucosal immune responses measured at the levels of antigen-specific antibodies, cytokine-secreting cells after antigen exposure, and antigen-specific lymphocyte proliferation. Intranasal immunization not only efficiently inhibited the bacterial colonization in respiratory organs, but also prevented alveolar tissue damage in infectious condition similar to that of a contaminated pig. Moreover, intranasal immunization with fragment #5 provided acquired protective immunity against intranasal challenge with A. pleuropneumoniae serotype 2. In addition, it conferred cross-protection against serotype 5, a heterologous pathogen that causes severe disease by ApxI and ApxII secretion. Collectively, intranasal immunization with fragment #5 of ApxIIA can be considered an efficient protective immunization procedure against A. pleuropneumoniae infection. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. The reciprocal link between sleep and immune responses.

    PubMed

    Del Gallo, F; Opp, M R; Imeri, L

    2014-01-01

    Good sleep is necessary for both physical and mental health; sleep and immune responses are reciprocally and closely linked. Sleep loss impairs the immune response, while, on the other hand, the immune response, activated for instance by an infection, alters sleep. Sleep alterations induced by immune activation are mediated by cytokines such as interleukin-1. In the past, it was thought that cytokines were produced only by the immune system, and active only there as signaling molecules. Today it is clear that IL-1 and other cytokines are present and active in the healthy brain, where they physiologically interact with the brain circuits and the neurotransmitter systems (for instance the serotonergic, GABAergic, and cholinergic systems) that control sleep. These interactions are altered by immune response, and, as a result, non-rapid eye movement (NREM) sleep is increased and fragmented, whereas rapid eye movements (REM) sleep is inhibited.

  1. B cell function in the immune response to helminths

    PubMed Central

    Harris, Nicola

    2010-01-01

    Similar T helper (Th)2-type immune responses are generated against different helminths parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important durin