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Sample records for inducing sterilizing immunity

  1. Steric-electronic effects in malarial peptides inducing sterile immunity

    SciTech Connect

    Moreno-Vranich, Armando; Patarroyo, Manuel E.

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Is it evident that the residues position are relevant regarding of {phi} angular value. Black-Right-Pointing-Pointer The geometry considered for detailing the alterations undergone by HABPs. Black-Right-Pointing-Pointer The inter planar interactions ruled by clashes between the atoms making them up. -- Abstract: Conserved Plasmodium falciparum high activity binding peptides' (HABPs) most relevant proteins involved in malaria parasite invasion are immunologically silent; critical binding residues must therefore be specifically replaced to render them highly immunogenic and protection-inducing. Such changes have a tremendous impact on these peptides' steric-electronic effects, such as modifications to peptide length peptide bonds and electronic orbitals' disposition, to allow a better fit into immune system MHCII molecules and better interaction with the TCR which might account for the final immunological outcome.

  2. Cellular and humoral immune effector mechanisms required for sterile protection against sporozoite challenge induced with the novel malaria vaccine candidate CelTOS.

    PubMed

    Bergmann-Leitner, Elke S; Legler, Patricia M; Savranskaya, Tatyana; Ockenhouse, Christian F; Angov, Evelina

    2011-08-11

    The malarial protein CelTOS, for cell-traversal protein for ookinetes and sporozoites, from Plasmodium berghei has been shown to mediate malarial invasion of both vertebrate and insect host cells and is required for establishing their successful infections. In the vertebrate host, Plasmodium sporozoites traverse via a complex passage through cellular barriers in the skin and the liver sinusoid to infect hepatocytes. Induction of immunity targeted to molecules involved in sporozoite motility and migration into hepatocytes may lead to abrogation of hepatocyte infection. We have previously demonstrated the potential of CelTOS as a target antigen for a pre-erythrocytic vaccine. The objective of the current study was to determine the potency of different vaccine platforms to induce protective immunity and determine the mode of action in protective immune responses. To this end, inbred Balb/c and outbred ICR mice were immunized with either the recombinant protein adjuvanted with Montanide ISA-720 or with a pCI-TPA plasmid encoding the P. berghei CelTOS (epidermal delivery by gene-gun) and assessed for the induction of protective responses against a homologous P. berghei challenge. Humoral and cellular immune responses induced by the various immunization regimens were evaluated in an effort to establish immune correlates. The results confirm that the CelTOS antigen is a potentially interesting pre-erythrocytic vaccine candidate and demonstrate that both arms of the adaptive immune system are required to mediate complete sterile protection against sporozoite challenge. PMID:21722682

  3. Secretion of Protective Antigens by Tissue-Stage Nematode Larvae Revealed by Proteomic Analysis and Vaccination-Induced Sterile Immunity

    PubMed Central

    Hewitson, James P.; Ivens, Al C.; Harcus, Yvonne; Filbey, Kara J.; McSorley, Henry J.; Murray, Janice; Bridgett, Stephen; Ashford, David; Dowle, Adam A.; Maizels, Rick M.

    2013-01-01

    Gastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen. Adults release immunomodulatory excretory-secretory (ES) products, but mice immunised with adult H. polygyrus ES become fully immune to challenge infection. ES products of the intestinal wall 4th stage (L4) larvae are similarly important in host-parasite interactions, as they readily generate sterile immunity against infection, while released material from the egg stage is ineffective. Proteomic analyses of L4 ES identifies protective antigen targets as well as potential tissue-phase immunomodulatory molecules, using as comparators the adult ES proteome and a profile of H. polygyrus egg-released material. While 135 proteins are shared between L4 and adult ES, 72 are L4 ES-specific; L4-specific proteins correspond to those whose transcription is restricted to larval stages, while shared proteins are generally transcribed by all life cycle forms. Two protein families are more heavily represented in the L4 secretome, the Sushi domain, associated with complement regulation, and the ShK/SXC domain related to a toxin interfering with T cell signalling. Both adult and L4 ES contain extensive but distinct arrays of Venom allergen/Ancylostoma secreted protein-Like (VAL) members, with acetylcholinesterases (ACEs) and apyrase APY-3 particularly abundant in L4 ES. Serum antibodies from mice vaccinated with L4 and adult ES react strongly to the VAL-1 protein and to ACE-1, indicating that these two antigens represent major vaccine targets for this intestinal nematode. We have thus defined an extensive and novel repertoire of H

  4. Secretion of protective antigens by tissue-stage nematode larvae revealed by proteomic analysis and vaccination-induced sterile immunity.

    PubMed

    Hewitson, James P; Ivens, Al C; Harcus, Yvonne; Filbey, Kara J; McSorley, Henry J; Murray, Janice; Bridgett, Stephen; Ashford, David; Dowle, Adam A; Maizels, Rick M

    2013-08-01

    Gastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen. Adults release immunomodulatory excretory-secretory (ES) products, but mice immunised with adult H. polygyrus ES become fully immune to challenge infection. ES products of the intestinal wall 4th stage (L4) larvae are similarly important in host-parasite interactions, as they readily generate sterile immunity against infection, while released material from the egg stage is ineffective. Proteomic analyses of L4 ES identifies protective antigen targets as well as potential tissue-phase immunomodulatory molecules, using as comparators the adult ES proteome and a profile of H. polygyrus egg-released material. While 135 proteins are shared between L4 and adult ES, 72 are L4 ES-specific; L4-specific proteins correspond to those whose transcription is restricted to larval stages, while shared proteins are generally transcribed by all life cycle forms. Two protein families are more heavily represented in the L4 secretome, the Sushi domain, associated with complement regulation, and the ShK/SXC domain related to a toxin interfering with T cell signalling. Both adult and L4 ES contain extensive but distinct arrays of Venom allergen/Ancylostoma secreted protein-Like (VAL) members, with acetylcholinesterases (ACEs) and apyrase APY-3 particularly abundant in L4 ES. Serum antibodies from mice vaccinated with L4 and adult ES react strongly to the VAL-1 protein and to ACE-1, indicating that these two antigens represent major vaccine targets for this intestinal nematode. We have thus defined an extensive and novel repertoire of H

  5. Atomic evidence that modification of H-bonds established with amino acids critical for host-cell binding induces sterile immunity against malaria

    SciTech Connect

    Patarroyo, Manuel E.; Cifuentes, Gladys; Pirajan, Camilo; Moreno-Vranich, Armando; Vanegas, Magnolia

    2010-04-09

    Based on the 3D X-ray crystallographic structures of relevant proteins of the malaria parasite involved in invasion to host cells and 3D NMR structures of High Activity Binding Peptides (HABPs) and their respective analogues, it was found that HABPs are rendered into highly immunogenic and sterile immunity inducers in the Aotus experimental model by modifying those amino acids that establish H-bonds with other HABPs or binding to host's cells. This finding adds striking and novel physicochemical principles, at the atomic level, for a logical and rational vaccine development methodology against infectious disease, among them malaria.

  6. 3D Analysis of the TCR/pMHCII Complex Formation in Monkeys Vaccinated with the First Peptide Inducing Sterilizing Immunity against Human Malaria

    PubMed Central

    López, Carolina; Yepes, Gloria; Patarroyo, Manuel E.

    2010-01-01

    T-cell receptor gene rearrangements were studied in Aotus monkeys developing high antibody titers and sterilizing immunity against the Plasmodium falciparum malaria parasite upon vaccination with the modified synthetic peptide 24112, which was identified in the Merozoite Surface Protein 2 (MSP-2) and is known to bind to HLA-DRβ1*0403 molecules with high capacity. Spectratyping analysis showed a preferential usage of Vβ12 and Vβ6 TCR gene families in 67% of HLA-DRβ1*0403-like genotyped monkeys. Docking of peptide 24112 into the HLA-DRβ1*0401–HA peptide–HA1.7TCR complex containing the VDJ rearrangements identified in fully protected monkeys showed a different structural signature compared to nonprotected monkeys. These striking results show the exquisite specificity of the TCR/pMHCII complex formation needed for inducing sterilizing immunity and provide important hints for a logical and rational methodology to develop multiepitopic, minimal subunit-based synthetic vaccines against infectious diseases, among them malaria. PMID:20333301

  7. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity

    PubMed Central

    Chuang, Ilin; Sedegah, Martha; Cicatelli, Susan; Spring, Michele; Polhemus, Mark; Tamminga, Cindy; Patterson, Noelle; Guerrero, Melanie; Bennett, Jason W.; McGrath, Shannon; Ganeshan, Harini; Belmonte, Maria; Farooq, Fouzia; Abot, Esteban; Banania, Jo Glenna; Huang, Jun; Newcomer, Rhonda; Rein, Lisa; Litilit, Dianne; Richie, Nancy O.; Wood, Chloe; Murphy, Jittawadee; Sauerwein, Robert; Hermsen, Cornelus C.; McCoy, Andrea J.; Kamau, Edwin; Cummings, James; Komisar, Jack; Sutamihardja, Awalludin; Shi, Meng; Epstein, Judith E.; Maiolatesi, Santina; Tosh, Donna; Limbach, Keith; Angov, Evelina; Bergmann-Leitner, Elke; Bruder, Joseph T.; Doolan, Denise L.; King, C. Richter; Carucci, Daniel; Dutta, Sheetij; Soisson, Lorraine; Diggs, Carter; Hollingdale, Michael R.; Ockenhouse, Christian F.; Richie, Thomas L.

    2013-01-01

    Background Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. Methodology/Principal Findings The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44–817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5–102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13–408; AMA1 348, range 88–1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. Significance The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was

  8. Long-term persistence of sterile immunity in a volunteer immunized with X-irradiated Plasmodium falciparum sporozoites.

    PubMed

    Edelman, R; Hoffman, S L; Davis, J R; Beier, M; Sztein, M B; Losonsky, G; Herrington, D A; Eddy, H A; Hollingdale, M R; Gordon, D M

    1993-10-01

    Three volunteers were immunized by repeated exposure to the bites of Plasmodium falciparum-infected, X-irradiated mosquitoes to characterize immunologic responses and duration of protective immunity. A primary series of immunizations had been shown previously to induce sterile immunity in these volunteers against sporozoite-induced P. falciparum malaria. In the current study, antibodies to sporozoites circulated at high levels for at least 9-12 months after the volunteers were administered booster bites from X-irradiated infective mosquitoes. One volunteer challenged a second time with P. falciparum 9 months after his last immunization was again shown to be protected, whereas all 5 control subjects developed patent infections. These results set a new standard for persistence of sterile immunity against experimental P. falciparum infection. PMID:8376823

  9. Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns.

    PubMed

    Gartlan, Kate H; Krashias, George; Wegmann, Frank; Hillson, William R; Scherer, Erin M; Greenberg, Philip D; Eisenbarth, Stephanie C; Moghaddam, Amin E; Sattentau, Quentin J

    2016-04-27

    Carbopol is a polyanionic carbomer used in man for topical application and drug delivery purposes. However parenteral administration of Carbopol in animal models results in systemic adjuvant activity including strong pro-inflammatory type-1 T-cell (Th1) polarization. Here we investigated potential pathways of immune activation by Carbopol by comparison with other well-characterized adjuvants. Carbopol administration triggered rapid and robust leukocyte recruitment, pro-inflammatory cytokine secretion and antigen capture largely by inflammatory monocytes. The induction of antigen specific Th1 cells by Carbopol was found to occur via a non-canonical pathway, independent of MyD88/TRIF signaling and in the absence of pattern-recognition-receptor (PRR) activation typically associated with Th1/Ig2a induction. Using multispectral fluorescence imaging (Imagestream) and electron microscopy we demonstrated that phagocytic uptake of Carbopol particles followed by entry into the phagosomal/lysosomal pathway elicited conformational changes to the polymer and reactive oxygen species (ROS) production. We therefore conclude that Carbopol may mediate its adjuvant activity via novel mechanisms of antigen presenting cell activation and Th1 induction, leading to enhanced IgG2a responses independent of microbial pattern recognition. PMID:27005810

  10. Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

    PubMed Central

    Gartlan, Kate H.; Krashias, George; Wegmann, Frank; Hillson, William R.; Scherer, Erin M.; Greenberg, Philip D.; Eisenbarth, Stephanie C.; Moghaddam, Amin E.; Sattentau, Quentin J.

    2016-01-01

    Carbopol is a polyanionic carbomer used in man for topical application and drug delivery purposes. However parenteral administration of Carbopol in animal models results in systemic adjuvant activity including strong pro-inflammatory type-1 T-cell (Th1) polarization. Here we investigated potential pathways of immune activation by Carbopol by comparison with other well-characterized adjuvants. Carbopol administration triggered rapid and robust leukocyte recruitment, pro-inflammatory cytokine secretion and antigen capture largely by inflammatory monocytes. The induction of antigen specific Th1 cells by Carbopol was found to occur via a non-canonical pathway, independent of MyD88/TRIF signaling and in the absence of pattern-recognition-receptor (PRR) activation typically associated with Th1/Ig2a induction. Using multispectral fluorescence imaging (Imagestream) and electron microscopy we demonstrated that phagocytic uptake of Carbopol particles followed by entry into the phagosomal/lysosomal pathway elicited conformational changes to the polymer and reactive oxygen species (ROS) production. We therefore conclude that Carbopol may mediate its adjuvant activity via novel mechanisms of antigen presenting cell activation and Th1 induction, leading to enhanced IgG2a responses independent of microbial pattern recognition. PMID:27005810

  11. Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs

    PubMed Central

    Dutta, Avijit; Huang, Ching-Tai; Lin, Chun-Yen; Chen, Tse-Ching; Lin, Yung-Chang; Chang, Chia-Shiang; He, Yueh-Chia

    2016-01-01

    Sterilizing immunity is a unique immune status, which prevents effective virus infection into the host. It is different from the immunity that allows infection but with subsequent successful eradication of the virus. Pre-infection induces sterilizing immunity to homologous influenza virus challenge in ferret. In our antigen-specific experimental system, mice pre-infected with PR8 influenza virus through nasal route are likewise resistant to reinfection of the same strain of virus. The virus is cleared before establishment of effective infection. Intramuscular influenza virus injection confers protection against re-infection with facilitated virus clearance but not sterilizing immunity. Pre-infection and intramuscular injection generates comparable innate immunity and antibody response, but only pre-infection induces virus receptor reduction and efficient antigen-specific T cell response in the lungs. Pre-infection with nH1N1 influenza virus induces virus receptor reduction but not PR8-specific T cell immune response in the lungs and cannot prevent infection of PR8 influenza virus. Pre-infection with PR8 virus induced PR8-specific T cell response in the lungs but cannot prevent infection of nH1N1 virus either. These results reveal that antigen-specific T cell immunity is required for sterilizing immunity. PMID:27596047

  12. Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs.

    PubMed

    Dutta, Avijit; Huang, Ching-Tai; Lin, Chun-Yen; Chen, Tse-Ching; Lin, Yung-Chang; Chang, Chia-Shiang; He, Yueh-Chia

    2016-01-01

    Sterilizing immunity is a unique immune status, which prevents effective virus infection into the host. It is different from the immunity that allows infection but with subsequent successful eradication of the virus. Pre-infection induces sterilizing immunity to homologous influenza virus challenge in ferret. In our antigen-specific experimental system, mice pre-infected with PR8 influenza virus through nasal route are likewise resistant to reinfection of the same strain of virus. The virus is cleared before establishment of effective infection. Intramuscular influenza virus injection confers protection against re-infection with facilitated virus clearance but not sterilizing immunity. Pre-infection and intramuscular injection generates comparable innate immunity and antibody response, but only pre-infection induces virus receptor reduction and efficient antigen-specific T cell response in the lungs. Pre-infection with nH1N1 influenza virus induces virus receptor reduction but not PR8-specific T cell immune response in the lungs and cannot prevent infection of PR8 influenza virus. Pre-infection with PR8 virus induced PR8-specific T cell response in the lungs but cannot prevent infection of nH1N1 virus either. These results reveal that antigen-specific T cell immunity is required for sterilizing immunity. PMID:27596047

  13. Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

    PubMed Central

    Schussek, Sophie; Trieu, Angela; Apte, Simon H.; Sidney, John; Sette, Alessandro

    2013-01-01

    Apical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity against Plasmodium sporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8+ and CD4+ T cell epitopes on Plasmodium yoelii AMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity. PMID:23836827

  14. Targeted gene silencing to induce permanent sterility.

    PubMed

    Dissen, G A; Lomniczi, A; Boudreau, R L; Chen, Y H; Davidson, B L; Ojeda, S R

    2012-08-01

    A non-surgical method to induce sterility would be a useful tool to control feral populations of animals. Our laboratories have experience with approaches aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A combination/modification of these methods may provide a useful framework for the design of approaches that can be used to sterilize cats and dogs. For this approach to succeed, it has to meet several conditions: it needs to target a gene essential for fertility. It must involve a method that can selectively silence the gene of interest. It also needs to deliver the silencing agent via a minimally invasive method. Finally, the silencing effect needs to be sustained for many years, so that expansion of the targeted population can be effectively prevented. In this article, we discuss this subject and provide a succinct account of our previous experience with: (i) molecular reagents able to disrupt reproductive cyclicity when delivered to regions of the brain involved in the control of reproduction and (ii) molecular reagents able to ameliorate neuronal disease when delivered systemically using a novel approach of gene therapy. PMID:22827375

  15. Phi ({Phi}) and psi ({Psi}) angles involved in malarial peptide bonds determine sterile protective immunity

    SciTech Connect

    Patarroyo, Manuel E.; Moreno-Vranich, Armando; Bermudez, Adriana

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer Phi ({Phi}) and psi ({Psi}) angles determine sterile protective immunity. Black-Right-Pointing-Pointer Modified peptide's tendency to assume a regular conformation related to a PPII{sub L}. Black-Right-Pointing-Pointer Structural modifications in mHABPs induce Ab and protective immunity. Black-Right-Pointing-Pointer mHABP backbone atom's interaction with HLA-DR{beta}1{sup Asterisk-Operator} is stabilised by H-bonds. -- Abstract: Modified HABP (mHABP) regions interacting with HLA-DR{beta}1{sup Asterisk-Operator} molecules have a more restricted conformation and/or sequence than other mHABPs which do not fit perfectly into their peptide binding regions (PBR) and do not induce an acceptable immune response due to the critical role of their {Phi} and {Psi} torsion angles. These angle's critical role was determined in such highly immunogenic, protection-inducing response against experimental malaria using the conformers (mHABPs) obtained by {sup 1}H-NMR and superimposed into HLA-DR{beta}1{sup Asterisk-Operator }-like Aotus monkey molecules; their phi ({Phi}) and psi ({Psi}) angles were measured and the H-bond formation between these molecules was evaluated. The aforementioned mHABP propensity to assume a regular conformation similar to a left-handed polyproline type II helix (PPII{sub L}) led to suggesting that favouring these conformations according to their amino acid sequence would lead to high antibody titre production and sterile protective immunity induction against malaria, thereby adding new principles or rules for vaccine development, malaria being one of them.

  16. Sterile Protective Immunity to Malaria is Associated with a Panel of Novel P. falciparum Antigens*

    PubMed Central

    Trieu, Angela; Kayala, Matthew A.; Burk, Chad; Molina, Douglas M.; Freilich, Daniel A.; Richie, Thomas L.; Baldi, Pierre; Felgner, Philip L.; Doolan, Denise L.

    2011-01-01

    The development of an effective malaria vaccine remains a global public health priority. Less than 0.5% of the Plasmodium falciparum genome has been assessed as potential vaccine targets and candidate vaccines have been based almost exclusively on single antigens. It is possible that the failure to develop a malaria vaccine despite decades of effort might be attributed to this historic focus. To advance malaria vaccine development, we have fabricated protein microarrays representing 23% of the entire P. falciparum proteome and have probed these arrays with plasma from subjects with sterile protection or no protection after experimental immunization with radiation attenuated P. falciparum sporozoites. A panel of 19 pre-erythrocytic stage antigens was identified as strongly associated with sporozoite-induced protective immunity; 16 of these antigens were novel and 85% have been independently identified in sporozoite and/or liver stage proteomic or transcriptomic data sets. Reactivity to any individual antigen did not correlate with protection but there was a highly significant difference in the cumulative signal intensity between protected and not protected individuals. Functional annotation indicates that most of these signature proteins are involved in cell cycle/DNA processing and protein synthesis. In addition, 21 novel blood-stage specific antigens were identified. Our data provide the first evidence that sterile protective immunity against malaria is directed against a panel of novel P. falciparum antigens rather than one antigen in isolation. These results have important implications for vaccine development, suggesting that an efficacious malaria vaccine should be multivalent and targeted at a select panel of key antigens, many of which have not been previously characterized. PMID:21628511

  17. Surgical sterilization: an underutilized procedure for evaluating the merits of induced sterility

    USGS Publications Warehouse

    Kennelly, James J.; Converse, Kathryn A.

    1993-01-01

    Despite more than 4 decades of effort, development of effective wildlife damage control programs based on sterilization of target species has met with limited success. This is partly due to the fact that investigators have assumed, rather than empirically tested, whether the reproductive strategies of the target populations were vulnerable to the planned treatment. Equally important, methods selected to include sterility usually involve a chemical agent that can affect sociosexual behaviors of the nuisance population. In this report, we illustrate how surgically induced sterility circumvents both problems--how the concept without the potentially confounding secondary effects of a chemical. We assessed the merits of initiating research to develop a male chemosterilant for Norway rats, red-winged blackbirds, beaver, and Canada geese by inducing sterility surgically. The infidelity of many red-winged females to their polygynous territorial male was surprising and argued against searching for a male sterilant. On the other hand, beaver and Canada goose studies confirmed previous reports that both form par-bonds and are monogamous. Both should be vulnerable to a male chemosterilant approach, and research toward this goal is justified.

  18. The Hepatitis B Vaccine Protects Re-Exposed Healthcare Workers, but Does Not Provide Sterilizing Immunity

    PubMed Central

    Werner, Jens M.; Abdalla, Adil; Gara, Naveen; Ghany, Marc G.; Rehermann, Barbara

    2013-01-01

    Background & Aims Infection with hepatitis B virus (HBV) can be prevented by vaccination with HBV surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for healthcare workers who were vaccinated as adults. Methods We investigated the immune mechanisms (antibody and T cell responses) of long-term protection by the HBV vaccine in 90 healthcare workers with occupational exposure to HBV, 10–28 y after vaccination. Results Fifty-nine of 90 health-care workers (65%) had levels of antibodies against HBs (anti-HBs) above the cut-off (>12 mIU/ml) and 30/90 (33%) had HBs-specific T cells that produced interferon (IFN)γ. Anti-HBs titers correlated with numbers of HBs-specific IFNγ-producing T cells, but not with time after vaccination. Whereas occupational exposure to HBV after vaccination did not induce antibodies to the HBV core protein (HBcore), the standard biomarker for HBV infection, CD4+ and CD8+ T cells against HBcore and polymerase antigens were detected. Similar numbers of HBcore- and polymerase-specific CD4+ and CD8+ T cells were detected in health-care workers with occupational exposure to HBV and in patients who acquired immunity via HBV infection. Most of the HBcore- and polymerase-specific T cells were CD45RO+CCR7−CD127− effector memory cells in exposed health-care workers and in patients with acquired immunity. In contrast, most of the vaccine-induced HBs-specific T cell cells were CD45RO−CCR7−CD127− and terminally differentiated. Conclusions HBsAg vaccine-induced immunity protects against future infection but does not provide sterilizing immunity, as evidenced by HBcore- and polymerase-specific CD8+ T cells in vaccinated health care workers with occupational exposure to HBV. The presence of HBcore- and HBV polymerase-specific T-cell responses is a more sensitive indicator of HBV exposure than detection of HBcore-specific antibodies. PMID:23916846

  19. Rosiglitazone-induced immune thrombocytopenia.

    PubMed

    Liu, Xiaojing; Huang, Tao; Sahud, Mervyn A

    2006-05-01

    Rosiglitazone is one of the members in the thiazolidinedione (TZD) class of anti-diabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to rosiglitazone maleate (Avandia) and proposed the mechanisms for rosiglitazone-induced thrombocytopenia. Tested by flow cytometry, the patient's serum was positive for rosiglitazone-induced antibody with the binding ratio of 5.93 (mean fluorescence intensity, MFI) in the presence of the patient's serum and rosiglitazone in a final concentration of 0.53 mmol/l. The antibody was found to bind both glycoprotein (GP) IIb-IIIa complex and GP Ib/IX complex by MAIPA assay using five different monoclonal antibodies (mAbs) against GP complexes Ib/IX, GPIIb/IIIa or GPIa/IIa. Immunoprecipitation studies showed that both GPIIb/IIIa and GP Ib/IX complex were precipitated by antibody in the presence, but not in the absence of rosiglitazone. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to the antidiabetic agent rosiglitazone maleate. This report documents the first case of rosiglitazone-induced immune thrombocytopenia. PMID:16702039

  20. Qualitative inheritance of water-stress induced apical sterility in wheat (Triticum aestivum).

    PubMed

    Mohammady-D, Shahram; Moore, Keith; Ollerenshaw, John

    2003-01-01

    Grain number per unit area is an effective component of grain yield in bread wheat. Water-stress induced apical sterility (tip sterility) reduces the number of grains and, consequently, the grain yield in semi-arid regions with a shortage of available water during the pre-anthesis period. Crosses between apical sterile and apical fertile varieties and selection lines were made and F1, BC1, and F2 populations were subjected to moderate water-stress to study the inheritance of this character. The F2 and BC1 plants were qualitatively categorised into two phenotypes and tested for monohybrid and dihybrid segregation hypotheses. All the spikes of F1 plants obtained from crosses between apical fertile and apical sterile varieties were fully fertile indicating apical fertility is dominant to apical sterility. The F2 segregation Results from crosses between apical fertile lines and Y82187 suggested two complementary dominant genes segregating independently were involved in tolerance to water-stress induced apical sterility. In other words, two dominant genes determine apical fertility in these crosses and if one of these loci is homozygous, recessive waterstress will induce apical sterility. One F2 population segregated for both apical sterility and vernalisation response. Semi-winter plants had more sterile spikelets and the result of chi-square test confirmed monhybrid segregation for vernalisation response. PMID:14641489

  1. X-ray-induced sterility in Aedes albopictus (Diptera: Culicidae) and male longevity following irradiation.

    PubMed

    Yamada, H; Parker, A G; Oliva, C F; Balestrino, F; Gilles, J R L

    2014-07-01

    The mosquito Aedes albopictus (Skuse, 1895) is a potent vector of several arboviral diseases, most notably chikungunya and dengue fever. In the context of the sterile insect technique (SIT), the sterilization of the male mosquitoes before their release can be achieved by gamma-ray irradiation. As gamma-ray irradiators are becoming increasingly problematic to purchase and transport, the suitability of an X-ray irradiator as an alternative for the sterilization of Ae. albopictus males was studied. The sterilization of up to 200,000 pupae at one time can be achieved with relative ease, and the sterility results obtained were comparable with those achieved by gamma irradiation, where 99% sterility is induced with a dose of 40 Gy. A significant reduction of longevity was observed in the latter stages of the males' life after irradiation treatments, especially at doses > 40 Gy, which is consistent with the negative effects on longevity induced by similar radiation doses using gamma rays. Females irradiated at 40 Gy were not only 100% sterile, but also failed to oviposit entirely, i.e., all of the females laid 0 eggs. Overall, it was found that the X-ray irradiator is generally suitable for the sterilization process for sterile insect technique programs, as it showed a high processing capacity, practicality, high effectiveness, and reproducibility. PMID:25118413

  2. Computational Modeling Predicts Interleukin-10 Control of Lesion Sterilization By Balancing Early Host-Immunity-Mediated Antimicrobial Responses With Caseation During Mycobacterium tuberculosis Infection

    PubMed Central

    Cilfone, Nicholas A.; Ford, Christopher B.; Marino, Simeone; Mattila, Joshua T.; Gideon, Hannah P.; Flynn, JoAnne L.; Kirschner, Denise E.; Linderman, Jennifer J.

    2014-01-01

    Although almost a third of the world’s population is infected with the bacterial pathogen Mycobacterium tuberculosis (Mtb), our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine interleukin-10 (IL-10) at the level of the granuloma has proven difficult due to lesional heterogeneity and the limitations of animal models. Here we take an in silico approach and, through a series of virtual experiments, we predict several novel roles for IL-10 in TB granulomas: (1) decreased levels of IL-10 lead to increased numbers of sterile lesions, but at the cost of early increased caseation, (2) small increases in early antimicrobial activity cause this increased lesion sterility, (3) IL-10 produced by activated macrophages is a major mediator of early antimicrobial activity and early host-induced caseation and (4) increasing levels of infected macrophage derived IL-10 promotes bacterial persistence by limiting the early antimicrobial response and preventing lesion sterilization. Our findings, currently only accessible using an in silico approach, suggest that IL-10 at the individual granuloma scale is a critical regulator of lesion outcome. These predictions suggest IL-10 related mechanisms that could be used as adjunctive therapies during TB. PMID:25512604

  3. Molecular mapping of a new induced gene for nuclear male sterility in sunflower (Helianthus annuus L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A new NMS line, NMS HA89-872, induced by mitomycin C and streptomycin carries a single recessive male-sterile gene ms6. An F2 population of 88 plants was obtained from a cross between nuclear male-sterile mutant NMS HA89-872 (msms) and male-fertile line RHA271 (MsMs). 225 SSR primers and 9 RFLP-deri...

  4. High temperature-induced sterility in the female Nile tilapia, Oreochromis niloticus.

    PubMed

    Pandit, Narayan Prasad; Bhandari, Ramji Kumar; Kobayashi, Yasuhisa; Nakamura, Masaru

    2015-03-01

    High temperature treatments induce germ cell loss in gonads of vertebrate animals, including fish. It could be a reliable source for induction of sterility if the treatments led to a permanent loss of germ cells. Here we report that heat treatment at 37 °C for 45-60 days caused a complete loss of germ cells in female Nile tilapia, Oreochromis niloticus, and that sterility was achieved in fish at all stages of their life cycle. Unlike previous observations, germ cells did not repopulate even after returning them to the water at control conditions suggesting permanent depletion of germ cells. Gonadal somatic cells immunopositive for 3β-hydroxysteroid dehydrogenase (3β-HSD) were clustered at one end of the germ cell depleted gonads close to the blood vessel. Serum level of testosterone, 11-ketotestosterone, and 17β-estradiol was significantly decreased in sterile fish compared to control. Body weight of sterile fish was higher than control fish at the end of experiment. Our observations of increased growth and permanent sterilization in the high temperature-treated fish suggest that this method could be an appropriate and eco-friendly tool for inducing sterility in fish with a higher thermal tolerance. PMID:25745814

  5. Sterilization System

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Cox Sterile Products, Inc.'s Rapid Heat Transfer Sterilizer employs a heat exchange process that induces rapid air movement; the air becomes the heat transfer medium, maintaining a uniform temperature of 375 degrees Fahrenheit. It features pushbutton controls for three timing cycles for different instrument loads, a six-minute cycle for standard unpackaged instruments, eight minutes for certain specialized dental/medical instruments and 12 minutes for packaged instruments which can then be stored in a drawer in sterile condition. System will stay at 375 degrees all day. Continuous operation is not expensive because of the sterilizer's very low power requirements.

  6. Whole Transcriptome Analysis Using Next-Generation Sequencing of Sterile-Cultured Eisenia andrei for Immune System Research

    PubMed Central

    Mikami, Yoshikazu; Fukushima, Atsushi; Kuwada-Kusunose, Takao; Sakurai, Tetsuya; Kitano, Taiichi; Komiyama, Yusuke; Iwase, Takashi; Komiyama, Kazuo

    2015-01-01

    Recently, earthworms have become a useful model for research into the immune system, and it is expected that results obtained using this model will shed light on the sophisticated vertebrate immune system and the evolution of the immune response, and additionally help identify new biomolecules with therapeutic applications. However, for earthworms to be used as a genetic model of the invertebrate immune system, basic molecular and genetic resources, such as an expressed sequence tag (EST) database, must be developed for this organism. Next-generation sequencing technologies have generated EST libraries by RNA-seq in many model species. In this study, we used Illumina RNA-sequence technology to perform a comprehensive transcriptome analysis using an RNA sample pooled from sterile-cultured Eisenia andrei. All clean reads were assembled de novo into 41,423 unigenes using the Trinity program. Using this transcriptome data, we performed BLAST analysis against the GenBank non-redundant (NR) database and obtained a total of 12,285 significant BLAST hits. Furthermore, gene ontology (GO) analysis assigned 78 unigenes to 24 immune class GO terms. In addition, we detected a unigene with high similarity to beta-1,3-glucuronyltransferase 1 (GlcAT-P), which mediates a glucuronyl transfer reaction during the biosynthesis of the carbohydrate epitope HNK-1 (human natural killer-1, also known as CD57), a marker of NK cells. The identified transcripts will be used to facilitate future research into the immune system using E. andrei. PMID:25706644

  7. Whole transcriptome analysis using next-generation sequencing of sterile-cultured Eisenia andrei for immune system research.

    PubMed

    Mikami, Yoshikazu; Fukushima, Atsushi; Kuwada-Kusunose, Takao; Sakurai, Tetsuya; Kitano, Taiichi; Komiyama, Yusuke; Iwase, Takashi; Komiyama, Kazuo

    2015-01-01

    Recently, earthworms have become a useful model for research into the immune system, and it is expected that results obtained using this model will shed light on the sophisticated vertebrate immune system and the evolution of the immune response, and additionally help identify new biomolecules with therapeutic applications. However, for earthworms to be used as a genetic model of the invertebrate immune system, basic molecular and genetic resources, such as an expressed sequence tag (EST) database, must be developed for this organism. Next-generation sequencing technologies have generated EST libraries by RNA-seq in many model species. In this study, we used Illumina RNA-sequence technology to perform a comprehensive transcriptome analysis using an RNA sample pooled from sterile-cultured Eisenia andrei. All clean reads were assembled de novo into 41,423 unigenes using the Trinity program. Using this transcriptome data, we performed BLAST analysis against the GenBank non-redundant (NR) database and obtained a total of 12,285 significant BLAST hits. Furthermore, gene ontology (GO) analysis assigned 78 unigenes to 24 immune class GO terms. In addition, we detected a unigene with high similarity to beta-1,3-glucuronyltransferase 1 (GlcAT-P), which mediates a glucuronyl transfer reaction during the biosynthesis of the carbohydrate epitope HNK-1 (human natural killer-1, also known as CD57), a marker of NK cells. The identified transcripts will be used to facilitate future research into the immune system using E. andrei. PMID:25706644

  8. Oxazolone-Induced Contact Hypersensitivity Reduces Lymphatic Drainage but Enhances the Induction of Adaptive Immunity

    PubMed Central

    Aebischer, David; Willrodt, Ann-Helen; Halin, Cornelia

    2014-01-01

    Contact hypersensitivity (CHS) induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC) migration to draining lymph nodes (dLNs). On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA) was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH) response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40) and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function. PMID:24911791

  9. Tumor-induced immune dysfunction.

    PubMed

    Kiessling, R; Wasserman, K; Horiguchi, S; Kono, K; Sjöberg, J; Pisa, P; Petersson, M

    1999-10-01

    Immune system-based approaches for the treatment of malignant disease over the past decades have often focused on cytolytic effector cells such as cytotoxic T lymphocytes (CTL), and natural killer (NK) cells. It has also been demonstrated that tumor-bearing mice can be cured using a wide variety of approaches, some of which involve cytokine-mediated enhancement of CTL and NK cell activity. However, the apparent success in mice stands in contrast to the current situation in the clinic, wherein only a minority of patients have thus far benefited from CTL- or NK cell-based antitumor approaches. The underlying causes of tumor-associated immune suppression of CTL and NK cell activity are discussed, and features of interest shared with HIV infection, leprosy, and rheumatoid arthritis are also be mentioned. Remarkable and very recent observations have shed more light upon the causes of dysfunctional alterations in CTL and NK cells often associated with these diseases, that in turn have suggested new immunotherapeutic approaches for cancer and infectious disease. PMID:10501847

  10. 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. PMID:25086685

  11. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  12. Targeted expression of cystatin restores fertility in cysteine protease induced male sterile tobacco plants.

    PubMed

    Shukla, Pawan; Subhashini, Mranu; Singh, Naveen Kumar; Ahmed, Israr; Trishla, Shalibhadra; Kirti, P B

    2016-05-01

    Fertility restoration in male sterile plants is an essential requirement for their utilization in hybrid seed production. In an earlier investigation, we have demonstrated that the targeted expression of a cysteine protease in tapetal cell layer resulted in complete male sterility in tobacco transgenic plants. In the present investigation, we have used a cystatin gene, which encodes for a cysteine protease inhibitor, from a wild peanut, Arachis diogoi and developed a plant gene based restoration system for cysteine protease induced male sterile transgenic tobacco plants. We confirmed the interaction between the cysteine protease and a cystatin of the wild peanut, A. diogoi through in silico modeling and yeast two-hybrid assay. Pollen from primary transgenic tobacco plants expressing cystatin gene under the tapetum specific promoter- TA29 restored fertility on cysteine protease induced male sterile tobacco plants developed earlier. This has confirmed the in vivo interaction of cysteine protease and cystatin in the tapetal cells, and the inactivation of cysteine protease and modulation of its negative effects on pollen fertility. Both the cysteine protease and cystatin genes are of plant origin in contrast to the analogous barnase-barstar system that deploys genes of prokaryotic origin. Because of the deployment of genes of plant origin, this system might not face biosafety problems in developing hybrids in food crops. PMID:26993235

  13. Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity.

    PubMed

    Broadley, Steven P; Plaumann, Ann; Coletti, Raffaele; Lehmann, Christin; Wanisch, Andreas; Seidlmeier, Amelie; Esser, Knud; Luo, Shanshan; Rämer, Patrick C; Massberg, Steffen; Busch, Dirk H; van Lookeren Campagne, Menno; Verschoor, Admar

    2016-07-13

    Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity. PMID:27345696

  14. Stress induced neuroendocrine-immune plasticity

    PubMed Central

    Liezmann, Christiane; Stock, Daniel; Peters, Eva M. J.

    2012-01-01

    Research over the past decade has revealed close interaction between the nervous and immune systems in regulation of peripheral inflammation linking psychosocial stress with chronic somatic disease and aging. Moreover emerging data suggests that chronic inflammations lead to a pro-inflammatory status underlying premature aging called inflammaging. In this context, the spleen can be seen as a switch board monitoring peripherally derived neuroendocrine-immune mediators in the blood and keeping up a close communication with the central stress response via its mainly sympathetic innervation. The effect aims at balanced and well-timed stress axis activation and immune adaptation in acute peripheral inflammatory events. Constant adjustment to the needs generated by environmental and endogenous challenges is provided by neuroendocrine-immune plasticity. However, maladaptive plasticity induced e.g., by chronic stress-axis activation and excessive non-neuronal derived neuroendocrine mediators may be at the heart of the observed stress sensitivity promote inflammaging under chronic inflammatory conditions. We here review the role of neurotransmitters, neuropeptides and neurotrophins as stress mediators modulating the immune response in the spleen and their potential role in inflammaging. PMID:23467333

  15. An efferocytosis-induced, IL-4–dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD

    PubMed Central

    Zeng, Melody Yue; Pham, Duy; Bagaitkar, Juhi; Liu, Jianyun; Otero, Karel; Shan, Ming; Wynn, Thomas A.; Brombacher, Frank; Brutkiewicz, Randy R.; Kaplan, Mark H.

    2013-01-01

    Efferocytosis of apoptotic neutrophils by macrophages following tissue injury is fundamental to the resolution of inflammation and initiation of tissue repair. Using a sterile peritonitis model in mice, we identified interleukin (IL)-4–producing efferocytosing macrophages in the peritoneum that activate invariant natural killer T (iNKT) cells to produce cytokines including IL-4, IL-13, and interferon-γ. Importantly, IL-4 from macrophages contributes to alternative activation of peritoneal exudate macrophages and augments type 2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4Rα expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The reduced NAD phosphate oxidase is also critical for this model, because in mice with X-linked chronic granulomatous disease (X-CGD) that lack oxidase subunits, activation of iNKT cells by X-CGD peritoneal exudate macrophages was impaired during sterile peritonitis, resulting in enhanced and prolonged inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of IL-4–producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair. PMID:23426944

  16. Sterile polystyrene culture dishes induce transformation of polyps into medusae in Aurelia aurita (Scyphozoa, Cnidaria).

    PubMed

    Herrmann, Klaus; Siefker, Barbara; Berking, Stefan

    2003-01-01

    Polyps of Aurelia aurita produce medusae once a year. Under laboratory conditions this process, termed strobilation, can be induced by lowering the incubation temperature for about two weeks. Here we report a fast induction of strobilation by sterile polystyrene culture dishes. The effect is abolished when the culture dishes are washed twice with hot water prior to the experiment. We recommend that polystyrene cultureware should be pre-washed whenever there is an indication of unusual effects. PMID:15801158

  17. Antitumor Immunity Induced after α Irradiation123

    PubMed Central

    Gorin, Jean-Baptiste; Ménager, Jérémie; Gouard, Sébastien; Maurel, Catherine; Guilloux, Yannick; Faivre-Chauvet, Alain; Morgenstern, Alfred; Bruchertseifer, Frank; Chérel, Michel; Davodeau, François; Gaschet, Joëlle

    2014-01-01

    Radioimmunotherapy (RIT) is a therapeutic modality that allows delivering of ionizing radiation directly to targeted cancer cells. Conventional RIT uses β-emitting radioisotopes, but recently, a growing interest has emerged for the clinical development of α particles. α emitters are ideal for killing isolated or small clusters of tumor cells, thanks to their specific characteristics (high linear energy transfer and short path in the tissue), and their effect is less dependent on dose rate, tissue oxygenation, or cell cycle status than γ and X rays. Several studies have been performed to describe α emitter radiobiology and cell death mechanisms induced after α irradiation. But so far, no investigation has been undertaken to analyze the impact of α particles on the immune system, when several studies have shown that external irradiation, using γ and X rays, can foster an antitumor immune response. Therefore, we decided to evaluate the immunogenicity of murine adenocarcinoma MC-38 after bismuth-213 (213Bi) irradiation using a vaccination approach. In vivo studies performed in immunocompetent C57Bl/6 mice induced a protective antitumor response that is mediated by tumor-specific T cells. The molecular mechanisms potentially involved in the activation of adaptative immunity were also investigated by in vitro studies. We observed that 213Bi-treated MC-38 cells release “danger signals” and activate dendritic cells. Our results demonstrate that α irradiation can stimulate adaptive immunity, elicits an efficient antitumor protection, and therefore is an immunogenic cell death inducer, which provides an attractive complement to its direct cytolytic effect on tumor cells. PMID:24862758

  18. Sedimentation rapidly induces an immune response and depletes energy stores in a hard coral

    NASA Astrophysics Data System (ADS)

    Sheridan, C.; Grosjean, Ph.; Leblud, J.; Palmer, C. V.; Kushmaro, A.; Eeckhaut, I.

    2014-12-01

    High sedimentation rates have been linked to reduced coral health within multiple systems; however, whether this is a direct result of compromised coral immunity has not been previously investigated. The potential effects of sedimentation on immunity of the hard coral Montipora patula were examined by comparing physiological responses of coral fragments inoculated with sterilized marine sediments and those under control conditions. Sediments were collected from terrestrial runoff-affected reefs in SW Madagascar and applied cyclically for a total of 24 h at a rate observed during precipitation-induced sedimentation events. Coral health was determined 24 h after the onset of the sedimentation stress through measuring metabolic proxies of O2 budget and lipid ratios. Immune response of the melanin synthesis pathway was measured by quantifying phenoloxidase activity and melanin deposits. Sedimentation induced both immune and metabolic responses in M. patula. Both phenoloxidase activity and melanin deposition were significantly higher in the sediment treatment compared to controls, indicating an induced immune response. Sediment-treated corals also showed a tendency towards increased respiration (during the night) and decreased photosynthesis (during the day) and a significant depletion of energy reserves as compared to controls. These data highlight that short-term (24 h) sedimentation, free of live microorganisms, compromises the health of M. patula. The energetically costly immune response, potentially elicited by residual endotoxins and other inflammatory particles associated with the sterile sediments, likely contributes to the energy depletion. Overall, exposure to sedimentation adversely affects coral health and continued exposure may lead to resource depletion and an increased susceptibility to disease.

  19. Drug-induced immune hemolytic anemia

    MedlinePlus

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making ...

  20. Drug-induced immune neutropenia/agranulocytosis.

    PubMed

    Curtis, Brian R

    2014-01-01

    Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/pL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole- trimethoprim, [3-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs-DIIN PMID:25247619

  1. Antiplatelet antibodies in oxaliplatin-induced immune thrombocytopenia

    PubMed Central

    McNamara, Michael J; Curtis, Brian R; McCrae, Keith R

    2014-01-01

    Lesson Drug-induced immune thrombocytopenia may be potentially fatal; here we report the development of severe thrombocytopenia with strong oxaliplatin-dependent antiplatelet antibodies. PMID:25057402

  2. Induced hyperlipaemia and immune challenge in locusts.

    PubMed

    Mullen, Lisa M; Lightfoot, Mary E; Goldsworthy, Graham J

    2004-05-01

    Injections of immunogens, such as beta-1,3-glucan or lipopolysaccharide (LPS), bring about a marked hyperlipaemia with associated changes in lipophorins and apolipophorin-III in the haemolymph of Locusta migratoria. These changes are similar to those observed after injection of adipokinetic hormone (AKH). The possibility that endogenous AKH is released as part of the response to these immunogens is investigated using passive immunisation against AKH-I, and measurement of AKH-I titre in the haemolymph after injection of immunogens. The data presented show that, despite the similarity of the changes brought about by the presence of immunogens in the haemolymph to those brought about by AKH, there is no release of endogenous AKH after injection of laminarin or LPS. A direct effect of the immunogens on release of neutral lipids by the fat body cannot be demonstrated in vitro, and the mechanism by which hyperlipaemia is induced during immune challenge remains uncertain. PMID:15121454

  3. U1 RNA Induces Innate Immunity Signaling

    PubMed Central

    Hoffman, Robert W.; Gazitt, Tal; Foecking, Mark F.; Ortmann, Robert A.; Misfeldt, Michael; Jorgenson, Rebecca; Young, Steven L.; Greidinger, Eric L.

    2006-01-01

    Objective The U1–70-kd RNP is a prominent target of autoimmunity in connective tissue diseases. In this study, we explored whether its endogenous ligand, U1 RNA, mediates a proimmune signal and may be immunogenic. Methods We assayed the proliferation of control and MyD88-knockout splenocytes in response to in vitro–synthesized U1 RNA, and measured interleukin-6 (IL-6) and IL-8 secretion induced by U1 RNA in a human cell line competent for signaling through Toll-like receptor 3 (TLR-3) and TLR-5. Results Treatment with U1 RNA or with poly(I-C), a known agonist of TLR-3, induced approximately twice as much control splenocyte proliferation as did treatment with RNase-digested U1 RNA. Proliferation in response to either poly(I-C) or U1 RNA by MyD88-knockout splenocytes was similarly attenuated. Similar to poly(I-C), U1 RNA induced significant secretion of both IL-6 and IL-8 from a TLR-3–expressing human cell line; in contrast, the TLR-5 agonist flagellin induced predominantly IL-8 secretion. Pretreatment of U1 RNA with RNase abolished IL-6 and IL-8 secretion. Conclusion U1 RNA is capable of inducing manifestations consistent with TLR-3 activation. The ability of U1 RNA (which has a substantial double-stranded secondary structure) to activate TLR-3 may contribute to the immunogenicity of the U1–70-kd autoantigen. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins. PMID:15457457

  4. Sterilization by Laparoscopy

    MedlinePlus

    ... sleep-like state to prevent pain during surgery. Human Immunodeficiency Virus (HIV): A virus that attacks certain cells of the body’s immune system and causes acquired immunodeficiency syndrome (AIDS). Hysteroscopic Sterilization: ...

  5. Drug-induced immune hemolytic anemia

    MedlinePlus

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  6. Single immunizing dose of recombinant adenovirus efficiently induces CD8+ T cell-mediated protective immunity against malaria.

    PubMed

    Rodrigues, E G; Zavala, F; Eichinger, D; Wilson, J M; Tsuji, M

    1997-02-01

    The immunogenicity of a recombinant replication defective adenovirus expressing a major malaria Ag, the circumsporozoite (CS) protein (AdPyCS), was determined using a rodent malaria model. A single immunizing dose of this construct induced a large number of CS-specific CD8+ and CD4+ T cells in the spleens of these animals, particularly when given by the s.c. or i.m. route. A single dose of AdPyCS also induced high titers of Abs to Plasmodium yoelii sporozoites in mice. No other form of presentation of the CS protein given as a single immunizing dose, i.e., irradiated sporozoites, recombinant vaccinia, or influenza virus, etc., elicits comparably high numbers of CS-specific CD8+ T cells. The high concentration of CS-specific CD8+ T cells in the spleen was relatively short-lived, decreasing to half of its original value by 4 wk and to one-third at 8 wk after AdPyCS inoculation. The decrease in splenic CS-specific CD4+ T cells was even more rapid. Most importantly, a single dose of inoculation of AdPyCS into mice rendered them highly resistant to sporozoite challenge, resulting in a 93% inhibition of liver stage development of the parasites. This protective effect was primarily mediated by CD8+ T cells, as shown by depletion of this T cell population, while depletion of the CD4+ T cell population had only a minor effect on anti-plasmodial activity. Moreover, the inoculation of mice with AdPyCS induces sterile immunity in a significant proportion of mice, preventing the occurrence of parasitemia. PMID:9013969

  7. De Novo Assembly and Transcriptome Analysis of Wheat with Male Sterility Induced by the Chemical Hybridizing Agent SQ-1

    PubMed Central

    Zhang, Gaisheng; Ju, Lan; Zhang, Jiao; Yu, Yongang; Niu, Na; Wang, Junwei; Ma, Shoucai

    2015-01-01

    Wheat (Triticum aestivum L.), one of the world’s most important food crops, is a strictly autogamous (self-pollinating) species with exclusively perfect flowers. Male sterility induced by chemical hybridizing agents has increasingly attracted attention as a tool for hybrid seed production in wheat; however, the molecular mechanisms of male sterility induced by the agent SQ-1 remain poorly understood due to limited whole transcriptome data. Therefore, a comparative analysis of wheat anther transcriptomes for male fertile wheat and SQ-1–induced male sterile wheat was carried out using next-generation sequencing technology. In all, 42,634,123 sequence reads were generated and were assembled into 82,356 high-quality unigenes with an average length of 724 bp. Of these, 1,088 unigenes were significantly differentially expressed in the fertile and sterile wheat anthers, including 643 up-regulated unigenes and 445 down-regulated unigenes. The differentially expressed unigenes with functional annotations were mapped onto 60 pathways using the Kyoto Encyclopedia of Genes and Genomes database. They were mainly involved in coding for the components of ribosomes, photosynthesis, respiration, purine and pyrimidine metabolism, amino acid metabolism, glutathione metabolism, RNA transport and signal transduction, reactive oxygen species metabolism, mRNA surveillance pathways, protein processing in the endoplasmic reticulum, protein export, and ubiquitin-mediated proteolysis. This study is the first to provide a systematic overview comparing wheat anther transcriptomes of male fertile wheat with those of SQ-1–induced male sterile wheat and is a valuable source of data for future research in SQ-1–induced wheat male sterility. PMID:25898130

  8. De Novo Assembly and Transcriptome Analysis of Wheat with Male Sterility Induced by the Chemical Hybridizing Agent SQ-1.

    PubMed

    Zhu, Qidi; Song, Yulong; Zhang, Gaisheng; Ju, Lan; Zhang, Jiao; Yu, Yongang; Niu, Na; Wang, Junwei; Ma, Shoucai

    2015-01-01

    Wheat (Triticum aestivum L.), one of the world's most important food crops, is a strictly autogamous (self-pollinating) species with exclusively perfect flowers. Male sterility induced by chemical hybridizing agents has increasingly attracted attention as a tool for hybrid seed production in wheat; however, the molecular mechanisms of male sterility induced by the agent SQ-1 remain poorly understood due to limited whole transcriptome data. Therefore, a comparative analysis of wheat anther transcriptomes for male fertile wheat and SQ-1-induced male sterile wheat was carried out using next-generation sequencing technology. In all, 42,634,123 sequence reads were generated and were assembled into 82,356 high-quality unigenes with an average length of 724 bp. Of these, 1,088 unigenes were significantly differentially expressed in the fertile and sterile wheat anthers, including 643 up-regulated unigenes and 445 down-regulated unigenes. The differentially expressed unigenes with functional annotations were mapped onto 60 pathways using the Kyoto Encyclopedia of Genes and Genomes database. They were mainly involved in coding for the components of ribosomes, photosynthesis, respiration, purine and pyrimidine metabolism, amino acid metabolism, glutathione metabolism, RNA transport and signal transduction, reactive oxygen species metabolism, mRNA surveillance pathways, protein processing in the endoplasmic reticulum, protein export, and ubiquitin-mediated proteolysis. This study is the first to provide a systematic overview comparing wheat anther transcriptomes of male fertile wheat with those of SQ-1-induced male sterile wheat and is a valuable source of data for future research in SQ-1-induced wheat male sterility. PMID:25898130

  9. Tribenuron-Methyl Induces Male Sterility through Anther-Specific Inhibition of Acetolactate Synthase Leading to Autophagic Cell Death.

    PubMed

    Zhao, Lun; Jing, Xue; Chen, Li; Liu, Yingjun; Su, Yanan; Liu, Tingting; Gao, Changbin; Yi, Bin; Wen, Jing; Ma, Chaozhi; Tu, Jinxing; Zou, Jitao; Fu, Tingdong; Shen, Jinxiong

    2015-12-01

    Tribenuron-methyl (TM) is a powerful sulfonylurea herbicide that inhibits branched-chain amino acid (BCAA) biosynthesis by targeting the catalytic subunit (CSR1) of acetolactate synthase (ALS). Selective induction of male sterility by foliar spraying of TM at low doses has been widely used for hybrid seed production in rapeseed (Brassica napus); however, the underlying mechanism remains unknown. Here, we report greater TM accumulation and subsequent stronger ALS inhibition and BCAA starvation in anthers than in leaves and stems after TM application. Constitutive or anther-specific expression of csr1-1D (a CSR1 mutant) eliminated anther-selective ALS inhibition and reversed the TM-induced male sterile phenotype in both rapeseed and Arabidopsis. The results of TM daub-stem experiments, combined with the observations of little TM accumulation in anthers and reversion of TM-induced male sterility by targeted expression of the TM metabolism gene Bel in either the mesophyll or phloem, suggested that foliar-sprayed TM was polar-transported to anthers mainly through the mesophyll and phloem. Microscopy and immunoblotting revealed that autophagy, a bulk degradation process induced during cell death, was elevated in TM-induced male sterile anthers and by anther-specific knockdown of ALS. Moreover, TM-induced pollen abortion was significantly inhibited by the autophagy inhibitor 3-MA. These data suggested that TM was polar-transported to anthers, resulting in BCAA starvation via anther-specific ALS inhibition and, ultimately, autophagic cell death in anthers. PMID:26362932

  10. Can VHS Virus Bypass the Protective Immunity Induced by DNA Vaccination in Rainbow Trout?

    PubMed Central

    Sepúlveda, Dagoberto; Lorenzen, Niels

    2016-01-01

    DNA vaccines encoding viral glycoproteins have been very successful for induction of protective immunity against diseases caused by rhabdoviruses in cultured fish species. However, the vaccine concept is based on a single viral gene and since RNA viruses are known to possess high variability and adaptation capacity, this work aimed at evaluating whether viral haemorrhagic septicaemia virus (VHSV), an RNA virus and member of Rhabdoviridae family, was able to evade the protective immune response induced by the DNA vaccination of rainbow trout. The experiments comprised repeated passages of a highly pathogenic VHSV isolate in a fish cell line in the presence of neutralizing fish serum (in vitro approach), and in rainbow trout immunized with the VHS DNA vaccine (in vivo approach). For the in vitro approach, the virus collected from the last passage (passaged virus) was as sensitive as the parental virus to serum neutralization, suggesting that the passaging did not promote the selection of virus populations able to bypass the neutralization by serum antibodies. Also, in the in vivo approach, where virus was passaged several times in vaccinated fish, no increased virulence nor increased persistence in vaccinated fish was observed in comparison with the parental virus. However, some of the vaccinated fish did get infected and could transmit the infection to naïve cohabitant fish. The results demonstrated that the DNA vaccine induced a robust protection, but also that the immunity was non-sterile. It is consequently important not to consider vaccinated fish as virus free in veterinary terms. PMID:27054895

  11. Cytological and comparative proteomic analyses on male sterility in Brassica napus L. induced by the chemical hybridization agent monosulphuron ester sodium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male sterility induced by a chemical hybridization agent (CHA) is an important tool for utilizing crop heterosis. Monosulphuron ester sodium (MES), a new acetolactate synthase-inhibitor herbicide belonging to the sulphonylurea family, has been developed as an effective CHA to induce male sterility i...

  12. [Genetic and cytological analyses of the male sterility mutation induced in a sorghum tissue culture with streptomycin].

    PubMed

    El'konin, L A; Tsvetova, M I

    2008-05-01

    Treatment of sorghum callus cultures with 500-1000 mg/l streptomycin led to a high regeneration frequency of plants with complete or partial male sterility (MS), up to 100% of all green regenerants. The induced MS mutation (ms-str) was preserved in the F1 and BC1 progenies and was genetically unstable: many families produced semisterile and fertile revertants, whose progenies again contained semisterile and sterile mutants. The ms-str mutation was maintained through eight generations via selection and self-pollination of semisterile plants. The mutation was inherited as a recessive nuclear mutation in tester crosses of sterile plants segregated in the progenies of fertile and semisterile revertants and was expressed only in single cases in a test cross for ms-str transfer through pollen of hybrids with restored male fertility. Recessive nuclear mutations determining a low plant height (dwarfness) and the lack of waxy bloom on the stem and leaves (bloomless) were found in male-sterile plants with the ms-str mutation. Cytological analysis of sterile plants reveal multiple alterations of various pollen development stages and tapetal cells: cytomyxis, defects of chromosome conjugation, distorted cytokinesis in meiotic division II, a lack of tetrad separation, a defective formation of the microspore coat, generation of microspores with two to four nuclei, and the formation of micronuclei and large vacuoles in tapetal cells. A possible transfer of the induced cytoplasmic MS mutation into the nuclear genome and the causes of the high genetic instability are discussed. PMID:18672800

  13. Programmatic Assessment of Potential Induced Radioactivity in Electron Beam Sterilization of Healthcare Products.

    PubMed

    Smith, Mark; Logar, John; Montgomery, Alan; Vrain, Olivier

    2016-08-01

    ISO 11137-1:2006 Sterilization of Healthcare Products-Radiation requires that the potential for induced radioactivity be evaluated for medical devices irradiated with electrons with energy more than 10 MeV. For a manufacturing operation where new devices are being developed, a practical program for making such an evaluation should be engrained in the process, including the device design phase, where selection of materials can make a difference in the potential for activation to occur as a result of the irradiation process. The program, which is based on general assumptions as to the likely activation processes and generalized process assessments is being implemented in three phases: (1) incorporating materials consideration in the design phase, (2) evaluating potential activation empirically, including measurement at the point of irradiation, and (3) implementing routine procedures for the program, including developing a data base of results for consideration in future design efforts. PMID:27356164

  14. Xenotransplantation exposes the etiology of azoospermia factor (AZF) induced male sterility.

    PubMed

    Barr, Justinn; Gordon, Daniel; Schedl, Paul; Deshpande, Girish

    2015-03-01

    Ramathal et al. have employed an elegant xenotransplantation technique to study the fate of human induced pluripotent stem cells (hiPSCs) from fertile males and from males carrying Y chromosome deletions of the azoospermia factor (AZF) region. When placed in a mouse testis niche, hiPSCs from fertile males differentiate into germ cell-like cells (GCLCs). Highlighting the crucial role of cell autonomous factors in male sterility, hiPSCs derived from azoospermic males prove to be less successful under similar circumstances. Their studies argue that the agametic "Sertoli cell only" phenotype of two of the AZF deletions likely arises from a defect in the maintenance of germline stem cells (GSCs) rather than from a defect in their specification. These observations underscore the importance of the dialogue between the somatic niche and its inhabitant stem cells, and open up interesting questions concerning the functioning of the somatic niche and how it communicates to the GSCs. PMID:25524208

  15. A case of oxaliplatin-induced immune-mediated thrombocytopenia

    PubMed Central

    Suh, Seong Eun; Jang, Moon Ju; Chong, So Young; Aster, Richard H.; Curtis, Brian R.

    2014-01-01

    Oxaliplatin is a platinum compound used in patients with gastrointestinal malignancies. It is known to evoke a drug-induced immune-mediated thrombocytopenia, which has not been reported in Korea. We describe a 53-year-old man who developed oxaliplatin-induced immune-mediated thrombocytopenia during chemotherapy for colon cancer. Oxaliplatin-dependent IgG platelet antibodies were detected in his serum on flow cytometry. He was treated with immunoglobulin and corticosteroids without any complications. Physicians should consider oxaliplatin-induced immune-mediated thrombocytopenia, when a sudden, isolated thrombocytopenia develops during chemotherapy with oxaliplatin. PMID:24724069

  16. [Inheritance of reversions to male fertility in male-sterile sorghum hybrids with 9E cytoplasm male sterility induced by environmental conditions].

    PubMed

    Elkonin, L A; Gerashchenkov, G A; Domanina, I V; Rozhnova, N A

    2015-03-01

    sorghum hybrids in the 9E cytoplasm. These data demonstrate that methylation of nuclear genes in sterility-inducing cytoplasm may be one of mechanisms causing the CMS phenomenon. PMID:26027370

  17. A Study of Long-Lived, Oxygen Induced Radicals in Gamma Sterilized Polyethylene*

    NASA Astrophysics Data System (ADS)

    Shah Jahan, M.; Durant, Jason

    2003-03-01

    Ultra high molecular weight polyethylene (UHMWPE) has been used for many years now as a load bearing component for hip-and knee-joint replacements. However, occasional failures of the joints have been attributed to post-gamma sterilization oxidation of the joints.^1 In this study, three grades of UHMWPE (GUR 4120, GUR 4150, and Himont 1900) samples (4 mm dia., 10 mm long) were sterilized (3.2 MRad 60 Co) in vacuum or nitrogen at 23^oC and then heated at 75^oC for one year during which the primary free radicals (alkyl/allyl) produced from irradiation decayed to 2-5% of their original values. The samples were then exposed to oxygen (air)and stored at 23^oC (room temperature). Free radical measurements were conducted at 23^oC using an X-band electron spin resonace spectrometer. It took about 100 days for the decay of the residual primary radicals and concurrent growth of the oxygen-induced radicals (OIR) to reach their extrema. Although the OIR is found to be stable on a short term, systematic measurements for four years have shown a gradual decay. The growth of the OIR is found to follow a general radial diffusion formula. While only stipulations have been made as to what the physical mechanism of the OIRÂ's decay is, it can be described by the equation: OIRd = PR_max - Rt, where PR_max is the maximum primary radical concentration, R is the decay constant, and t is time. 1. Jahan et al., J. Biomed. Mater. Res., 25 (1991), 1005. * Work supported in part by funds from the NSF Biosurface Center

  18. Postpartum Sterilization

    MedlinePlus

    ... sterilization. In tubal sterilization, the fallopian tubes are closed off or removed. Tubal sterilization prevents the egg ... through the incision. The tubes are cut and closed with special thread or removed completely. The incision ...

  19. CD8(+) T cells specific to a single Yersinia pseudotuberculosis epitope restrict bacterial replication in the liver but fail to provide sterilizing immunity.

    PubMed

    Shen, Haiqian; Gonzalez-Juarbe, Norberto; Blanchette, Krystle; Crimmins, Gregory; Bergman, Molly A; Isberg, Ralph R; Orihuela, Carlos J; Dube, Peter H

    2016-09-01

    CD8(+) T cells use contact-dependent cytolysis of target cells to protect the host against intracellular pathogens. We have previously shown that CD8(+) T cells and perforin are required to protect against the extracellular pathogen Yersinia pseudotuberculosis. Here we establish an experimental system where CD8(+) T cells specific to a single model antigen are the only memory response present at time of challenge. Using mice immunized with a vaccine strain of Listeria monocytogenes that expresses secreted ovalbumin (Lm-OVA), we show that OVA-specific CD8(+) T cells are generated and provide limited protection against challenge with virulent OVA(+)Y. pseudotuberculosis. Perforin expression by OVA-specific CD8(+) T cells was required, as Lm-OVA-immunized perforin-deficient mice showed higher bacterial burden as compared to Lm-OVA-immunized perforin-sufficient mice. Surprisingly, antigen-specific T cell protection waned over time, as Lm-OVA-immune mice eventually succumbed to Yersinia infection. Kinetic analysis of infection in mice with and without OVA-specific CD8(+) T cells revealed that bacterial numbers increased sharply in OVA-naïve mice until death, while OVA-immune mice held bacterial burden to a lower level throughout the duration of illness until death. Clonal analysis of bacterial populations in OVA-naïve and OVA-immune mice at distinct time points revealed equivalent and severe bottle-neck effects for bacteria in both sets of mice immediately after intravenous challenge, demonstrating a dominant role for other aspects of the immune system regardless of CD8(+) T cell status. These studies indicate that CD8(+) T cells against a single antigen can restrict Y. pseudotuberculosis colonization in a perforin-dependent manner, but ultimately are insufficient in their ability to provide sterilizing immunity and protect against death. PMID:27268148

  20. Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity

    PubMed Central

    Hori, Tomohide; Kuribayashi, Kagemasa; Saito, Kanako; Wang, Linan; Torii, Mie; Uemoto, Shinji; Iida, Taku; Yagi, Shintaro; Kato, Takuma

    2015-01-01

    After the first observation of the immunosuppressive effects of ultraviolet (UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells (Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery. PMID:25815267

  1. Dominant male sterility in sorghum: effect of nuclear background on inheritance of tissue-culture-induced mutation.

    PubMed

    Elkonin, Lev A

    2005-11-01

    Occurrence of genetic instability and formation of stable mutations are basic genetic processes. This study demonstrates that nuclear background may influence the formation of stable dominant nuclear gene of male sterility (MS) on the basis of unstable mutation, which was induced in tissue culture of the sorghum haploid (cv. Milo-145). The mutants with complete or partial MS segregated in variable ratios in the progenies of diploid regenerants were obtained from different experiments on cultivation of haploid tissues. In the Milo-145 genetic background the mutation demonstrated somatic instability and was gradually eliminated by self-pollination of partially sterile plants. Hybridization of the MS-plants with the sorghum line SK-723, a fertility-restorer of the cytoplasmic MS A1 (milo) type, maintained the induced mutation. By repeated backcrossing of MS-plants with SK-723, the male-sterile versions of this line (SK-723- Ms(tc)) have been created. In BC-generations, fertile, partially and completely sterile plants were observed. The MS-plants from BC-generations are proposed to contain a dominant gene Ms(tc) while fertile plants were ms(tc)/ms(tc) homozygotes. Crossing the original MS-plants with SK-723 was a key factor in stabilization of the Ms(tc) gene. Dominant expression of the Ms(tc) was observed in male-sterile versions of other sorghum lines created by backcrossing to SK-723- Ms(tc). The lines fertility-restorers for this mutation have been revealed. In the crosses of restored F1 hybrids with emasculated plants of the non-restoring line, the Ms(tc) has been transferred through the pollen and manifested in the F1 generation. The possibility of the Ms(tc) originating as a result of interaction of an unstable allele of the Milo-145 with the SK-723 genome is discussed. PMID:16205908

  2. Active immunization by a dengue virus-induced cytokine.

    PubMed Central

    Chaturvedi, U C; Mukerjee, R; Dhawan, R

    1994-01-01

    Dengue type 2 virus (DV)-induced cytotoxic factor (CF) is capable of reproducing various pathological lesions in mice that are seen in human dengue. The present study was undertaken to investigate the protective effect of active immunization of mice with CF. Mice were immunized with 5 microgram of CF and prevention of CF-induced increase in capillary permeability and damage to the blood-brain barrier were studied at weekly intervals, up to 48 weeks, by challenging with 3 microgram of CF. Maximum protection against increase in capillary permeability and damage to the blood-brain barrier was observed in week 4 after immunization. A breakthrough in the protection occurred with higher doses of CF in a dose-dependent manner. Challenge with a lethal intracerebral (i.c.) dose of DV showed significantly prolonged mean survival time and delayed onset of symptoms of sickness in the immunized mice compared with the normal mice, but the titre of the virus in the brain was similar in the two groups. On i.p. challenge with the virus the protection against damage to the blood-brain barrier was 86 +/- 7% at week 4 and 17 +/- 4% at week 26 after immunization. Sera obtained from the immunized mice showed the presence of CF-specific antibodies by ELISA, Western blot, and by neutralization of the cytotoxic activity of CF in vitro. The present study describes successful prevention of a cytokine-induced pathology by specific active immunization. PMID:8187327

  3. Immune markers and correlates of protection for vaccine induced immune responses.

    PubMed

    Thakur, Aneesh; Pedersen, Lasse E; Jungersen, Gregers

    2012-07-13

    Vaccines have been a major innovation in the history of mankind and still have the potential to address the challenges posed by chronic intracellular infections including tuberculosis, HIV and malaria which are leading causes of high morbidity and mortality across the world. Markers of an appropriate humoral response currently remain the best validated correlates of protective immunity after vaccination. Despite advancements in the field of immunology over the past few decades currently there are, however, no sufficiently validated immune correlates of vaccine induced protection against chronic infections in neither human nor veterinary medicine. Technological and conceptual advancements within cell-mediated immunology have led to a number of new immunological read-outs with the potential to emerge as correlates of vaccine induced protection. For T(H)1 type responses, antigen-specific production of interferon-gamma (IFN-γ) has been promoted as a quantitative marker of protective cell-mediated immune responses over the past couple of decades. More recently, however, evidence from several infections has pointed towards the quality of the immune response, measured through increased levels of antigen-specific polyfunctional T cells capable of producing a triad of relevant cytokines, as a better correlate of sustained protective immunity against this type of infections. Also the possibilities to measure antigen-specific cytotoxic T cells (CTL) during infection or in response to vaccination, through recombinant major histocompatibility complex (MHC) class I tetramers loaded with relevant peptides, has opened a new vista to include CTL responses in the evaluation of protective immune responses. Here, we review different immune markers and new candidates for correlates of a protective vaccine induced immune response against chronic infections and how successful they have been in defining the protective immunity in human and veterinary medicine. PMID:22658928

  4. Spacecraft sterilization.

    NASA Technical Reports Server (NTRS)

    Kalfayan, S. H.

    1972-01-01

    Spacecraft sterilization is a vital factor in projects for the successful biological exploration of other planets. The microorganisms of major concern are the fungi and bacteria. Sterilization procedures are oriented toward the destruction of bacterial spores. Gaseous sterilants are examined, giving attention to formaldehyde, beta-propiolactone, ethylene oxide, and the chemistry of the bactericidal action of sterilants. Radiation has been seriously considered as another method for spacecraft sterilization. Dry heat sterilization is discussed together with the effects of ethylene oxide decontamination and dry heat sterilization on materials.

  5. N2O induces mitotic polyploidization in anther somatic cells and restores fertility in sterile interspecific hybrid lilies

    PubMed Central

    Nukui, Shotarou; Kitamura, Satomi; Hioki, Tomoyo; Ootsuka, Hideaki; Miyoshi, Kazumitsu; Satou, Takao; Takatori, Yuka; Oomiya, Tomo; Okazaki, Keiichi

    2011-01-01

    Fertile plants undergoing male gametogenesis can be treated with nitrous oxide (N2O) gas to obtain 2n male gametes. N2O treatment is also expected to restore the fertility of interspecific hybrids through meiotic restitution or mitotic amphidiploidization. However, this technique has few applications to date, and it is un-known how N2O treatment restores fertility in sterile hybrids. To establish optimal N2O treatment conditions and determine its cytological mechanism of action, we treated various sized floral buds with N2O gas at different anther developmental stages from fertile and sterile hybrid lilies. N2O treatment using the optimal 1–4 mm floral buds induced mitotic polyploidization of male archesporial cells to produce 2n pollen in fertile hybrid lilies. In sterile hybrid lilies, N2O treatment doubled the chromosome number in male archesporial cells followed by homologous chromosome pairing and normal meiosis in pollen mother cells (PMC), resulting in restoration of pollen fertility. Backcrossing the resultant fertile pollen to Lilium × formolongi produced many triploid BC1 plants. Thus N2O treatment at the archesporial cell proliferating stage effectively overcame pollen sterility in hybrid lilies, resulting in fertile, 2n pollen grains that could produce progeny. The procedure presented here will promote interspecific or interploidy hybridization of lilies. PMID:23136469

  6. Neutralizing antibodies to HIV-1 induced by immunization

    PubMed Central

    McCoy, Laura E.

    2013-01-01

    Most neutralizing antibodies act at the earliest steps of viral infection and block interaction of the virus with cellular receptors to prevent entry into host cells. The inability to induce neutralizing antibodies to HIV has been a major obstacle to HIV vaccine research since the early days of the epidemic. However, in the past three years, the definition of a neutralizing antibody against HIV has been revolutionized by the isolation of extremely broad and potent neutralizing antibodies from HIV-infected individuals. Considerable hurdles remain for inducing neutralizing antibodies to a protective level after immunization. Meanwhile, novel technologies to bypass the induction of antibodies are being explored to provide prophylactic antibody-based interventions. This review addresses the challenge of inducing HIV neutralizing antibodies upon immunization and considers notable recent advances in the field. A greater understanding of the successes and failures for inducing a neutralizing response upon immunization is required to accelerate the development of an effective HIV vaccine. PMID:23401570

  7. Laser Induced Breakdown Spectroscopy as an In-Space Sample Return Canister Sterilization Method and Instrument

    NASA Astrophysics Data System (ADS)

    Dreyer, C. B.; Spear, J. R.; Lynch, K. L.; Johnson, L.; Bauer, A. J.

    2012-10-01

    LIBS applied to sterilize a surface via vaporization can be applied in space or on a planetary surface while providing direct characterization of ablated material. Applications include sample return or mitigation of sample cross contamination.

  8. Novel vaccine development strategies for inducing mucosal immunity

    PubMed Central

    Fujkuyama, Yoshiko; Tokuhara, Daisuke; Kataoka, Kosuke; Gilbert, Rebekah S; McGhee, Jerry R; Yuki, Yoshikazu; Kiyono, Hiroshi; Fujihashi, Kohtaro

    2012-01-01

    To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed. PMID:22380827

  9. CRISPR-Induced Distributed Immunity in Microbial Populations

    PubMed Central

    Young, Mark J.; Weitz, Joshua S.; Whitaker, Rachel J.

    2014-01-01

    In bacteria and archaea, viruses are the primary infectious agents, acting as virulent, often deadly pathogens. A form of adaptive immune defense known as CRISPR-Cas enables microbial cells to acquire immunity to viral pathogens by recognizing specific sequences encoded in viral genomes. The unique biology of this system results in evolutionary dynamics of host and viral diversity that cannot be fully explained by the traditional models used to describe microbe-virus coevolutionary dynamics. Here, we show how the CRISPR-mediated adaptive immune response of hosts to invading viruses facilitates the emergence of an evolutionary mode we call distributed immunity - the coexistence of multiple, equally-fit immune alleles among individuals in a microbial population. We use an eco-evolutionary modeling framework to quantify distributed immunity and demonstrate how it emerges and fluctuates in multi-strain communities of hosts and viruses as a consequence of CRISPR-induced coevolution under conditions of low viral mutation and high relative numbers of viral protospacers. We demonstrate that distributed immunity promotes sustained diversity and stability in host communities and decreased viral population density that can lead to viral extinction. We analyze sequence diversity of experimentally coevolving populations of Streptococcus thermophilus and their viruses where CRISPR-Cas is active, and find the rapid emergence of distributed immunity in the host population, demonstrating the importance of this emergent phenomenon in evolving microbial communities. PMID:25000306

  10. A Nonhuman Primate Scrub Typhus Model: Protective Immune Responses Induced by pKarp47 DNA Vaccination in Cynomolgus Macaques

    PubMed Central

    Chattopadhyay, Suchismita; Jiang, Ju; Nawtaisong, Pruksa; Lee, John S.; Tan, Esterlina; Dela Cruz, Eduardo; Burgos, Jasmin; Abalos, Rodolfo; Blacksell, Stuart D.; Lombardini, Eric; Turner, Gareth D.; Day, Nicholas P. J.; Richards, Allen L.

    2015-01-01

    We developed an intradermal (ID) challenge cynomolgus macaque (Macaca fascicularis) model of scrub typhus, the leading cause of treatable undifferentiated febrile illness in tropical Asia, caused by the obligate intracellular bacterium, Orientia tsutsugamushi. A well-characterized animal model is required for the development of clinically relevant diagnostic assays and evaluation of therapeutic agents and candidate vaccines. We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp. Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses. Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi–specific, IFN-γ–producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls. This study demonstrates a vaccine-induced immune response capable of conferring sterile immunity against high-dose homologous ID challenge of O. tsutsugamushi in a nonhuman primate model, and it provides insight into cell-mediated immune control of O. tsutsugamushi and dissemination dynamics, highlights the importance of bacteremia indices for evaluation of both natural and vaccine-induced immune responses, and importantly, to our knowledge, has determined the first phenotypic correlates of immune protection in scrub typhus. We conclude that this model is suitable for detailed investigations into vaccine-induced

  11. A nonhuman primate scrub typhus model: protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques.

    PubMed

    Paris, Daniel H; Chattopadhyay, Suchismita; Jiang, Ju; Nawtaisong, Pruksa; Lee, John S; Tan, Esterlina; Dela Cruz, Eduardo; Burgos, Jasmin; Abalos, Rodolfo; Blacksell, Stuart D; Lombardini, Eric; Turner, Gareth D; Day, Nicholas P J; Richards, Allen L

    2015-02-15

    We developed an intradermal (ID) challenge cynomolgus macaque (Macaca fascicularis) model of scrub typhus, the leading cause of treatable undifferentiated febrile illness in tropical Asia, caused by the obligate intracellular bacterium, Orientia tsutsugamushi. A well-characterized animal model is required for the development of clinically relevant diagnostic assays and evaluation of therapeutic agents and candidate vaccines. We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp. Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses. Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi-specific, IFN-γ-producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls. This study demonstrates a vaccine-induced immune response capable of conferring sterile immunity against high-dose homologous ID challenge of O. tsutsugamushi in a nonhuman primate model, and it provides insight into cell-mediated immune control of O. tsutsugamushi and dissemination dynamics, highlights the importance of bacteremia indices for evaluation of both natural and vaccine-induced immune responses, and importantly, to our knowledge, has determined the first phenotypic correlates of immune protection in scrub typhus. We conclude that this model is suitable for detailed investigations into vaccine-induced immune

  12. Induced immunity against hepatitis B virus.

    PubMed

    Said, Zeinab Nabil Ahmed; Abdelwahab, Kouka Saadeldin

    2015-06-28

    Prevention of hepatitis B virus (HBV) infection with its consequent development of HBV chronic liver disease and hepatocellular carcinoma is a global mandatory goal. Fortunately, safe and effective HBV vaccines are currently available. Universal hepatitis B surface antigen HBV vaccination coverage is almost done. Growing knowledge based upon monitoring and surveillance of HBV vaccination programs has accumulated and the policy of booster vaccination has been evaluated. This review article provides an overview of the natural history of HBV infection, immune responses and the future of HBV infection. It also summarizes the updated sources, types and uses of HBV vaccines, whether in the preclinical phase or in the post-field vaccination. PMID:26140085

  13. Induced immunity against hepatitis B virus

    PubMed Central

    Said, Zeinab Nabil Ahmed; Abdelwahab, Kouka Saadeldin

    2015-01-01

    Prevention of hepatitis B virus (HBV) infection with its consequent development of HBV chronic liver disease and hepatocellular carcinoma is a global mandatory goal. Fortunately, safe and effective HBV vaccines are currently available. Universal hepatitis B surface antigen HBV vaccination coverage is almost done. Growing knowledge based upon monitoring and surveillance of HBV vaccination programs has accumulated and the policy of booster vaccination has been evaluated. This review article provides an overview of the natural history of HBV infection, immune responses and the future of HBV infection. It also summarizes the updated sources, types and uses of HBV vaccines, whether in the preclinical phase or in the post-field vaccination. PMID:26140085

  14. Immune-stimulating complexes as adjuvants for inducing local and systemic immunity after oral immunization with protein antigens.

    PubMed Central

    Mowat, A M; Maloy, K J; Donachie, A M

    1993-01-01

    Orally active synthetic vaccines containing purified antigens would have many benefits for immunizing against systemic and mucosal diseases. However, several factors have limited the development of such vaccines, including the poor immunogenicity of purified proteins and their usual ability to induce tolerance when given orally. Here, we show that incorporation of ovalbumin (OVA) into immune-stimulating complexes (ISCOMS) containing saponin prevents the induction of oral tolerance in mice. In parallel, the spleen and mesenteric lymph node of mice fed OVA ISCOMS are primed for class I major histocompatibility complex (MHC)-restricted cytotoxic T-cell activity which recognizes physiologically processed epitopes on OVA. Oral immunization with OVA ISCOMS also stimulates high secretory IgA antibody responses in the intestine itself, as well as serum IgG antibodies. None of these active immune responses are detectable in mice fed OVA alone. Despite the potent priming of mucosal priming by OVA ISCOMS, re-exposure to antigen does not induce the intestinal immunopathology found in other systems after the breakdown of oral tolerance. Thus, ISCOMS have several unique properties as vectors for oral immunization and could provide a basis for future mucosal vaccines. PMID:7508416

  15. [Immune-regulating effect of phenibut under lipopolysaccharide-induced immune stress conditions].

    PubMed

    Samotrueva, M A; Tiurenkov, I N; Teplyĭ, D L; Kuleshevskaia, N R; Khlebtsova, E V

    2010-05-01

    The immunoregulating effect of phenibut has been demonstrated on the model of immune stress caused by the injection of lipopolysaccharide from Pseudomonas aeruginosa. The degree of expression of the specific (in a delayed-type hypersensitivity reaction and passive hemagglutination) and nonspecific (phagocytic activity of neutrophils) links of immunomodulation was studied. The formation of lipopolysaccharide (LPS) induced immune stress is characterized by the increase of the indicated parameters of immunity. It is found that phenibut (under intraabdominal injection of 25 mg/kg within 5 days) removes the manifestations of hyperreactivity of the cellular link of immunity, and also restores the amount of phagocytic cells, which is evidence of the immunomodulating properties of the drug under conditions of hyperimmunization. PMID:20597368

  16. Maternal immunity enhances Mycoplasma hyopneumoniae vaccination induced cell-mediated immune responses in piglets

    PubMed Central

    2014-01-01

    Background Passively acquired maternal derived immunity (MDI) is a double-edged sword. Maternal derived antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are critical immediate defenses for the neonate; however, MDI may interfere with the induction of active immunity in the neonate, i.e. passive interference. The effect of antigen-specific MDI on vaccine-induced AMI and CMI responses to Mycoplasma hyopneumoniae (M. hyopneumoniae) was assessed in neonatal piglets. To determine whether CMI and AMI responses could be induced in piglets with MDI, piglets with high and low levels of maternal M. hyopneumoniae-specific immunity were vaccinated against M. hyopneumoniae at 7 d of age. Piglet M. hyopneumoniae-specific antibody, lymphoproliferation, and delayed type hypersensitivity (DTH) responses were measured 7 d and 14 d post vaccination. Results Piglets with M. hyopneumoniae-specific MDI failed to show vaccine-induced AMI responses; there was no rise in M. hyopneumoniae antibody levels following vaccination of piglets in the presence of M. hyopneumoniae-specific MDI. However, piglets with M. hyopneumoniae-specific MDI had primary (antigen-specific lymphoproliferation) and secondary (DTH) M. hyopneumoniae-specific CMI responses following vaccination. Conclusions In this study neonatal M. hyopneumoniae-specific CMI was not subject to passive interference by MDI. Further, it appears that both maternal derived and endogenous CMI contribute to M. hyopneumoniae-specific CMI responses in piglets vaccinated in the face of MDI. PMID:24903770

  17. Nanomaterial Induced Immune Responses and Cytotoxicity.

    PubMed

    Ali, Ashraf; Suhail, Mohd; Mathew, Shilu; Shah, Muhammad Ali; Harakeh, Steve M; Ahmad, Sultan; Kazmi, Zulqarnain; Alhamdan, Mohammed Abdul Rahman; Chaudhary, Adeel; Damanhouri, Ghazi Abdullah; Qadri, Ishtiaq

    2016-01-01

    Nanomaterials are utilized in a wide array of end user products such as pharmaceuticals, electronics, clothes and cosmetic products. Due to its size (< 100 nm), nanoparticles have the propensity to enter through the airway and skin, making its path perilous with the potential to cause damages of varying severity. Once within the body, these particles have unconstrained access to different tissues and organs including the brain, liver, and kidney. As a result, nanomaterials may cause the perturbation of the immune system eliciting an inflammatory response and cytotoxicity. This potential role is dependent on many factors such as the characteristics of the nanomaterials, presence or absence of diseases, and genetic predisposition. Cobalt and nickel nanoparticles, for example, were shown to have inflammogenic properties, while silver nanoparticles were shown to reduce allergic inflammation. Just as asbestos fibers, carbon nanotubes were shown to cause lungs damage. Some nanomaterials were shown, based on animal studies, to result in cell damage, leading to the formation of pre-cancerous lesions. This review highlights the impact of nanomaterials on immune system and its effect on human health with toxicity consideration. It recommends the development of suitable animal models to study the toxicity and bio-clearance of nanomaterials and propose safety guidelines. PMID:27398432

  18. ROLE OF THE NALP3 INFLAMMASOME IN ACETAMINOPHEN-INDUCED STERILE INFLAMMATION AND LIVER INJURY

    PubMed Central

    Williams, C. David; Antoine, Daniel J.; Shaw, Patrick J.; Benson, Craig; Farhood, Anwar; Williams, Dominic P.; Kanneganti, Thirumala-Devi; Park, B. Kevin; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this investigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (Caspase-1, ASC and NALP3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. PMID:21396389

  19. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury.

    PubMed

    Williams, C David; Antoine, Daniel J; Shaw, Patrick J; Benson, Craig; Farhood, Anwar; Williams, Dominic P; Kanneganti, Thirumala-Devi; Park, B Kevin; Jaeschke, Hartmut

    2011-05-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300mg/kg APAP for 24h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. PMID:21396389

  20. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

    SciTech Connect

    Williams, C. David; Antoine, Daniel J.; Shaw, Patrick J.; Benson, Craig; Farhood, Anwar; Williams, Dominic P.; Kanneganti, Thirumala-Devi; Park, B. Kevin; Jaeschke, Hartmut

    2011-05-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1{beta} (IL-1{beta}), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1{beta} is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1{beta} and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

  1. Immunization with genetically attenuated P52-deficient Plasmodium berghei sporozoites induces a long-lasting effector memory CD8+ T cell response in the liver

    PubMed Central

    2011-01-01

    Background The induction of sterile immunity and long lasting protection against malaria has been effectively achieved by immunization with sporozoites attenuated by gamma-irradiation or through deletion of genes. For mice immunized with radiation attenuated sporozoites (RAS) it has been shown that intrahepatic effector memory CD8+ T cells are critical for protection. Recent studies have shown that immunization with genetically attenuated parasites (GAP) in mice is also conferred by liver effector memory CD8+ T cells. Findings In this study we analysed effector memory cell responses after immunization of GAP that lack the P52 protein. We demonstrate that immunization with p52-GAP sporozoites also results in a strong increase of effector memory CD8+ T cells, even 6 months after immunization, whereas no specific CD4+ effector T cells response could be detected. In addition, we show that the increase of effector memory CD8+ T cells is specific for the liver and not for the spleen or lymph nodes. Conclusions These results indicate that immunization of mice with P. berghei p52-GAP results in immune responses that are comparable to those induced by RAS or GAP lacking expression of UIS3 or UIS4, with an important role implicated for intrahepatic effector memory CD8+ T cells. The knowledge of the mediators of protective immunity after immunization with different GAP is important for the further development of vaccines consisting of genetically attenuated sporozoites. PMID:22004696

  2. Downy mildew incidence of pearl millet hybrids with different male-sterility inducing cytoplasms.

    PubMed

    Yadav, O P

    1996-02-01

    The use of different sources of cytoplasmic male sterility (CMS) in hybrid seed production of pearl millet [Pennisetum glaucum (L.) R. Br.] is advocated to avoid possible disease epidemics occurring due to cytoplasmic uniformity. The effects of commercially unexploited, but potentially exploitable, sources of CMS, like A2, A3 and A4, on downy mildew [Sclerospora graminicola (Sacc.) Schroet] incidence were studied by using the disease incidence of isonuclear hybrids with male-sterile and fertile cytoplasm. The mean downy mildew incidence of hybrids carrying different male-sterile cytoplasm was similar to that of hybrids retaining the fertile cytoplasm. The cytoplasm accounted for only 0.6% of the total variation and its effect was non-significant; pollinators could explain most of the variation in determining the disease incidence of hybrids. This suggested that these male-sterile cytoplasms are not linked to downy mildew susceptibility and thus can be exploited commercially to broaden the cytoplasmic base of the male-sterile lines and, ultimately, of hybrids. PMID:24166178

  3. WSSV-induced crayfish Dscam shows durable immune behavior.

    PubMed

    Ng, Tze Hann; Hung, Hsin-Yi; Chiang, Yi-An; Lin, Jia-Hung; Chen, Yi-Ning; Chuang, Ya-Chu; Wang, Han-Ching

    2014-09-01

    One of the major gaps in our understanding of arthropod specific immune priming concerns the mechanism[s] by which the observed long-term (>2 weeks) protective effects might be mediated. Hypervariable Dscam (Down syndrome cell adhesion molecule) might support arthropod innate immunity with specificity for more extended periods. We show here that, in the relatively long-lived arthropod Cherax quadricarinatus, CqDscam does not behave like a typical, immediately-acting, short-lived innate immune factor: CqDscam was not induced within hours after challenge with a lethal virus, but instead was only up-regulated after 2-5 days. This initial response faded within ∼ 2 weeks, but another maximum was reached ∼ 1 month later. At around 2 months after the initial challenge, the virus-induced CqDscam bound to the virus virion and acted to neutralize the virus However, although CqDscam helped crayfish to survive during persistent infection, it nevertheless failed to provide any enhanced protection against a subsequent WSSV challenge. Thus, CqDscam is capable of supporting extended anti-virus immune memory in arthropods. Also, during a persistent virus infection, the balance of "immune firepower" in crayfish appears to be altered such that the general immune factors become depleted while CqDscam becomes relatively predominant. PMID:24973514

  4. Reversible Sterilization

    ERIC Educational Resources Information Center

    Largey, Gale

    1977-01-01

    Notes that difficult questions arise concerning the use of sterilization for alleged eugenic and euthenic purposes. Thus, how reversible sterilization will be used with relation to the poor, mentally ill, mentally retarded, criminals, and minors, is questioned. (Author/AM)

  5. Sterile technique

    MedlinePlus

    Sterile gloves ... water and soap A sterile kit or pad Gloves (sometimes these are in your kit) A clean, ... border around it. Throw the wrapper away. Your gloves may be separate or inside the kit. To ...

  6. Cytological and Comparative Proteomic Analyses on Male Sterility in Brassica napus L. Induced by the Chemical Hybridization Agent Monosulphuron Ester Sodium

    PubMed Central

    Li, Zhanjie; Cui, Jianmin; Hu, Shengwu; Zhao, Huixian; Chen, Mingshun

    2013-01-01

    Male sterility induced by a chemical hybridization agent (CHA) is an important tool for utilizing crop heterosis. Monosulphuron ester sodium (MES), a new acetolactate synthase-inhibitor herbicide belonging to the sulphonylurea family, has been developed as an effective CHA to induce male sterility in rapeseed (Brassica napus L.). To understand MES-induced male sterility in rapeseed better, comparative cytological and proteomic analyses were conducted in this study. Cytological analysis indicated that defective tapetal cells and abnormal microspores were gradually generated in the developing anthers of MES-treated plants at various development stages, resulting in unviable microspores and male sterility. A total of 141 differentially expressed proteins between the MES-treated and control plants were revealed, and 131 of them were further identified by MALDI-TOF/TOF MS. Most of these proteins decreased in abundance in tissues of MES-treated rapeseed plants, and only a few increased. Notably, some proteins were absent or induced in developing anthers after MES treatment. These proteins were involved in several processes that may be crucial for tapetum and microspore development. Down-regulation of these proteins may disrupt the coordination of developmental and metabolic processes, resulting in defective tapetum and abnormal microspores that lead to male sterility in MES-treated plants. Accordingly, a simple model of CHA-MES-induced male sterility in rapeseed was established. This study is the first cytological and dynamic proteomic investigation on CHA-MES-induced male sterility in rapeseed, and the results provide new insights into the molecular events of male sterility. PMID:24244648

  7. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1.

    PubMed

    Vacchelli, Erika; Ma, Yuting; Baracco, Elisa E; Sistigu, Antonella; Enot, David P; Pietrocola, Federico; Yang, Heng; Adjemian, Sandy; Chaba, Kariman; Semeraro, Michaela; Signore, Michele; De Ninno, Adele; Lucarini, Valeria; Peschiaroli, Francesca; Businaro, Luca; Gerardino, Annamaria; Manic, Gwenola; Ulas, Thomas; Günther, Patrick; Schultze, Joachim L; Kepp, Oliver; Stoll, Gautier; Lefebvre, Céline; Mulot, Claire; Castoldi, Francesca; Rusakiewicz, Sylvie; Ladoire, Sylvain; Apetoh, Lionel; Bravo-San Pedro, José Manuel; Lucattelli, Monica; Delarasse, Cécile; Boige, Valérie; Ducreux, Michel; Delaloge, Suzette; Borg, Christophe; André, Fabrice; Schiavoni, Giovanna; Vitale, Ilio; Laurent-Puig, Pierre; Mattei, Fabrizio; Zitvogel, Laurence; Kroemer, Guido

    2015-11-20

    Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses. PMID:26516201

  8. Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor.

    PubMed

    Qin, Suofu; Ni, Ming; Wang, Xiuyun; Maurier-Mahé, Florence; Shurland, Dixie-Lee; Rodrigues, Gerard A

    2011-12-01

    Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis. Cellular extracts can trigger ARPE-19 cell inflammatory responses, producing cytokines that lead to an increase in ARPE-19 cell monolayer permeability. Addition of recombinant HSP90β mimics the induction of chemokines IL-8 and MCP-1 in cultured RPE cells, suggesting that released HSP90 can incite RPE cell sterile inflammatory responses. Consistent with this, classical HSP90 inhibitors were shown to substantially reduce necrosis-induced cytokine production and permeability increases in ARPE-19 cells. Moreover, a cell-impermeable inhibitor, 17-N,N-dimethylaminoethylamino-17-demethoxy-geldanamycin-N-oxide, also efficiently inhibited necrosis-induced cytokine production and TNF-α/IL-1β-induced increase in ARPE-19 cell permeability in vitro and endotoxin-induced development of uveitis in vivo, suggesting that HSP90 can contribute to necrosis-induced RPE inflammatory responses. Collectively, our data identify HSP90 as a pro-inflammatory molecule in RPE cell sterile inflammatory responses. PMID:22019372

  9. Harnessing DNA-induced immune responses for improving cancer vaccines

    PubMed Central

    Herrada, Andrés A.; Rojas-Colonelli, Nicole; González-Figueroa, Paula; Roco, Jonathan; Oyarce, César; Ligtenberg, Maarten A.; Lladser, Alvaro

    2012-01-01

    DNA vaccines have emerged as an attractive strategy to promote protective cellular and humoral immunity against the encoded antigen. DNA vaccines are easy to generate, inexpensive to produce and purify at large-scale, highly stable and safe. In addition, plasmids used for DNA vaccines act as powerful “danger signals” by stimulating several DNA-sensing innate immune receptors that promote the induction of protective adaptive immunity. The induction of tumor-specific immune responses represents a major challenge for DNA vaccines because most of tumor-associated antigens are normal non-mutated self-antigens. As a consequence, induction of potentially self-reactive T cell responses against such poorly immunogenic antigens is controlled by mechanisms of central and peripheral tolerance as well as tumor-induced immunosuppression. Although several DNA vaccines against cancer have reached clinical testing, disappointing results have been observed. Therefore, the development of new adjuvants that strongly stimulate the induction of antitumor T cell immunity and counteract immune-suppressive regulation is an attractive approach to enhance the potency of DNA vaccines and overcome tumor-associated tolerance. Understanding the DNA-sensing signaling pathways of innate immunity that mediate the induction of T cell responses elicited by DNA vaccines represents a unique opportunity to develop novel adjuvants that enhance vaccine potency. The advance of DNA adjuvants needs to be complemented with the development of potent delivery systems, in order to step toward successful clinical application. Here, we briefly discuss recent evidence showing how to harness DNA-induced immune response to improve the potency of cancer vaccines and counteract tumor-associated tolerance. PMID:23111166

  10. Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation

    PubMed Central

    Ewer, Katie J.; O’Hara, Geraldine A.; Duncan, Christopher J. A.; Collins, Katharine A.; Sheehy, Susanne H.; Reyes-Sandoval, Arturo; Goodman, Anna L.; Edwards, Nick J.; Elias, Sean C.; Halstead, Fenella D.; Longley, Rhea J.; Rowland, Rosalind; Poulton, Ian D.; Draper, Simon J.; Blagborough, Andrew M.; Berrie, Eleanor; Moyle, Sarah; Williams, Nicola; Siani, Loredana; Folgori, Antonella; Colloca, Stefano; Sinden, Robert E.; Lawrie, Alison M.; Cortese, Riccardo; Gilbert, Sarah C.; Nicosia, Alfredo; Hill, Adrian V. S.

    2013-01-01

    Induction of antigen-specific CD8+ T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8+ T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/106 peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8+ T cells, but not antibodies, correlates with sterile protection and delay in time to patency (Pcorrected=0.005). Vaccine-induced CD8+ T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells. PMID:24284865

  11. Intranasal Immunization with Nontypeable Haemophilus influenzae Outer Membrane Vesicles Induces Cross-Protective Immunity in Mice

    PubMed Central

    Roier, Sandro; Leitner, Deborah R.; Iwashkiw, Jeremy; Schild-Prüfert, Kristina; Feldman, Mario F.; Krohne, Georg; Reidl, Joachim; Schild, Stefan

    2012-01-01

    Abstract Haemophilus influenzae is a Gram-negative human-restricted bacterium that can act as a commensal and a pathogen of the respiratory tract. Especially nontypeable H. influenzae (NTHi) is a major threat to public health and is responsible for several infectious diseases in humans, such as pneumonia, sinusitis, and otitis media. Additionally, NTHi strains are highly associated with exacerbations in patients suffering from chronic obstructive pulmonary disease. Currently, there is no licensed vaccine against NTHi commercially available. Thus, this study investigated the utilization of outer membrane vesicles (OMVs) as a potential vaccine candidate against NTHi infections. We analyzed the immunogenic and protective properties of OMVs derived from various NTHi strains by means of nasopharyngeal immunization and colonization studies with BALB/c mice. The results presented herein demonstrate that an intranasal immunization with NTHi OMVs results in a robust and complex humoral and mucosal immune response. Immunoprecipitation revealed the most important immunogenic proteins, such as the heme utilization protein, protective surface antigen D15, heme binding protein A, and the outer membrane proteins P1, P2, P5 and P6. The induced immune response conferred not only protection against colonization with a homologous NTHi strain, which served as an OMV donor for the immunization mixtures, but also against a heterologous NTHi strain, whose OMVs were not part of the immunization mixtures. These findings indicate that OMVs derived from NTHi strains have a high potential to act as a vaccine against NTHi infections. PMID:22880074

  12. DEVELOPMENT OF MOLECULAR BIOMARKERS TO MEASURE ENVIRONMENTALLY INDUCED IMMUNE RESPONSES

    EPA Science Inventory

    This study will generate a panel of sensitive molecular biomarkers to measure environmentally induced changes in systemic and local immune responses within small biological samples. Once tested and characterized, these reagents can be immediately incorporated as a part of the...

  13. Specific humoral and cellular immunity induced by Trypanosoma cruzi DNA immunization in a canine model

    PubMed Central

    2013-01-01

    Chagas disease has a high incidence in Mexico and other Latin American countries. Because one of the most important known methods of prevention is vector control, which has been effective only in certain areas of South America, the development of a vaccine to protect people at risk has been proposed. In this study, we assessed the cellular and humoral immune response generated following immunization with pBCSP and pBCSSP4 plasmids containing the genes encoding a trans-sialidase protein (present in all three forms of T. cruzi) and an amastigote specific glycoprotein, respectively, in a canine model. Thirty-five beagle dogs were divided randomly into 5 groups (n = 7) and were immunized twice intramuscularly with 500 μg of pBCSSP4, pBCSP, pBk-CMV (empty plasmid) or saline solution. Fifteen days after the last immunization the 4 groups were infected intraperitoneally with 500 000 metacyclic trypomastigotes. The fifth group was unimmunized/infected. The parasitaemia in the immunized/infected dogs was for a shorter period (14 vs. 29 days) and the parasite load was lower. The concentration of IgG1 (0.612 ± 0.019 O.D.) and IgG2 (1.167 ± 0.097 O.D.) subclasses was measured (absorbance) 15 days after the last immunization with both recombinant plasmids, the majority of which were IgG2. The treatment of parasites using the serum from dogs immunized with pBCSP and pBCSSP4 plasmids produced 54% (± 11.8) and 68% (± 21.4) complement-mediated lysis, respectively. At 12 h post immunization, an increase in cytokines was not observed; however, vaccination with pBCSSP4 significantly increased the levels of IFN-γ and IL-10 at 9 months post-infection. The recombinant plasmid immunization stimulated the spleen cell proliferation showing a positive stimulatory index above 2.0. In conclusion, immunization using both genes effectively induces a humoral and cellular immune response. PMID:23497041

  14. Specific humoral and cellular immunity induced by Trypanosoma cruzi DNA immunization in a canine model.

    PubMed

    Arce-Fonseca, Minerva; Ballinas-Verdugo, Martha A; Zenteno, Emma R Abreu; Suárez-Flores, Davinia; Carrillo-Sánchez, Silvia C; Alejandre-Aguilar, Ricardo; Rosales-Encina, José Luis; Reyes, Pedro A; Rodríguez-Morales, Olivia

    2013-01-01

    Chagas disease has a high incidence in Mexico and other Latin American countries. Because one of the most important known methods of prevention is vector control, which has been effective only in certain areas of South America, the development of a vaccine to protect people at risk has been proposed. In this study, we assessed the cellular and humoral immune response generated following immunization with pBCSP and pBCSSP4 plasmids containing the genes encoding a trans-sialidase protein (present in all three forms of T. cruzi) and an amastigote specific glycoprotein, respectively, in a canine model. Thirty-five beagle dogs were divided randomly into 5 groups (n=7) and were immunized twice intramuscularly with 500 μg of pBCSSP4, pBCSP, pBk-CMV (empty plasmid) or saline solution. Fifteen days after the last immunization the 4 groups were infected intraperitoneally with 500,000 metacyclic trypomastigotes. The fifth group was unimmunized/infected. The parasitaemia in the immunized/infected dogs was for a shorter period (14 vs. 29 days) and the parasite load was lower. The concentration of IgG1 (0.612±0.019 O.D.) and IgG2 (1.167±0.097 O.D.) subclasses was measured (absorbance) 15 days after the last immunization with both recombinant plasmids, the majority of which were IgG2. The treatment of parasites using the serum from dogs immunized with pBCSP and pBCSSP4 plasmids produced 54% (±11.8) and 68% (±21.4) complement-mediated lysis, respectively. At 12 h post immunization, an increase in cytokines was not observed; however, vaccination with pBCSSP4 significantly increased the levels of IFN-γ and IL-10 at 9 months post-infection. The recombinant plasmid immunization stimulated the spleen cell proliferation showing a positive stimulatory index above 2.0. In conclusion, immunization using both genes effectively induces a humoral and cellular immune response. PMID:23497041

  15. Specific panicle responses resulting from MSMA-induced straighthead sterility in rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Straighthead is a physiological disorder of rice causing sterility. A particular characteristic of straighthead is panicles that remain upright because of the light weight of the unfilled grains and hulls which may be distorted into a crescent or parrot-beak shape. Monosodium acid methanearsonate (M...

  16. Coupling to the surface of liposomes alters the immunogenicity of hepatitis C virus-derived peptides and confers sterile immunity.

    PubMed

    Takagi, Akira; Kobayashi, Nobuharu; Taneichi, Maiko; Uchida, Tetsuya; Akatsuka, Toshitaka

    2013-01-01

    We have previously demonstrated that antigens chemically coupled to the surface of liposomes consisting of unsaturated fatty acids were cross-presented by antigen presenting cells to cytotoxic T lymphocytes (CTLs). Liposomal form of immunodominant CTL epitope peptides derived from lymphocytic choriomeningitis virus exhibited highly efficient antiviral CTL responses in immunized mice. In this study, we coupled 15 highly conserved immunodominant CTL epitope peptides derived from hepatitis C virus (HCV) to the surface of liposomes. We also emulsified the peptides in incomplete Freund's adjuvant, and compared the immune responses of the two methods of presenting the peptides by cytotoxicity induction and interferon-gamma (IFN-γ) production by CD8(+) T cells of the immunized mice. We noticed significant variations of the immunogenicity of each peptide between the two antigen delivery systems. In addition, the immunogenicity profiles of the peptides were also different from those observed in the mice infected with recombinant adenoviruses expressing HCV proteins as previously reported. Induction of anti-viral immunity by liposomal peptides was tested by the challenge experiments using recombinant vaccinia viruses expressing corresponding HCV epitopes. One D(b)-restricted and three HLA-A(*)0201-restricted HCV CTL epitope peptides on the surface of liposomes were found to confer complete protection to immunized mice with establishment of long-term memory. Interestingly, their protective efficacy seemed to correlate with the induction of IFN-γ producing cells rather than the cytotoxicity induction suggesting that the immunized mice were protected through non-cytolytic mechanisms. Thus, these liposomal peptides might be useful as HCV vaccines not only for prevention but also for therapeutic use. PMID:23159619

  17. Inducible immune proteins in the dampwood termite Zootermopsis angusticollis

    NASA Astrophysics Data System (ADS)

    Rosengaus, Rebeca B.; Cornelisse, Tara; Guschanski, Katerina; Traniello, James F. A.

    2007-01-01

    Dampwood termites, Zootermopsis angusticollis (Isoptera: Termopsidae), mount an immune response to resist microbial infection. Here we report on results of a novel analysis that allowed us to electrophoretically assess changes in hemolymph proteins in the same individual before and after exposure to a pathogen. We demonstrate that contact with a sublethal concentration of the entomopathogenic fungus Metarhizium anisopliae (Deuteromycotina:Hypomycetes) induces the production of protective proteins in nymphs, pseudergates (false workers), and soldiers. Termites exposed to an immunizing dosage of fungal conidia consistently showed an enhancement of constitutive proteins (62-85 kDa) in the hemolymph as well as an induction of novel proteins (28-48 kDa) relative to preimmunization levels. No significant differences in protein banding patterns relative to baseline levels in control and naïve termites were observed. Incubating excised and eluted induced proteins produced by immunized pseudergates or immunized soldiers with conidia significantly reduced the germination of the fungus. The fungistatic effect of eluted proteins differed significantly among five colonies examined. Our results show that the upregulation of protective proteins in the hemolymph underscores the in vivo immune response we previously recorded in Z. angusticollis.

  18. A Drosophila immune response against Ras-induced overgrowth

    PubMed Central

    Hauling, Thomas; Krautz, Robert; Markus, Robert; Volkenhoff, Anne; Kucerova, Lucie; Theopold, Ulrich

    2014-01-01

    ABSTRACT Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12), both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria), which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity. PMID:24659248

  19. Adenosine signaling and the energetic costs of induced immunity.

    PubMed

    Lazzaro, Brian P

    2015-04-01

    Life history theory predicts that trait evolution should be constrained by competing physiological demands on an organism. Immune defense provides a classic example in which immune responses are presumed to be costly and therefore come at the expense of other traits related to fitness. One strategy for mitigating the costs of expensive traits is to render them inducible, such that the cost is paid only when the trait is utilized. In the current issue of PLOS Biology, Bajgar and colleagues elegantly demonstrate the energetic and life history cost of the immune response that Drosophila melanogaster larvae induce after infection by the parasitoid wasp Leptopilina boulardi. These authors show that infection-induced proliferation of defensive blood cells commands a diversion of dietary carbon away from somatic growth and development, with simple sugars instead being shunted to the hematopoetic organ for rapid conversion into the raw energy required for cell proliferation. This metabolic shift results in a 15% delay in the development of the infected larva and is mediated by adenosine signaling between the hematopoietic organ and the central metabolic control organ of the host fly. The adenosine signal thus allows D. melanogaster to rapidly marshal the energy needed for effective defense and to pay the cost of immunity only when infected. PMID:25915419

  20. Genetic immunization in the lung induces potent local and systemic immune responses.

    PubMed

    Song, Kaimei; Bolton, Diane L; Wei, Chih-Jen; Wilson, Robert L; Camp, Jeremy V; Bao, Saran; Mattapallil, Joseph J; Herzenberg, Leonore A; Herzenberg, Leonard A; Andrews, Charla A; Sadoff, Jerald C; Goudsmit, Jaap; Pau, Maria Grazia; Seder, Robert A; Kozlowski, Pamela A; Nabel, Gary J; Roederer, Mario; Rao, Srinivas S

    2010-12-21

    Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens. PMID:21135247

  1. Immunization with avian metapneumovirus harboring chicken Fc induces higher immune responses.

    PubMed

    Paudel, Sarita; Easwaran, Maheswaran; Jang, Hyun; Jung, Ho-Kyoung; Kim, Joo-Hun; Shin, Hyun-Jin

    2016-07-15

    In this study, we evaluated the immune responses of avian metapneumovirus harboring chicken Fc molecule. Stable Vero cells expressing chicken Fc chimera on its surface (Vero-cFc) were established, and we confirmed that aMPV grown in Vero-cFc incorporated host derived chimera Fc into the aMPV virions. Immunization of chicken with aMPV-cFc induced higher level of antibodies and inflammatory cytokines; (Interferon (IFN)-γ and Interleukin (IL)-1β) compared to those of aMPV. The increased levels of antibodies and inflammatory cytokines in chicken immunized with aMPV-cFc were statistically significantly (p<0.05) to that of aMPV and control. The aMPV-cFc group also generated the highest neutralizing antibody response. After challenges, chickens immunized with aMPV-cFc showed much less pathological signs in nasal turbinates and trachea so that we could confirm aMPV-cFc induced higher protection than that of aMPV. The greater ability of aMPV harboring chicken Fc to that of aMPV presented it as a possible vaccine candidate. PMID:27130629

  2. Drug-Induced Glomerular Disease: Immune-Mediated Injury

    PubMed Central

    Markowitz, Glen S.; Radhakrishnan, Jai

    2015-01-01

    Drug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-like syndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agents have been linked to immune-mediated glomerular disease, often with associated autoantibody formation. Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, and making this distinction is important in the diagnosis and management of these patients. Here, drug-induced, ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed. PMID:26092827

  3. Radiation-induced effects and the immune system in cancer

    PubMed Central

    Kaur, Punit; Asea, Alexzander

    2012-01-01

    Chemotherapy and radiation therapy (RT) are standard therapeutic modalities for patients with cancers, and could induce various tumor cell death modalities, releasing tumor-derived antigens as well as danger signals that could either be captured for triggering anti-tumor immune response. Historic studies examining tissue and cellular responses to RT have predominantly focused on damage caused to proliferating malignant cells leading to their death. However, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, particularly with respect to effects on immune cells and infiltrating tumors. This review will focus on immunologic consequences of RT and discuss the therapeutic reprogramming of immune responses in tumors and how it regulates efficacy and durability to RT. PMID:23251903

  4. Immune-mediated drug-induced liver disease.

    PubMed

    Liu, Zhang-Xu; Kaplowitz, Neil

    2002-08-01

    Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued. PMID:12362579

  5. The Role of Probiotics and Prebiotics in Inducing Gut Immunity

    PubMed Central

    Vieira, Angélica T.; Teixeira, Mauro M.; Martins, Flaviano S.

    2013-01-01

    The gut immune system is influenced by many factors, including dietary components and commensal bacteria. Nutrients that affect gut immunity and strategies that restore a healthy gut microbial community by affecting the microbial composition are being developed as new therapeutic approaches to treat several inflammatory diseases. Although probiotics (live microorganisms) and prebiotics (food components) have shown promise as treatments for several diseases in both clinical and animal studies, an understanding of the molecular mechanisms behind the direct and indirect effects on the gut immune response will facilitate better and possibly more efficient therapy for diseases. In this review, we will first describe the concept of prebiotics, probiotics, and symbiotics and cover the most recently well-established scientific findings regarding the direct and indirect mechanisms by which these dietary approaches can influence gut immunity. Emphasis will be placed on the relationship of diet, the microbiota, and the gut immune system. Second, we will highlight recent results from our group, which suggest a new dietary manipulation that includes the use of nutrient products (organic selenium and Lithothamnium muelleri) and probiotics (Saccharomyces boulardii UFMG 905 and Bifidobacterium sp.) that can stimulate and manipulate the gut immune response, inducing intestinal homeostasis. Furthermore, the purpose of this review is to discuss and translate all of this knowledge into therapeutic strategies and into treatment for extra-intestinal compartment pathologies. We will conclude by discussing perspectives and molecular advances regarding the use of prebiotics or probiotics as new therapeutic strategies that manipulate the microbial composition and the gut immune responses of the host. PMID:24376446

  6. The role of probiotics and prebiotics in inducing gut immunity.

    PubMed

    Vieira, Angélica T; Teixeira, Mauro M; Martins, Flaviano S

    2013-01-01

    The gut immune system is influenced by many factors, including dietary components and commensal bacteria. Nutrients that affect gut immunity and strategies that restore a healthy gut microbial community by affecting the microbial composition are being developed as new therapeutic approaches to treat several inflammatory diseases. Although probiotics (live microorganisms) and prebiotics (food components) have shown promise as treatments for several diseases in both clinical and animal studies, an understanding of the molecular mechanisms behind the direct and indirect effects on the gut immune response will facilitate better and possibly more efficient therapy for diseases. In this review, we will first describe the concept of prebiotics, probiotics, and symbiotics and cover the most recently well-established scientific findings regarding the direct and indirect mechanisms by which these dietary approaches can influence gut immunity. Emphasis will be placed on the relationship of diet, the microbiota, and the gut immune system. Second, we will highlight recent results from our group, which suggest a new dietary manipulation that includes the use of nutrient products (organic selenium and Lithothamnium muelleri) and probiotics (Saccharomyces boulardii UFMG 905 and Bifidobacterium sp.) that can stimulate and manipulate the gut immune response, inducing intestinal homeostasis. Furthermore, the purpose of this review is to discuss and translate all of this knowledge into therapeutic strategies and into treatment for extra-intestinal compartment pathologies. We will conclude by discussing perspectives and molecular advances regarding the use of prebiotics or probiotics as new therapeutic strategies that manipulate the microbial composition and the gut immune responses of the host. PMID:24376446

  7. Bacterial Outer Membrane Vesicles Induce Plant Immune Responses.

    PubMed

    Bahar, Ofir; Mordukhovich, Gideon; Luu, Dee Dee; Schwessinger, Benjamin; Daudi, Arsalan; Jehle, Anna Kristina; Felix, Georg; Ronald, Pamela C

    2016-05-01

    Gram-negative bacteria continuously pinch off portions of their outer membrane, releasing membrane vesicles. These outer membrane vesicles (OMVs) are involved in multiple processes including cell-to-cell communication, biofilm formation, stress tolerance, horizontal gene transfer, and virulence. OMVs are also known modulators of the mammalian immune response. Despite the well-documented role of OMVs in mammalian-bacterial communication, their interaction with plants is not well studied. To examine whether OMVs of plant pathogens modulate the plant immune response, we purified OMVs from four different plant pathogens and used them to treat Arabidopsis thaliana. OMVs rapidly induced a reactive oxygen species burst, medium alkalinization, and defense gene expression in A. thaliana leaf discs, cell cultures, and seedlings, respectively. Western blot analysis revealed that EF-Tu is present in OMVs and that it serves as an elicitor of the plant immune response in this form. Our results further show that the immune coreceptors BAK1 and SOBIR1 mediate OMV perception and response. Taken together, our results demonstrate that plants can detect and respond to OMV-associated molecules by activation of their immune system, revealing a new facet of plant-bacterial interactions. PMID:26926999

  8. Flagella-induced immunity against experimental cholera in adult rabbits.

    PubMed Central

    Yancey, R J; Willis, D L; Berry, L J

    1979-01-01

    The adult rabbit ligated ileal loop model was used to evaluate the prophylactic potential of a crude flagellar (CF) vaccine produced from the classical. Inaba strain CA401. A greater than 1,000-fold increase in the challenge inoculum was required to induce an intestinal fluid response in actively immunized adult rabbits equivalent to that produced in unimmunized animals. Similar protection was afforded against challenge with classical and El Tor biotypes of both Inaba and Ogawa serotypes. Highly virulent 35S-labeled vibrios were inhibited in their ability to associated with the intestinal mucosa of CF-immunized rabbits. The protection conferred by CF immunization was found to be superior to that of a commercial bivalent vaccine and also to that of glutaraldehyde-treated cholera toxoid. The critical immunogenic component of CF appears to be a flagella-derived protein. The immunogenicity of CF was destroyed by heat treatment, and absorption of CF-immune serum with aflagellated mutant vibrios did not diminish its ability to confer a high level of passive protection. The intestinal protection of CF-immunized rabbits was completely reversed by the introduction of both goat anti-rabbit immunoglobulins A and G, but by neither alone. PMID:478635

  9. Transgenic male-sterile plant induced by an unedited atp9 gene is restored to fertility by inhibiting its expression with antisense RNA.

    PubMed Central

    Zabaleta, E; Mouras, A; Hernould, M; Suharsono; Araya, A

    1996-01-01

    We have previously shown that the expression of an unedited atp9 chimeric gene correlated with male-sterile phenotype in transgenic tobacco plant. To study the relationship between the expression of chimeric gene and the male-sterile trait, hemizygous and homozygous transgenic tobacco lines expressing the antisense atp9 RNA were constructed. The antisense producing plants were crossed with a homozygous male-sterile line, and the F1 progeny was analyzed. The offspring from crosses between homozygous lines produced only male-fertile plants, suggesting that the expression antisense atp9 RNA abolishes the effect of the unedited chimeric gene. In fact, the plants restored to male fertility showed a dramatic reduction of the unedited atp9 transcript levels, resulting in normal flower development and seed production. These results support our previous observation that the expression of unedited atp9 gene can induce male sterility. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8855343

  10. Is immunity a mechanism contributing to statin-induced diabetes?

    PubMed Central

    Henriksbo, Brandyn D; Schertzer, Jonathan D

    2015-01-01

    Statins lower cholesterol and are commonly prescribed for prevention and treatment of cardiovascular disease risk. Statins have pleotropic actions beyond cholesterol lowering, including decreased protein prenylation, which can alter immune function. The general anti-inflammatory effect of statins may be a key pleiotropic effect that improves cardiovascular disease risk. However, a series of findings have shown that statins increase the pro-inflammatory cytokine, IL-1β, via decreased protein prenylation in immune cells. IL-1β can be regulated by the NLRP3 inflammasome containing caspase-1. Statins have been associated with an increased risk of new onset diabetes. Inflammation can promote ineffective insulin action (insulin resistance), which often precedes diabetes. This review highlights the links between statins, insulin resistance and immunity via the NLRP3 inflammasome. We propose that statin-induced changes in immunity should be investigated as a mechanism underlying increased risk of diabetes. It is possible that statin-related insulin resistance occurs through a separate pathway from various mechanisms that confer cardiovascular benefits. Therefore, understanding the potential mechanisms that segregate statin-induced cardiovascular effects from those that cause dysglycemia may lead to improvements in this drugs class. PMID:26451278

  11. Salmonella enterica induces and subverts the plant immune system

    PubMed Central

    García, Ana V.; Hirt, Heribert

    2014-01-01

    Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Although it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs), such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI). Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS) as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, these data suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity. PMID:24772109

  12. Requirements for innate immune pathways in environmentally induced autoimmunity.

    PubMed

    Pollard, Kenneth Michael; Kono, Dwight H

    2013-01-01

    There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity. PMID:23557436

  13. Antitumor immunity induced by hybrid murine tumor cells: requirements for optimal immunization

    SciTech Connect

    McCune, C.S.; O'Donnell, R.W.; Horan, P.K.; Budd, H.S.; Spennacchio, J.L.; Chuang, C.; Henshaw, E.C.

    1982-09-01

    Hybrid tumor cells have been evaluated for their ability to induce specific antitumor immunity in inbred female C3H/He mice challenged with the syngeneic BA tumor. Hybrid cells were produced by fusion of BA cells with a BALB/c renal adenocarcinoma, which is hypoxanthine phosphoribosyl transferase-deficient and grows well in culture. Corynebacterium parvum was evaluated as an adjuvant for BA and hybrid cells. The BA tumor was shown to be poorly immunogenic, and four weekly injections of BA cells alone or C. parvum alone did not confer significant immunity. When BA cells and C. parvum were mixed, survival time was prolonged and most mice remained tumor-free. Hybrid cell lines derived from the BA tumor were produced in culture in unlimited quantities and were successfully used as immunogens. The addition of C. parvum to hybrids gave a significant incremental increase in survival when compared to the survival resulting from immunization by hybrids without adjuvant. When hybrids without adjuvant were used, several weekly injections were required for effective immunization. Irradiated and unirradiated hybrids were compared, and it was found that irradiation did not diminish hybrid immunogenicity. The potential problems and advantages of this concept of therapy are discussed.

  14. Radiation exposure induces inflammasome pathway activation in immune cells.

    PubMed

    Stoecklein, Veit M; Osuka, Akinori; Ishikawa, Shizu; Lederer, Madeline R; Wanke-Jellinek, Lorenz; Lederer, James A

    2015-02-01

    Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation. PMID:25539818

  15. Hepatotoxicants induce cytokine imbalance in response to innate immune system.

    PubMed

    Goto, Shima; Deguchi, Jiro; Nishio, Naoki; Nomura, Naruaki; Funabashi, Hitoshi

    2015-06-01

    In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro- and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro- and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI. PMID:25972199

  16. Protective immunity spectrum induced by immunization with a vaccine from the TBEV strain Sofjin.

    PubMed

    Chernokhaeva, L L; Rogova, Yu V; Vorovitch, M F; Romanova, L Iu; Kozlovskaya, L I; Maikova, G B; Kholodilov, I S; Karganova, G G

    2016-04-29

    Tick-borne encephalitis (TBE) circulates widely in the territory of Eurasia with up to 10,000 cases registered annually. The TBE virus (TBEV) includes three main subtypes: European, Siberian and Far-Eastern, and two new Asiatic variants, phylogenetically distant from the others. The inactivated antigen of European or Far-Eastern strains is used in commercial TBE vaccines. A set of 14 TBEV strains, isolated in 1937-2008, with different passage histories, representing all subtypes and variants, was used in this work. The chosen set covers almost all the TBE area. Sera of mice, immunized with the TBE vaccine Moscow, prepared from the TBEV strain Sofjin, were studied in a plaque neutralization test against the set of TBEV strains. The vaccine induced antibodies at a protective titer against all TBEV strains and Omsk hemorrhagic fever virus (OHFV) with Е protein amino acid distances of 0.008-0.069, but not against Powassan virus. We showed that after a course of two immunizations, factors such as the period between vaccinations (1-4 weeks), the challenging virus dose (30-1000 LD50) and terms of challenge (1-4 weeks after the last immunization) did not significantly affect the assessment of protective efficacy of the vaccine in vivo. The protective effect of the TBE vaccine Moscow against the set of TBEV strains and the OHFV was demonstrated in in vivo experiments. TBE vaccine Moscow did not protect mice against 10 LD50 of the Powassan virus. We showed that this range of Е protein amino acid distances between the vaccine strain and challenging virus do not have a decisive impact on the TBE vaccine protective effect in vitro and in vivo. Moreover, the TBE vaccine Moscow induces an immune response protective against a wide range of TBEV variants. PMID:27013433

  17. Progress in development of immunocontraceptive vaccines for permanent non-surgical sterilization of cats and dogs.

    PubMed

    Munks, M W

    2012-08-01

    Each year, millions of cats and dogs are euthanized worldwide. There are insufficient resources to control shelter animals in developed countries, as well as feral cat and wild dog population levels, with current surgical sterilization techniques. Thus, population control of these animals will likely depend on the development of new non-surgical methods for cat and dog sterilization. One promising area of research is the development of contraceptive vaccines, or immunocontraceptives. In this article, previous approaches aimed at developing contraceptive vaccines will be reviewed, with a focus on those most related to sterilization of cats and dogs. There are a number of steps in reproduction that have been, or could be, targeted by the immune system, and the advantages and obstacles for inducing immunity to each of these will be discussed. Our current understanding of how these vaccines cause sterility, and our current ability to dissect these mechanisms in cats and dogs, also will be discussed. PMID:22827374

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  20. Immune response to stem cells and strategies to induce tolerance.

    PubMed

    Batten, Puspa; Rosenthal, Nadia A; Yacoub, Magdi H

    2007-08-29

    Although recent progress in cardiovascular tissue engineering has generated great expectations for the exploitation of stem cells to restore cardiac form and function, the prospects of a common mass-produced cell resource for clinically viable engineered tissues and organs remain problematic. The refinement of stem cell culture protocols to increase induction of the cardiomyocyte phenotype and the assembly of transplantable vascularized tissue are areas of intense current research, but the problem of immune rejection of heterologous cell type poses perhaps the most significant hurdle to overcome. This article focuses on the potential advantages and problems encountered with various stem cell sources for reconstruction of the damaged or failing myocardium or heart valves and also discusses the need for integrating advances in developmental and stem cell biology, immunology and tissue engineering to achieve the full potential of cardiac tissue engineering. The ultimate goal is to produce 'off-the-shelf' cells and tissues capable of inducing specific immune tolerance. PMID:17584730

  1. Immunity-Based Evolutionary Interpretation of Diet-Induced Thermogenesis.

    PubMed

    Liao, Wan-Hui; Henneberg, Maciej; Langhans, Wolfgang

    2016-06-14

    Diet-induced thermogenesis (DIT) has often been argued to be a physiological defense against obesity, but no empirical proof of its effectiveness in limiting human body weight gain is available. We here propose an immune explanation of DIT-i.e., that it results from the coevolution of host and gut microbiota (especially Firmicutes) that ferment ingested food and proliferate, causing periodic, vagally mediated increases in thermogenesis aimed at curtailing their expansion. Because of this evolutionary adaptive significance related to the immune system, DIT is not effective as an "adaptation" to maintain a certain body mass. Were DIT an effective adaptation to prevent obesity, the current obesity epidemic might not have occurred. PMID:27304499

  2. The role of cytokines in immune changes induced by spaceflight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Miller, E. S.

    1993-01-01

    It has become apparent that spaceflight alters many immune responses. Among the regulatory components of the immune response that have been shown to be affected by spaceflight is the cytokine network. Spaceflight, as well as model systems of spaceflight, have been shown to affect the production and action of various cytokines including interferons, interleukins, colony stimulating factors, and tumor necrosis factors. These changes have been shown not to involve a general shutdown of the cytokine network but, rather, to involve selective alterations of specific cytokine functions by spaceflight. The full breadth of changes in cytokines induced by spaceflight, as well as mechanisms, duration, adaptation, reversibility, and significance to resistance to infection and neoplastic diseases, remains to be established.

  3. The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility

    PubMed Central

    Di Micco, Pierpaolo; D'Uva, Maristella; Strina, Ida; Mollo, Antonio; Amato, Valeria; Niglio, Alferio; De Placido, Giuseppe

    2004-01-01

    Background D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. Patients and Methods We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis. Statistical

  4. Sterile Neutrinos

    NASA Astrophysics Data System (ADS)

    Palazzo, Antonio

    2016-05-01

    Several anomalies recorded in short-baseline neutrino experiments suggest the possibility that the standard 3-flavor framework may be incomplete and point towards a manifestation of new physics. Light sterile neutrinos provide a credible solution to these puzzling results. Here, we present a concise review of the status of the neutrino oscillations within the 3+1 scheme, the minimal extension of the standard 3-flavor framework endowed with one sterile neutrino species. We emphasize the potential role of LBL experiments in the searches of CP violation related to sterile neutrinos and their complementarity with the SBL experiments.

  5. Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge

    PubMed Central

    Rowe, Rachel K; Ellis, Gavin I; Harrison, Jordan L; Bachstetter, Adam D; Corder, Gregory F; Van Eldik, Linda J; Taylor, Bradley K; Marti, Francesc

    2016-01-01

    Background Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are

  6. Sterile technique

    MedlinePlus

    ... kit) A clean, dry surface Clean paper towels Wash your hands well and keep all work surfaces ... To open a sterile pad or kit: Wash your hands with soap and running ... palms, fingers, and between your fingers thoroughly. Wash ...

  7. Tubal Sterilization

    MedlinePlus

    ... you feel after the operation depends on your general health, the type of procedure and your tolerance to ... to work after sterilization? That depends on your general health, your attitude, your job and the type of ...

  8. Sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Kopp, J.; Machado, P. A. N.; Maltoni, M.; Schwetz, T.

    2016-06-01

    We characterize statistically the indications of a presence of one or more light sterile neutrinos from MiniBooNE and LSND data, together with the reactor and gallium anomalies, in the global context. The compatibility of the aforementioned signals with null results from solar, atmospheric, reactor, and accelerator experiments is evaluated. We conclude that a severe tension is present in the global fit, and therefore the addition of eV-scale sterile neutrinos does not satisfactorily explain the anomalies.

  9. [Auto-immune hypoglycemic syndrome induced by pyritinol].

    PubMed

    Faguer de Moustier, B; Burgard, M; Boitard, C; Desplanque, N; Fanjoux, J; Tchobroutsky, G

    1988-01-01

    The auto-immune hypoglycemic syndrome is characterized by the association of hypoglycemia (clinical and/or biological) and anti-insulin antibodies in patients who have never received exogenous insulin. Initially this syndrome was most often described in Japanese patients some of whom were treated with drugs containing a sulfydril group. We now recall the case of a female caucasian patient treated with Pyritinol for rhumatoid polyarthritis and who presented severe spontaneous hypoglycemia linked with the presence of anti-insulin antibodies in her serum. The level of her antibodies decreased abruptly on suspension of the drug. The recent and more developed characterization techniques of the different forms of circulating insulin and of their antibodies may help to differenciate an auto-immune hypoglycemia from hypoglycemia due to the secret auto-administration of bovine and porcine insuline, and permit us to suggest that an abnormality in the structure of the molecule of insulin might be a cause of this syndrome. However, the exact mechanism of hypoglycemia linked with the presence of anti-insulin auto-antibodies is not yet clear as is the predisposition of a drug with a sulfydril group to induce such an auto-immune phenomenon. PMID:3066650

  10. Targeted approaches to induce immune tolerance for Pompe disease therapy.

    PubMed

    Doerfler, Phillip A; Nayak, Sushrusha; Corti, Manuela; Morel, Laurence; Herzog, Roland W; Byrne, Barry J

    2016-01-01

    Enzyme and gene replacement strategies have developed into viable therapeutic approaches for the treatment of Pompe disease (acid α-glucosidase (GAA) deficiency). Unfortunately, the introduction of GAA and viral vectors encoding the enzyme can lead to detrimental immune responses that attenuate treatment benefits and can impact patient safety. Preclinical and clinical experience in addressing humoral responses toward enzyme and gene therapy for Pompe disease have provided greater understanding of the immunological consequences of the provided therapy. B- and T-cell modulation has been shown to be effective in preventing infusion-associated reactions during enzyme replacement therapy in patients and has shown similar success in the context of gene therapy. Additional techniques to induce humoral tolerance for Pompe disease have been the targeted expression or delivery of GAA to discrete cell types or tissues such as the gut-associated lymphoid tissues, red blood cells, hematopoietic stem cells, and the liver. Research into overcoming preexisting immunity through immunomodulation and gene transfer are becoming increasingly important to achieve long-term efficacy. This review highlights the advances in therapies as well as the improved understanding of the molecular mechanisms involved in the humoral immune response with emphasis on methods employed to overcome responses associated with enzyme and gene therapies for Pompe disease. PMID:26858964

  11. Targeted approaches to induce immune tolerance for Pompe disease therapy

    PubMed Central

    Doerfler, Phillip A; Nayak, Sushrusha; Corti, Manuela; Morel, Laurence; Herzog, Roland W; Byrne, Barry J

    2016-01-01

    Enzyme and gene replacement strategies have developed into viable therapeutic approaches for the treatment of Pompe disease (acid α-glucosidase (GAA) deficiency). Unfortunately, the introduction of GAA and viral vectors encoding the enzyme can lead to detrimental immune responses that attenuate treatment benefits and can impact patient safety. Preclinical and clinical experience in addressing humoral responses toward enzyme and gene therapy for Pompe disease have provided greater understanding of the immunological consequences of the provided therapy. B- and T-cell modulation has been shown to be effective in preventing infusion-associated reactions during enzyme replacement therapy in patients and has shown similar success in the context of gene therapy. Additional techniques to induce humoral tolerance for Pompe disease have been the targeted expression or delivery of GAA to discrete cell types or tissues such as the gut-associated lymphoid tissues, red blood cells, hematopoietic stem cells, and the liver. Research into overcoming preexisting immunity through immunomodulation and gene transfer are becoming increasingly important to achieve long-term efficacy. This review highlights the advances in therapies as well as the improved understanding of the molecular mechanisms involved in the humoral immune response with emphasis on methods employed to overcome responses associated with enzyme and gene therapies for Pompe disease. PMID:26858964

  12. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    PubMed

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. PMID:26520214

  13. Neuro-immune interactions in chemical-induced airway hyperreactivity.

    PubMed

    Devos, Fien C; Boonen, Brett; Alpizar, Yeranddy A; Maes, Tania; Hox, Valérie; Seys, Sven; Pollaris, Lore; Liston, Adrian; Nemery, Benoit; Talavera, Karel; Hoet, Peter H M; Vanoirbeek, Jeroen A J

    2016-08-01

    Asthma may be induced by chemical sensitisers, via mechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitro intracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using an in vivo model, in which an airway challenge with TDI induces AHR in TDI-sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, in Trpa1 and Trpv1 knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficient Kit(Wsh) (/Wsh) mice, and in wild-type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR. PMID:27126687

  14. Immunological aspects of the immune response induced by mosquito allergens.

    PubMed

    Cantillo, José Fernando; Fernández-Caldas, Enrique; Puerta, Leonardo

    2014-01-01

    Allergies caused by mosquito bites may produce local or systemic reactions. The inhalation of mosquito allergens may also cause asthma and/or allergic rhinoconjunctivitis in sensitized individuals. The mechanisms implicated in the development of these immune responses involve IgE antibodies, different subtypes of IgG and proinflammatory cytokines as well as basophils, eosinophils and mast cells. Several allergenic components have been identified in the saliva and bodies of mosquitoes and some of these are present in different mosquito species. The most common species implicated in allergic reactions belong to the genera Aedes, Culex and Anopheles. Several Aedes aegypti allergens have been cloned and sequenced. The recombinant molecules show IgE reactivity similar to that of the native allergens, making them good candidates for the diagnosis of mosquito allergies. Allergen-specific immunotherapy with mosquito extracts induces a protective response characterized by a decreased production of IgE antibodies, increased IgG levels, a reduction in the severity of cutaneous and respiratory symptoms and the need for medication. The aims of this review are to summarize the progress made in the characterization of mosquito allergens and discuss the types of immune responses induced by mosquito bites and the inhalation of mosquito allergens in atopic individuals. PMID:25661054

  15. Immunization

    MedlinePlus

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

  16. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  17. Immunization

    MedlinePlus

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

  18. Antitumor immune responses induced by photodynamic immunotherapy in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Robinson, Karen E.; Adams, Robert L.; Singhal, Anil K.; Nordquist, Robert E.

    1998-05-01

    A new laser immunotherapy was used to treat metastatic mammary rat tumors. This new modality consists of three components: a near-infrared diode laser, a photosensitizer, and an immunoadjuvant. The sensitizer-adjuvant solution was injected directly to the tumor, followed by a non-invasive laser application. The new method resulted in total eradication of the treated primary tumors and eradication of untreated metastases at remote sites. Observed was the long-term survival of treated tumor-bearing rats: up to 120 days after tumor inoculation, a 300% increase in survival length compared with untreated control tumor-bearing rats. In addition, the successfully treated rats were refractory to tumor rechallenge with 10 times of the original tumor dose. Fluorescein and peroxidase immunochemical assays were also performed using sera from cured rats as the primary antibody. Strong antibody binding to both live and preserved tumor cells was observed. Western blot analysis, using the cured rat serum as primary antibody also showed distinctive protein binding, suggesting the induction of tumor-specific humoral immune response. These results indicated that an immune response was induced by the treatment of laser, photosensitizer and immunoadjuvant.

  19. Molecular diversity of male sterility inducing and male-fertile cytoplasms in the genus Helianthus.

    PubMed

    Horn, R.

    2002-03-01

    The organisation of mtDNA was investigated for 28 sources of cytoplasmic male sterility (CMS) and a fertile line (normal cytoplasm) of Helianthus annuus by Southern hybridisation. In addition to nine known mitochondrial genes ( atp6, atp9, cob, coxI, coxII, coxIII, 18S, 5S and nd5) three probes for the open reading frames in the rearranged area of PET1, orfH522, orfH708 and orfH873, were used. Genetic similarities of the investigat-ed cytoplasms varied between 0.3 and 1. Cluster analyses using the UPGMA method allowed the distinction of ten mitochondrial (mt) types between the 29 investigated cytoplasms. Most mitochondrial types comprise two or more CMS sources, which could not be further separated, like the PET1-like CMS sources (with the exception of ANO1 and PRR1), or ANN1/ANN2/ANN3, ANN4/ ANN5, ARG3/RIG1, BOL1/EXI1/PEF1/PEP1 and GIG1/ PET2. ANL1, ANL2 and the fertile cytoplasms are also regarded as one mitochondrial type. Unique banding patterns were only observed for ANT1 ( atp6), MAX1 ( atp6, orfH522 and orfH708) and PRR1 ( coxII). However, four of the mitochondrial types showed unique hybridisation signals: ANN4/ANN5 had characteristic bands for atp6 and orfH708, PEF1/PEP1/EXI1/BOL1 for atp6and coxII, and PET2/GIG1 for atp9. The PET1-like cytoplasms all shared the same patterns for orfH522, orfH708and cob (except ANO1). It could be demonstrated that CMS sources, like, e.g., PET2 and PEF1, are different from PET1 in mtDNA organisation and the CMS mechanism. Therefore, these CMS sources represent interesting candidates for the development of new hybrid breeding systems based on new CMS mechanisms. PMID:12582659

  20. Human placenta-derived adherent cells induce tolerogenic immune responses.

    PubMed

    Liu, Wei; Morschauser, Andrew; Zhang, Xin; Lu, Xiaohua; Gleason, Joseph; He, Shuyang; Chen, Hong-Jung; Jankovic, Vladimir; Ye, Qian; Labazzo, Kristen; Herzberg, Uri; Albert, Vivian R; Abbot, Stewart E; Liang, Bitao; Hariri, Robert

    2014-05-01

    Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14(+) monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells. PMID:25505962

  1. Polar Lipids of Burkholderia pseudomallei Induce Different Host Immune Responses

    PubMed Central

    Gonzalez-Juarrero, Mercedes; Mima, Naoko; Trunck, Lily A.; Schweizer, Herbert P.; Bowen, Richard A.; Dascher, Kyle; Mwangi, Waithaka; Eckstein, Torsten M.

    2013-01-01

    Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs) and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor) molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster. PMID:24260378

  2. Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1-Humanized Mice

    PubMed Central

    McCaw, Shannon E.; Strobel, Lea; Frosch, Matthias

    2014-01-01

    Neisseria meningitidis asymptomatically colonizes the human upper respiratory tract but is also the cause of meningitis and severe septicemia. Carriage or disease evokes an immune response against the infecting strain. Hitherto, we have known little about the breadth of immunity induced by natural carriage of a single strain or its implications for subsequent infectious challenge. In this study, we establish that transgenic mice expressing human CEACAM1 support nasal colonization by a variety of strains of different capsular types. Next, we nasally challenged these mice with either of the N. meningitidis strains H44/76 (serogroup B, ST-32) and 90/18311 (serogroup C, ST-11), while following the induction of strain-specific immunoglobulin. When these antisera were tested for reactivity with a diverse panel of N. meningitidis strains, very low levels of antibody were detected against all meningococcal strains, yet a mutually exclusive “fingerprint” of high-level cross-reactivity toward certain strains became apparent. To test the efficacy of these responses for protection against subsequent challenge, CEACAM1-humanized mice exposed to strain 90/18311 were then rechallenged with different N. meningitidis strains. As expected, the mice were immune to challenge with the same strain and with a closely related ST-11 strain, 38VI, while H44/76 (ST-32) could still colonize these animals. Notably, however, despite the paucity of detectable humoral response against strain 196/87 (ST-32), this strain was unable to colonize the 90/18311-exposed mice. Combined, our data suggest that current approaches may underestimate the actual breadth of mucosal protection gained through natural exposure to N. meningitidis strains. PMID:25368118

  3. Among-lake reciprocal transplants induce convergent expression of immune genes in threespine stickleback.

    PubMed

    Stutz, William E; Schmerer, Matthew; Coates, Jessica L; Bolnick, Daniel I

    2015-09-01

    Geographic variation in parasite communities can drive evolutionary divergence in host immune genes. However, biotic and abiotic environmental variation can also induce plastic differences in immune function among populations. At present, there is little information concerning the relative magnitudes of heritable vs. induced immune divergence in natural populations. We examined immune gene expression profiles of threespine stickleback (Gasterosteus aculeatus) from six lakes on Vancouver Island, British Columbia. Parasite community composition differs between lake types (large or small, containing limnetic- or benthic-like stickleback) and between watersheds. We observed corresponding differences in immune gene expression profiles among wild-caught stickleback, using a set of seven immune genes representing distinct branches of the immune system. To evaluate the role of environmental effects on this differentiation, we experimentally transplanted wild-caught fish into cages in their native lake, or into a nearby foreign lake. Transplanted individuals' immune gene expression converged on patterns typical of their destination lake, deviating from their native expression profile. Transplant individuals' source population had a much smaller effect, suggesting relatively weak genetic underpinning of population differences in immunity, as viewed through gene expression. This strong environmental regulation of immune gene expression provides a counterpoint to the large emerging literature documenting microevolution and genetic diversification of immune function. Our findings illustrate the value of studying immunity in natural environmental settings where the immune system has evolved and actively functions. PMID:26118468

  4. Unveiling Unexpected Immune Activities Induced by Your Pneumococcal Vaccine

    PubMed Central

    Hurwitz, Julia L.

    2016-01-01

    ABSTRACT In modern-day vaccine design, a good pneumococcal capsular polysaccharide vaccine is measured by its ability to induce opsonic antibodies. These antibodies label bacteria for phagocytosis by neutrophils and thereby overcome the capsule’s barrier function. Doyle and Pirofski have raised a serious challenge to the current paradigm by describing anti-capsular antibodies that are highly protective but nonopsonic [C.R. Doyle and L. Pirofski, mBio 7(1):e02260-15, 2016, doi:10.1128/mBio.02260-15]. In fact, some functions are not related to neutrophils or phagocytosis at all. An increased awareness of these activities is critical not only for accurate comparisons of vaccine candidates but also for improvements in vaccination outcomes in settings of neutropenia. When vaccine developers select a single gatekeeper assay (e.g., an opsonophagocytic assay for bacteria or a neutralization assay for viruses), promising vaccine candidates may be missed. Doyle and Pirofski stress that multiple functions, not just one, should be investigated to enhance discovery of antibody mechanisms and to best assess vaccine-induced correlates of immune protection. PMID:26908576

  5. A cardiac myosin-specific autoimmune response is induced by immunization with Trypanosoma cruzi proteins.

    PubMed

    Leon, Juan S; Daniels, Melvin D; Toriello, Krista M; Wang, Kegiang; Engman, David M

    2004-06-01

    Trypanosoma cruzi is the protozoan parasite that causes Chagas' heart disease, a potentially fatal cardiomyopathy prevalent in Central and South America. Infection with T. cruzi induces cardiac myosin autoimmunity in susceptible humans and mice, and this autoimmunity has been suggested to contribute to cardiac inflammation. To address how T. cruzi induces cardiac myosin autoimmunity, we investigated whether immunity to T. cruzi antigens could induce cardiac myosin-specific autoimmunity in the absence of live parasites. We immunized A/J mice with a T. cruzi Brazil-derived protein extract emulsified in complete Freund's adjuvant and found that these mice developed cardiac myosin-specific delayed-type hypersensitivity (DTH) and autoantibodies in the absence of detectable cardiac damage. The induction of autoimmunity was specific since immunization with extracts of the related protozoan parasite Leishmania amazonensis did not induce myosin autoimmunity. The immunogenetic makeup of the host was important for this response, since C57BL/6 mice did not develop cardiac myosin DTH upon immunization with T. cruzi extract. Perhaps more interesting, mice immunized with cardiac myosin developed T. cruzi-specific DTH and antibodies. This DTH was also antigen specific, since immunization with skeletal myosin and myoglobin did not induce T. cruzi-specific immunity. These results suggest that immunization with cardiac myosin or T. cruzi antigen can induce specific, bidirectionally cross-reactive immune responses in the absence of detectable cardiac damage. PMID:15155647

  6. Differences in immune responses against Leishmania induced by infection and by immunization with killed parasite antigen: implications for vaccine discovery.

    PubMed

    Mendonça, Sergio C F

    2016-01-01

    The leishmaniases are a group of diseases caused by different species of the protozoan genus Leishmania and transmitted by sand fly vectors. They are a major public health problem in almost all continents. There is no effective control of leishmaniasis and its geographical distribution is expanding in many countries. Great effort has been made by many scientists to develop a vaccine against leishmaniasis, but, so far, there is still no effective vaccine against the disease. The only way to generate protective immunity against leishmaniasis in humans is leishmanization, consisting of the inoculation of live virulent Leishmania as a means to acquire long-lasting immunity against subsequent infections. At present, all that we know about human immune responses to Leishmania induced by immunization with killed parasite antigens came from studies with first generation candidate vaccines (killed promastigote extracts). In the few occasions that the T cell-mediated immune responses to Leishmania induced by infection and immunization with killed parasite antigens were compared, important differences were found both in humans and in animals. This review discusses these differences and their relevance to the development of a vaccine against leishmaniasis, the major problems involved in this task, the recent prospects for the selection of candidate antigens and the use of attenuated Leishmania as live vaccines. PMID:27600664

  7. Immune mechanisms in acetaminophen-induced acute liver failure.

    PubMed

    Krenkel, Oliver; Mossanen, Jana C; Tacke, Frank

    2014-12-01

    An overdose of acetaminophen (N-acetyl-p-aminophenol, APAP), also termed paracetamol, can cause severe liver damage, ultimately leading to acute liver failure (ALF) with the need of liver transplantation. APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fraction of the metabolized APAP forms cytotoxic mitochondrial protein adducts, leading to hepatocyte necrosis. The course of disease is not only critically influenced by dose of APAP and the initial hepatocyte damage, but also by the inflammatory response following acetaminophen-induced liver injury (AILI). As revealed by mouse models of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release danger-associated-molecular patterns (DAMPs), which are recognized by resident hepatic macrophages, Kupffer cell (KC), and neutrophils, leading to the activation of these cells. Activated hepatic macrophages release various proinflammatory cytokines, such as TNF-α or IL-1β, as well as chemokines (e.g., CCL2) thereby further enhancing inflammation and increasing the influx of immune cells, like bone-marrow derived monocytes and neutrophils. Monocytes are mainly recruited via their receptor CCR2 and aggravate inflammation. Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, in cooperation with neutrophils, also involved in the resolution of inflammation. Besides macrophages and neutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatory response following an APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possibly further perpetuate inflammation in AILI. Understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression is essential to identify novel therapeutic targets for human disease. PMID:25568858

  8. Gonadal Transcriptome Analysis in Sterile Double Haploid Japanese Flounder

    PubMed Central

    Wang, Guixing; Jiang, Hongbo; Wang, Yufen; Sun, Zhaohui; Jiang, Xiufeng; Yu, Qinghai; Liu, Haijin

    2015-01-01

    Sterility is a serious problem that can affect all bionts. In teleosts, double haploids (DHs) induced by mitogynogenesis are often sterile. This sterility severely restricts the further application of DHs for production of clones, genetic analysis, and breeding. However, sterile DH individuals are good source materials for investigation of the molecular mechanisms of gonad development, especially for studies into the role of genes that are indispensable for fish reproduction. Here, we used the Illumina sequencing platform to analyze the transcriptome of sterile female DH Japanese flounder in order to identify major genes that cause sterility and to provide a molecular basis for an intensive study of gonadal development in teleosts. Through sequencing, assembly, and annotation, we obtained 52,474 contigs and found that 60.7% of these shared homologies with existing sequences. A total of 1225 differentially expressed unigenes were found, including 492 upregulated and 733 downregulated genes. Gene Ontology and KEGG analyses showed that genes showing significant upregulation, such as CYP11A1, CYP11B2, CYP17, CYP21, HSD3β, bcl2l1, and PRLR, principally correlated with sterol metabolic process, steroid biosynthetic process, and the Jak-stat signaling pathway. The significantly downregulated genes were primarily associated with immune response, antigen processing and presentation, cytokine–cytokine receptor interaction, and protein digestion and absorption. Using a co-expression network analysis, we conducted a comprehensive comparison of gene expression in the gonads of fertile and sterile female DH Japanese flounder. Identification of genes showing significantly different expression will provide further insights into DH reproductive dysfunction and oocyte maturation processes in teleosts. PMID:26580217

  9. Recombinant varicella vaccines induce neutralizing antibodies and cellular immune responses to SIV and reduce viral loads in immunized rhesus macaques

    PubMed Central

    Traina-Dorge, V.; Pahar, B.; Marx, P.; Kissinger, P.; Montefiori, D.; Ou, Y.; Gray, W.L.

    2010-01-01

    The development of an effective AIDS vaccine remains one of the highest priorities in HIV research. The live, attenuated varicella-zoster virus (VZV) Oka vaccine, safe and effective for prevention of chickenpox and zoster, also has potential as a recombinant vaccine against other pathogens, including human immunodeficiency virus (HIV). The simian varicella model, utilizing simian varicella virus (SVV), offers an approach to evaluate recombinant varicella vaccine candidates. Recombinant SVV (rSVV) vaccine viruses expressing simian immunodeficiency virus (SIV) env and gag antigens were constructed. The hypothesis tested was that a live, attenuated rSVV-SIV vaccine will induce immune responses against SIV in the rhesus macaques and provide protection against SIV challenge. The results demonstrated that rSVV-SIV vaccination induced low levels of neutralizing antibodies and cellular immune responses to SIV in immunized rhesus macaques and significantly reduced viral loads following intravenous challenge with pathogenic SIVmac251-CX-1. PMID:20654666

  10. Inducible Sterilization of Zebrafish by Disruption of Primordial Germ Cell Migration

    PubMed Central

    Wong, Ten-Tsao; Collodi, Paul

    2013-01-01

    During zebrafish development, a gradient of stromal-derived factor 1a (Sdf1a) provides the directional cue that guides the migration of the primordial germ cells (PGCs) to the gonadal tissue. Here we describe a method to produce large numbers of infertile fish by inducing ubiquitous expression of Sdf1a in zebrafish embryos resulting in disruption of the normal PGC migration pattern. A transgenic line of zebrafish, Tg(hsp70:sdf1a-nanos3, EGFP), was generated that expresses Sdf1a under the control of the heat-shock protein 70 (hsp70) promoter and nanos3 3?UTR. To better visualize the PGCs, the Tg(hsp70:sdf1a-nanos3, EGFP) fish were crossed with another transgenic line, Tg(kop:DsRed-nanos3), that expresses DsRed driven by the PGC-specific kop promoter. Heat treatment of the transgenic embryos caused an induction of Sdf1a expression throughout the embryo resulting in the disruption of their normal migration. Optimal embryo survival and disruption of PGC migration was achieved when transgenic embryos at the 4- to 8-cell stage were incubated at 34.5°C for 18 hours. Under these conditions, disruption of PGC migration was observed in 100% of the embryos. Sixty-four adult fish were developed from three separate batches of heat-treated embryos and all were found to be infertile males. When each male was paired with a wild-type female, only unfertilized eggs were produced and histological examination revealed that each of the adult male fish possessed severely under-developed gonads that lacked gametes. The results demonstrate that inducible Sdf1a expression is an efficient and reliable strategy to produce infertile fish. This approach makes it convenient to generate large numbers of infertile adult fish while also providing the capability to maintain a fertile brood stock. PMID:23826390

  11. Pleomorphic forms of Borrelia burgdorferi induce distinct immune responses.

    PubMed

    Meriläinen, Leena; Brander, Heini; Herranen, Anni; Schwarzbach, Armin; Gilbert, Leona

    2016-01-01

    Borrelia burgdorferi is the causative agent of tick-borne Lyme disease. As a response to environmental stress B. burgdorferi can change its morphology to a round body form. The role of B. burgdorferi pleomorphic forms in Lyme disease pathogenesis has long been debated and unclear. Here, we demonstrated that round bodies were processed differently in differentiated macrophages, consequently inducing distinct immune responses compared to spirochetes in vitro. Colocalization analysis indicated that the F-actin participates in internalization of both forms. However, round bodies end up less in macrophage lysosomes than spirochetes suggesting that there are differences in processing of these forms in phagocytic cells. Furthermore, round bodies stimulated distinct cytokine and chemokine production in these cells. We confirmed that spirochetes and round bodies present different protein profiles and antigenicity. In a Western blot analysis Lyme disease patients had more intense responses to round bodies when compared to spirochetes. These results suggest that round bodies have a role in Lyme disease pathogenesis. PMID:27139815

  12. Radiation sterilization of ketoprofen

    NASA Astrophysics Data System (ADS)

    Katušin-Ražem, Branka; Hamitouche, Katia; Maltar-Strmečki, Nadica; Kos, Karmen; Pucić, Irina; Britvić-Budicin, Smiljana; Ražem, Dušan

    2005-06-01

    Radiation sterilization of ketoprofen (KP) dry powder was investigated by selected physico-chemical methods. High-performance liquid chromatography, ultraviolet spectrophotometry, infrared spectrophotometry, differential scanning calorimetry, X-ray diffraction and electron spin resonance spectroscopy did not show any significant degradation at sterilization dose 25 kGy. To determine the nature, extent and direction of radiation-induced changes, KP was irradiated to extremely high doses, much higher than necessary to achieve sterility. The irradiated KP did not show any difference of XRD patterns up to 200 kGy; with DSC and IR some changes were detected only above 1000 and 2000 kGy, respectively; HPLC has shown about 5% destruction at 2000 kGy. Acetyl benzophenon (AcBph) was generated by irradiation with G(AcBph)=(1.6±0.1)×10 -8 mol J -1. Ames test has shown no mutagenicity of KP irradiated with 3000 kGy or of the oily mixure of radiolytic products isolated from it. Solid KP has proven to be very stable on irradiation, and irradiation has been found to be a suitable method for its sterilization.

  13. Th1-biased immune responses induced by DNA-based immunizations are mediated via action on professional antigen-presenting cells to up-regulate IL-12 production

    PubMed Central

    Asakura, Y; Liu, L -J; Shono, N; Hinkula, J; Kjerrström, A; Aoki, I; Okuda, K; Wahren, B; Fukushima, J

    2000-01-01

    The efficacy of DNA-based immunization in conferring protective immunity against certain microbial pathogens including human immunodeficiency virus type 1 (HIV-1) has been described. The potential advantage of DNA-based immunization over the traditional vaccines largely results from its capacity to efficiently induce Th1-biased immune responses against an encoded antigen. We describe how Th1-biased immune responses are induced by DNA-based immunization, using a DNA vaccine construct encoding HIV-1 gp160 cDNA and an eukaryotic expression plasmid carrying murine IFN-γ cDNA. Transfection of an eukaryotic expression plasmid carrying immunostimulatory sequences (ISS) as well as a gene of interest (DNA vaccine) into professional antigen presenting cells (APC) induced transactivation of IL-12 mRNA, which resulted in antigen-specific Th1-biased immune responses against the encoded antigen. Th1-biased immune responses induced by DNA-based immunization were substantially upregulated by a codelivery of an ectopic IFN-γ expression system, and this augmentation was mediated via action on professional antigen presenting cells to upregulate IL-12 production. Taken together, it appears likely that Th1-biased immune responses induced by DNA-based immunization are mediated via action on professional antigen-presenting cells to produce IL-12. Interestingly, the model provided strikingly resembles that previously described in infection with Listeria monocytogenes, an intracellular Gram-positive bacterium that induces strong Th1-biased immune responses. The result suggests that DNA-based immunization mimics certain aspects of natural infection with microbial organisms like attenuated vaccines, which in turn provides a rationale to the question of why DNA-based immunization so efficiently induces protective immunity against these microbial pathogens. PMID:10606974

  14. Locally administered T cells from mice immunized with lipopolysaccharide (LPS) accelerate LPS-induced bone resorption.

    PubMed

    Ozaki, Yukio; Ukai, Takashi; Yamaguchi, Masayuki; Yokoyama, Miho; Haro, Esperanza R Ayón; Yoshimoto, Mayumi; Kaneko, Takashi; Yoshinaga, Miho; Nakamura, Hirotaka; Shiraishi, Chiaki; Hara, Yoshitaka

    2009-06-01

    T cells play important roles in bone destruction and osteoclastogenesis and are found in chronic destructive bone lesions. Lipopolysaccharide (LPS) is one of several pathological factors involved in inflammatory bone destruction. We previously described the importance of T cells in the inflammatory bone resorption that occurs after repeated LPS administration. However, whether local or systemic T cells are important for inflammatory bone resorption and whether immunization of host animals influences bone resorption remain unclear. The present study examines the effects of local extant T cells from LPS-immunized mice on LPS-induced bone resorption. T cells from LPS-immunized or non-immunized mice were injected together with LPS into the gingival tissues of mice with severe combined immunodeficiency disease that lack both T and B cells. We histomorphometrically evaluated bone resorption at sites of T cell injections and examined the influence of T cells from LPS-immunized mice on osteoclastogenesis in vitro. We found that locally administered T cells from LPS-immunized but not non-immunized mice accelerated LPS-induced bone resorption in vivo. Moreover, T cells from LPS-immunized mice increased osteoclastogenesis in vitro induced by receptor activator of NF-kappa B ligand and LPS and anti-tumor necrosis factor (TNF)-alpha antibody inhibited this increase. These results demonstrated that local extant T cells accelerate inflammatory bone resorption. Furthermore, T cells from LPS-immunized mice appear to elevate LPS-induced bone resorption using TNF-alpha. PMID:19437611

  15. Inducible viral receptor, A possible concept to induce viral protection in primitive immune animals.

    PubMed

    Pasharawipas, Tirasak

    2011-01-01

    A pseudolysogen (PL) is derived from the lysogenic Vibrio harveyi (VH) which is infected with the VHS1 (Vibrio harveyi Siphoviridae-like 1) bacteriophage. The lysogenic Vibrio harveyi undergoes an unequivalent division of the extra-chromosomal VHS1 phage genome and its VH host chromosome and produces a true lysogen (TL) and pseudolysogen (PL). The PL is tolerant to super-infection of VHS1, as is of the true lysogen (TL), but the PL does not contain the VHS1 phage genome while the TL does. However, the PL can become susceptible to VHS1 phage infection if the physiological state of the PL is changed. It is postulated that this is due to a phage receptor molecule which can be inducible to an on-and-off regulation influence by an alternating condition of the bacterial host cell. This characteristic of the PL leads to speculate that this phenomenon can also occur in high organisms with low immunity such as shrimp. This article proposes a hypothesis that the viral receptor molecule on the target cell can play a crucial role in which the invertebrate aquaculture animals can become tolerant to viral infection. A possible mechanism may be that the target cell disrupts the viral receptor molecule to prevent super infection. This concept can explain a mechanism for the prevention of viral infection in invertebrate animals which do not have acquired immunity in response to pathogens. It can guide us to develop a mechanism of immunity to viral infection in low-evolved-immune animals. Also, it can be an additional mechanism that exists in high immune organism, as in human for the prevention of viral infection. PMID:21711515

  16. Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.

    PubMed

    Huang, Jing; Li, Xiangming; Coelho-dos-Reis, Jordana G A; Zhang, Min; Mitchell, Robert; Nogueira, Raquel Tayar; Tsao, Tiffany; Noe, Amy R; Ayala, Ramses; Sahi, Vincent; Gutierrez, Gabriel M; Nussenzweig, Victor; Wilson, James M; Nardin, Elizabeth H; Nussenzweig, Ruth S; Tsuji, Moriya

    2015-12-01

    In this study, we developed human immune system (HIS) mice that possess functional human CD4+ T cells and B cells, named HIS-CD4/B mice. HIS-CD4/B mice were generated by first introducing HLA class II genes, including DR1 and DR4, along with genes encoding various human cytokines and human B cell activation factor (BAFF) to NSG mice by adeno-associated virus serotype 9 (AAV9) vectors, followed by engrafting human hematopoietic stem cells (HSCs). HIS-CD4/B mice, in which the reconstitution of human CD4+ T and B cells resembles to that of humans, produced a significant level of human IgG against Plasmodium falciparum circumsporozoite (PfCS) protein upon immunization. CD4+ T cells in HIS-CD4/B mice, which possess central and effector memory phenotypes like those in humans, are functional, since PfCS protein-specific human CD4+ T cells secreting IFN-γ and IL-2 were detected in immunized HIS-CD4/B mice. Lastly, PfCS protein-immunized HIS-CD4/B mice were protected from in vivo challenge with transgenic P. berghei sporozoites expressing the PfCS protein. The immune sera collected from protected HIS-CD4/B mice reacted against transgenic P. berghei sporozoites expressing the PfCS protein and also inhibited the parasite invasion into hepatocytes in vitro. Taken together, these studies show that our HIS-CD4/B mice could mount protective human anti-malaria immunity, consisting of human IgG and human CD4+ T cell responses both specific for a human malaria antigen. PMID:26410104

  17. Hysteroscopic Sterilization

    MedlinePlus

    ... sleep-like state to prevent pain during surgery. Human Immunodeficiency Virus (HIV): A virus that attacks certain cells of the body’s immune system and causes acquired immunodeficiency syndrome (AIDS). Hysterosalpingography (HSG): ...

  18. Evaluation of the Contribution of Multiple DAMPs and DAMP Receptors in Cell Death-Induced Sterile Inflammatory Responses

    PubMed Central

    Patel, Zubin; Rock, Kenneth L.

    2014-01-01

    When cells die by necrosis in vivo they stimulate an inflammatory response. It is thought that this response is triggered when the injured cells expose proinflammatory molecules, collectively referred to as damage associated molecular patterns (DAMPs), which are recognized by cells or soluble molecules of the innate or adaptive immune system. Several putative DAMPs and/or their receptors have been identified, but whether and how much they participate in responses in vivo is incompletely understood, and they have not previously been compared side-by-side in the same models. This study focuses on evaluating the contribution of multiple mechanisms that have been proposed to or potentially could participate in cell death-induced inflammation: The third component of complement (C3), ATP (and its receptor P2X7), antibodies, the C-type lectin receptor Mincle (Clec4e), and protease-activated receptor 2 (PAR2). We investigate the role of these factors in cell death-induced inflammation to dead cells in the peritoneum and acetaminophen-induced liver damage. We find that mice deficient in antibody, C3 or PAR2 have impaired inflammatory responses to dying cells. In contrast there was no reduction in inflammation to cell death in the peritoneum or liver of mice that genetically lack Mincle, the P2X7 receptor or that were treated with apyrase to deplete ATP. These results indicate that antibody, complement and PAR2 contribute to cell death-induced inflammation but that Mincle and ATP- P2X7 receptor are not required for this response in at least 2 different in vivo models. PMID:25127469

  19. [Sterilization of women].

    PubMed

    Tandberg, A

    1988-01-30

    The records of 209 women sterilized in the Lillehammer (Norway) county hospital during the period 1980-82 were examined for age, residence, parity, method of operation, induced abortions and frequency of complications. The patients were sent a questionnaire 6 months after the operation and were asked about how long they had felt unable to work after the operation, whether they regretted the operation, and whether they were satisfied with the cosmetic results. 96% of the patients returned the questionnaires. On the average the women had had 2.4 children at the time of sterilization. Those who had received induced abortions at the same time had 2.5 children. Women resident in the city had 2.1 children, those in the country had 2.4 children. None had 6 children. 20% had received abortion simultaneously. Aside from 1 patient who had transitory paresis in the left arm due to faulty padding in a shoulder support, there were no complications noted in the material. 2 patients regretted the operation. Neither of them had had simultaneous abortion. 1 of these had 1 child. Advised to be sterilized because of severe preeclampsia in her 1st pregnancy, she desired more children. The other, who had 4 children, gave decreased libido as the cause for her regret. Of the 177 who had had laparoscopy, only 6 patients (3.5%) said that they were dissatisfied with the appearance of the scar. PMID:3353913

  20. H. hepaticus-induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial-induced immune response

    PubMed Central

    García, Alexis; Zeng, Yu; Muthupalani, Sureshkumar; Ge, Zhongming; Potter, Amanda; Mobley, Melissa W.; Boussahmain, Chakib; Feng, Yan; Wishnok, John S.; Fox, James G.

    2011-01-01

    Chronic microbial infection influence cancer progression but the mechanisms that link them remain unclear. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates enzymes involved in endobiotic and xenobiotic metabolism. CAR activation is a mechanism of xenobiotic tumor promotion, however, the effects of chronic microbial infection on tumor promotion have not been studied in the context of CAR function. Here we report that CAR limits the effects of chronic infection-associated progression of liver cancer. CAR knockout (KO) and wild-type (WT) male mice were treated or not with the tumor initiator diethylnitrosamine (DEN) at 5 weeks of age and then orally inoculated with Helicobacter hepaticus (Hh) or sterile media at 8 weeks of age. At 50 weeks postinoculation mice were euthanized for histopathological, microbiological, molecular, and metabolomic analyses. Hh infection induced comparable hepatitis in WT and KO mice with or without DEN that correlated with significant upregulation of Tnfα and toll receptor Tlr2. Notably, DEN-treated Hh-infected KO mice exhibited increased numbers of liver lobes with dysplasia and neoplasia, as well as increased multiplicity of neoplasia, relative to similarly treated WT mice. Enhanced tumor promotion was associated with decreased hepatic expression of P450 enzymes Cyp2b10 and Cyp3a11, increased expression of Camp, and increased serum concentrations of chenodeoxycholic acid. Together, our findings suggest that liver tumor promotion is enhanced by an impaired metabolic detoxification of endobiotics and a persistent microbial-induced immune response. PMID:21335546

  1. Immunizations.

    PubMed

    Sanford, Christopher A; Jong, Elaine C

    2016-03-01

    Vaccinations are a cornerstone of the pretravel consultation. The pretravel provider should assess a traveler's past medical history, planned itinerary, activities, mode of travel, and duration of stay and make appropriate vaccine recommendations. Given that domestic vaccine-preventable illnesses are more common in international travelers than are exotic or low-income nation-associated vaccine-preventable illnesses, clinicians should first ensure that travelers are current regarding routine immunizations. Additional immunizations may be indicated in some travelers. Familiarity with geographic distribution and seasonality of infectious diseases is essential. Clinicians should be cognizant of which vaccines are live, as there exist contraindications for live vaccines. PMID:26900111

  2. Psychological stress may induce increased humoral and decreased cellular immunity.

    PubMed

    Paik, I H; Toh, K Y; Lee, C; Kim, J J; Lee, S J

    2000-01-01

    Stress alters immune function and affects different immune cell populations in different ways. The authors examined whether psychological stress has different effects on the production of macrophage, T-helper 1(Th1) cell, and T-helper 2(Th2) cell-derived cytokines. Forty-two college students were recruited and their blood was sampled on the day they were to take a stressful academic examination and again 4 weeks after the examination. The stress from the academic examination significantly increased IL-1 beta, IL-6, and IL-10 and decreased IFN-gamma production. These findings suggest that examination stress may increase Th2 cell-mediated humoral immunity and macrophage activities and may decrease Th1 cell-mediated cellular immunity. PMID:11209594

  3. Sterilization-Induced Changes in Surface Topography of Biodegradable POSS-PCLU and the Cellular Response of Human Dermal Fibroblasts.

    PubMed

    Yildirimer, Lara; Seifalian, Alexander M

    2015-06-01

    The field of tissue engineering is rapidly evolving, generating numerous biodegradable materials suited as regeneration platforms. Material sterility is of fundamental importance for clinical translation; however, a few studies have systematically researched the effects of different sterilization methods on biodegradable materials. Here, we exposed a novel bioabsorbable nanocomposite based on a poly(ɛ-caprolactone urea) urethane backbone integrating polyhedral oligomeric silsesquioxane nanoparticles (POSS-PCLU) to autoclave, microwave, antibiotics, and 70% ethanol sterilization and systematically correlated differences in material characteristics to the attachment, viability, proliferative capacity, and shape of human dermal fibroblasts (HDFa). Nanotopographical profiling of autoclaved or microwaved surfaces revealed relatively deep nano-grooves, increasing total surface area, roughness, and hydrophobicity, which resulted in significantly fewer adherent cells. Antibiotics or 70% ethanol-treated surfaces displayed shallower nano-grooves, a more hydrophilic character, and significantly greater cellular adhesion (p<0.05). In fact, relative cell proliferation on ethanol-treated films surpassed that of cells grown on every other surface by a factor of 9 over 7 days. Filamentous actin staining demonstrated spindle-like morphologies characteristic of HDFa when grown on ethanol-treated films as opposed to cells grown on other films that were significantly more spread out (p<0.05). We argue that treatment with 70% ethanol serves not only as a laboratory-based sterilizing agent but also as a postproduction processing tool to enhance cytocompatibility of tissue engineering scaffolds. PMID:25398409

  4. Acute psychological stress induces short-term variable immune response.

    PubMed

    Breen, Michael S; Beliakova-Bethell, Nadejda; Mujica-Parodi, Lilianne R; Carlson, Joshua M; Ensign, Wayne Y; Woelk, Christopher H; Rana, Brinda K

    2016-03-01

    In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific. PMID:26476140

  5. Costs of an induced immune response on sexual display and longevity in field crickets.

    PubMed

    Jacot, Alain; Scheuber, Hannes; Brinkhof, Martin W G

    2004-10-01

    Immune system activation may benefit hosts by generating resistance to parasites. However, natural resources are usually limited, causing a trade-off between the investment in immunity and that in other life-history or sexually selected traits. Despite its importance for the evolution of host defense, state-dependent fitness costs of immunity received little attention under natural conditions. In a field experiment we manipulated the nutritional condition of male field crickets Gryllus campestris and subsequently investigated the effect of an induced immune response through inoculation of bacterial lipopolysaccharides. Immune system activation caused a condition-dependent reduction in body condition, which was proportional to the condition-gain during the preceding food-supplementation period. Independent of nutritional condition, the immune insult induced an enduring reduction in daily calling rate, whereas control-injected males fully regained their baseline level of sexual signaling following a temporary decline. Since daily calling rate affects female mate choice under natural conditions, this suggests a decline in male mating success as a cost of induced immunity. Food supplementation enhanced male life span, whereas the immune insult reduced longevity, independent of nutritional status. Thus, immune system activation ultimately curtails male fitness due to a combined decline in sexual display and life span. Our field study thus indicates a key role for fitness costs of induced immunity in the evolution of host defense. In particular, costs expressed in sexually selected traits might warrant the honest advertisement of male health status, thus representing an important mechanism in parasite-mediated sexual selection. PMID:15562690

  6. Lentiviral vector encoding ubiquitinated hepatitis B core antigen induces potent cellular immune responses and therapeutic immunity in HBV transgenic mice.

    PubMed

    Dai, Shenglan; Zhuo, Meng; Song, Linlin; Chen, Xiaohua; Yu, Yongsheng; Zang, Guoqing; Tang, Zhenghao

    2016-07-01

    Predominant T helper cell type 1 (Th1) immune responses accompanied by boosted HBV-specific cytotoxic T lymphocyte (CTL) activity are essential for the clearance of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients. Ubiquitin (Ub) serves as a signal for the target protein to be recognized and degraded through the ubiquitin-proteasome system (UPS). Ubiquitinated hepatitis B core antigen (Ub-HBcAg) has been proved to be efficiently degraded into the peptides, which can be presented by major histocompatibility complex (MHC) class I resulting in stimulating cell-mediated responses. In the present study, lentiviral vectors encoding Ub-HBcAg (LV-Ub-HBcAg) were designed and constructed as a therapeutic vaccine for immunotherapy. HBcAg-specific cellular immune responses and anti-viral effects induced by LV-Ub-HBcAg were evaluated in HBV transgenic mice. We demonstrated that immunization with LV-Ub-HBcAg promoted the secretion of cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), generated remarkably high percentages of IFN-γ-secreting CD8(+) T cells and CD4(+) T cells, and enhanced HBcAg-specific CTL activity in HBV transgenic mice. More importantly, vaccination with LV-Ub-HBcAg could efficiently decreased the levels of serum hepatitis B surface antigen (HBsAg), HBV DNA and the expression of HBsAg and HBcAg in liver tissues of HBV transgenic mice. In addition, LV-Ub-HBcAg could upregulate the expression of T cell-specific T-box transcription factor (T-bet) and downregulate the expression of GATA-binding protein 3 (GATA-3) in spleen T lymphocytes. The therapeutic vaccine LV-Ub-HBcAg could break immune tolerance, and induce potent HBcAg specific cellular immune responses and therapeutic effects in HBV transgenic mice. PMID:26874581

  7. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells.

    PubMed

    Aliberti, Julio

    2016-01-01

    Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions. PMID:27034589

  8. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells

    PubMed Central

    Aliberti, Julio

    2016-01-01

    Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions. PMID:27034589

  9. Opioid-induced central immune signaling: implications for opioid analgesia

    PubMed Central

    Grace, Peter M.; Maier, Steven F.; Watkins, Linda R.

    2015-01-01

    Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by toll like receptor 4, purinergic, ceramide and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted. PMID:25833219

  10. Mechanistic Differences Leading to Infectious and Sterile Inflammation.

    PubMed

    Behnia, Faranak; Sheller, Samantha; Menon, Ramkumar

    2016-05-01

    Inflammation is a physiologic component of pregnancy and parturition. Overwhelming intrauterine inflammatory load promotes quiescent feto-maternal tissues into a contractile phenotype. Like inflammation, oxidative stress is an inevitable component of both pregnancy and parturition. Pathologic activation of host innate immune response to adverse pregnancy conditions can lead to premature activation of inflammatory and oxidative stress. Inflammation and oxidative stress markers seen with both sterile and infectious inflammation are often similar; therefore, it is difficult to understand causality of conditions like spontaneous preterm birth. This review demonstrates potential mechanistic pathways of activation of sterile and infectious inflammation. We demonstrate the activation of two unique pathways of inflammation by factors that are well-documented proxies for oxidative stress (cigarette smoke extract) and infection (lipopolysaccharide). Sterile inflammation seen after exposure to an oxidative stress inducer is due to cellular elemental damage resulting in p38 mitogen-activated protein kinase (MAPK) induced cellular senescence. Infectious inflammation is through activation of transcription factor NF-κB and independent of oxidative stress-associated damages and p38 MAPK-induced senescence. Understanding the differences in the inflammatory pathway activation by various risk factors is important to design better screening, diagnostic and intervention strategies to reduce the risks of adverse pregnancy outcomes. PMID:26840942

  11. A mechanism for trauma induced muscle wasting and immune dysfunction

    NASA Astrophysics Data System (ADS)

    Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

    A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

  12. Mycobacterial infection induces a specific human innate immune response

    PubMed Central

    Blischak, John D.; Tailleux, Ludovic; Mitrano, Amy; Barreiro, Luis B.; Gilad, Yoav

    2015-01-01

    The innate immune system provides the first response to infection and is now recognized to be partially pathogen-specific. Mycobacterium tuberculosis (MTB) is able to subvert the innate immune response and survive inside macrophages. Curiously, only 5–10% of otherwise healthy individuals infected with MTB develop active tuberculosis (TB). We do not yet understand the genetic basis underlying this individual-specific susceptibility. Moreover, we still do not know which properties of the innate immune response are specific to MTB infection. To identify immune responses that are specific to MTB, we infected macrophages with eight different bacteria, including different MTB strains and related mycobacteria, and studied their transcriptional response. We identified a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. This subset includes genes involved in phagosome maturation, superoxide production, response to vitamin D, macrophage chemotaxis, and sialic acid synthesis. We suggest that genetic variants that affect the function or regulation of these genes should be considered candidate loci for explaining TB susceptibility. PMID:26586179

  13. Epitope spreading induced by immunization with synthetic SSB peptides

    PubMed Central

    DING, MIN; ZHANG, JIANZHONG

    2016-01-01

    Sjogren's syndrome type B (SSB)/La antibody is an autoantibody generally observed in connective tissue diseases whereas double-stranded deoxyribonucleic acid (dsDNA) antibodies are the most characteristic autoantibodies found in systemic lupus erythematosus (SLE) patients. The relationship of these autoantibodies remains unclear. The aim of the study was to determine the profile of antibody production in rabbits immunized with synthetic SSB peptides alone or with dsDNA. For this purpose, 214–225aa peptide of SSB antigen was synthesized based on the organic chemistry solid-phase peptide synthesis. Rabbits were immunized with the following antigens: i) synthetic SSB peptides linked with keyhole limpet hemocyanin (KLH); ii) dsDNA; iii) SSB plus dsDNA; iv) KLH; and v) phosphate-buffered saline. SSB peptide antibody was measured using the enzyme-linked immunosorbent assay while extractable nuclear antigens (ENA) antibody and dsDNA antibody were measured by immunoblotting and immunofluorescence, respectively. The results showed that a specific anti-SSB peptide antibody was produced following immunization with SSB epitope alone or with dsDNA. The SSB peptide antibody titer in the coimmunization group was higher than that of the SSB alone group. In addition, antibodies against ribonucleoprotein (RNP), Smith and/or dsDNA were detected in rabbits of the coimmunization group. The presence of anti-dsDNA antibodies in the rabbits immunized with SSB peptide suggested the induction of epitope spreading. In conclusions, SSB antibodies were produced in rabbits immunized with SSB peptide or SSB+dsDNA, whereas SSB antibody titers were higher in the coimmunization group. Furthermore, coimmunization was associated with epitope spreading. PMID:27347030

  14. Mast cells mediate the immune suppression induced by dermal exposure to JP-8 jet fuel.

    PubMed

    Limón-Flores, Alberto Y; Chacón-Salinas, Rommel; Ramos, Gerardo; Ullrich, Stephen E

    2009-11-01

    Applying jet propulsion-8 (JP-8) jet fuel to the skin of mice induces immune suppression. Applying JP-8 to the skin of mice suppresses T-cell-mediated immune reactions including, contact hypersensitivity (CHS) delayed-type hypersensitivity and T-cell proliferation. Because dermal mast cells play an important immune regulatory role in vivo, we tested the hypothesis that mast cells mediate jet fuel-induced immune suppression. When we applied JP-8 to the skin of mast cell deficient mice CHS was not suppressed. Reconstituting mast cell deficient mice with wild-type bone marrow derived mast cells (mast cell "knock-in mice") restored JP-8-induced immune suppression. When, however, mast cells from prostaglandin E(2) (PGE(2))-deficient mice were used, the ability of JP-8 to suppress CHS was not restored, indicating that mast cell-derived PGE(2) was activating immune suppression. Examining the density of mast cells in the skin and lymph nodes of JP-8-treated mice indicated that jet fuel treatment caused an initial increase in mast cell density in the skin, followed by increased numbers of mast cells in the subcutaneous space and then in draining lymph nodes. Applying JP-8 to the skin increased mast cell expression of CXCR4, and increased the expression of CXCL12 by draining lymph node cells. Because CXCL12 is a chemoattractant for CXCR4+ mast cells, we treated JP-8-treated mice with AMD3100, a CXCR4 antagonist. AMD3100 blocked the mobilization of mast cells to the draining lymph node and inhibited JP-8-induced immune suppression. Our findings demonstrate the importance of mast cells in mediating jet fuel-induced immune suppression. PMID:19726579

  15. Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection

    PubMed Central

    Hewitson, James P.; Filbey, Kara J.; Esser-von Bieren, Julia; Camberis, Mali; Schwartz, Christian; Murray, Janice; Reynolds, Lisa A.; Blair, Natalie; Robertson, Elaine; Harcus, Yvonne; Boon, Louis; Huang, Stanley Ching-Cheng; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Voehringer, David; Le Gros, Graham; Harris, Nicola; Maizels, Rick M.

    2015-01-01

    Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations. PMID:25816012

  16. Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

    PubMed Central

    Vanpouille-Box, Claire; Hindré, François

    2012-01-01

    Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome. PMID:23087900

  17. Retnla (Relma/Fizz1) suppresses helminth-induced Th2-Type immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. Using Retnla deficient (-/-) mice and three helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite...

  18. Kinetics of immunosuppression of sporozoite-induced immunity by Mycobacterium bovis BCG.

    PubMed Central

    Smrkovski, L L

    1982-01-01

    The data reported in this study demonstrate that the vaccination of NIH/Nmri mice with viable Mycobacterium bovis BCG organisms induces a state of immunosuppression that renders the recipient animals incapable of a protective immune response to the malaria sporozoite vaccine. The expression of this altered protective immune response is dependent upon the dosage of the two live vaccines, as well as upon the sequence of their administration. Data presented here show that the skin test responses (Arthus and delayed type) of BCG-vaccinated mice do not correlate with the suppression of sporozoite immunity. Evidence is also presented to support the hypothesis that the abrogated immune response to sporozoite vaccination induced by BCG is a result of a loss of immunological memory. PMID:6215354

  19. Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

    PubMed Central

    Makidon, Paul E.; Janczak, Katarzyna W.; Blanco, Luz P.; Swanson, Benjamin; Smith, Douglas M.; Pham, Tiffany; Szabo, Zsuzsanna; Kukowska-Latallo, Jolanta F.; Baker, James R.

    2014-01-01

    Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1– and Th-17–balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell–mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses. PMID:24532579

  20. Mumps virus-induced innate immune responses in mouse Sertoli and Leydig cells

    PubMed Central

    Wu, Han; Shi, Lili; Wang, Qing; Cheng, Lijing; Zhao, Xiang; Chen, Qiaoyuan; Jiang, Qian; Feng, Min; Li, Qihan; Han, Daishu

    2016-01-01

    Mumps virus (MuV) infection frequently causes orchitis and impairs male fertility. However, the mechanisms underlying the innate immune responses to MuV infection in the testis have yet to be investigated. This study showed that MuV induced innate immune responses in mouse Sertoli and Leydig cells through TLR2 and retinoic acid-inducible gene I (RIG-I) signaling, which result in the production of proinflammatory cytokines and chemokines, including TNF-α, IL-6, MCP-1, CXCL10, and type 1 interferons (IFN-α and IFN-β). By contrast, MuV did not induce the cytokine production in male germ cells. In response to MuV infection, Sertoli cells produced higher levels of proinflammatory cytokines and chemokines but lower levels of type 1 IFNs than Leydig cells did. The MuV-induced cytokine production by Sertoli and Leydig cells was significantly reduced by the knockout of TLR2 or the knockdown of RIG-I signaling. The local injection of MuV into the testis triggered the testicular innate immune responses in vivo. Moreover, MuV infection suppressed testosterone synthesis by Leydig cells. This is the first study examining the innate immune responses to MuV infection in testicular cells. The results provide novel insights into the mechanisms underlying the MuV-induced innate immune responses in the testis. PMID:26776505

  1. An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection

    PubMed Central

    Sariol, Carlos A.; Mattocks, Melissa D.; Wahala M. P. B., Wahala; Yingsiwaphat, Vorraphun; Collier, Martha L.; Whitley, Jill; Mikkelsen, Rochelle; Rodriguez, Idia V.; Martinez, Melween I.; de Silva, Aravinda; Johnston, Robert E.

    2013-01-01

    Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans. PMID:23302884

  2. Improved immune response to recombinant influenza nucleoprotein formulated with ISCOMATRIX.

    PubMed

    Cargnelutti, Diego E; Sanchez, Maria V; Alvarez, Paula; Boado, Lorena; Glikmann, Graciela; Mattion, Nora; Scodeller, Eduardo A

    2012-03-01

    Current influenza vaccines elicit antibodies effective against homologous strains, but new strategies are urgently needed for protection against emerging epidemic or pandemic strains. Although influenza vaccine candidates based on the viral nucleoprotein (NP) or matrix protein do not elicit sterilizing immunity, they have the advantage of inducing immunity that may cover a larger number of viral strains. In this study, recombinant NP produced in Escherichia coli was purified and formulated in combination with the adjuvant ISCOMATRIX. This formulation increased a NP-specific immunity in mice, with a Th1 profile, and may constitute a promising low-cost influenza vaccine candidate, with ability to stimulate humoral and cellular immune responses.. PMID:22450799

  3. Variations in the structure and transcription of the mitochondrial atp and cox genes in wild Solanum species that induce male sterility in eggplant (S. melongena).

    PubMed

    Yoshimi, M; Kitamura, Y; Isshiki, S; Saito, T; Yasumoto, K; Terachi, T; Yamagishi, H

    2013-07-01

    In order to determine the molecular basis of cytoplasmic male sterility (CMS) in alloplasmic lines of eggplant, the genomic structures and transcription patterns of mitochondrial ATP synthase subunit (atp) and cytochrome oxidase subunit (cox) genes were studied for wild and cultivated eggplants. Alloplasmic eggplant lines with cytoplasms of wild Solanum species showing either anther indehiscent type of CMS or non-pollen production type of CMS were studied with the cultivated eggplant Solanum melongena, used as a control. Southern hybridization of the mitochondrial genes indicated the difference between the two types of CMS and showed complete identity within each type. The cytoplasmic patterns of all wild species differed from that of the cultivated eggplant. Thus, the cytoplasm of the six wild eggplants and the one cultivated eggplant was classified into three groups. Male sterile plants of both types of CMS showed novel transcription patterns of atp1, whereas a different transcription pattern of cox2 was observed only in the anther indehiscent type. Based on these differences, we determined the DNA sequences of about a 4 kbp segment in the atp1 region. Although the coding and 3' flanking regions were almost identical among the cytoplasms, the 5' flanking region was completely different and novel open reading frames (orfs) were found for each of the CMS types and the cultivated eggplant. The cytoplasm of Solanum kurzii inducing the anther indehiscent type CMS had orf312, and those of Solanum aethiopicum and Solanum grandifolium of non-pollen production type CMS had orf218. The correspondence between the transcription patterns of these orfs and phenotypic expression of male sterility strongly suggests that these orfs are causal genes for each type of CMS. PMID:23604528

  4. Glucose supplement reverses the fasting-induced suppression of cellular immunity in Mongolian gerbils (Meriones unguiculatus).

    PubMed

    Xu, De-Li; Wang, De-Hua

    2011-10-01

    Glucose plays an important role in immunity. Three day fasting will decrease cellular immunity and blood glucose levels in Mongolian gerbils (Meriones unguiculatus). In the present study, we tested the hypothesis that glucose supplement can reverse the fasting-induced suppression in cellular immunity in gerbils. Twenty-eight male gerbils were selected and randomly divided into fed and fasting groups. Half of the gerbils in each group were then provided with either 10% glucose water or pure water. After 66 h, each gerbil was injected with phytohaemagglutinin (PHA) solution to challenge cellular immunity. Results showed that glucose supplement restored blood glucose levels in fasted gerbils to those of the fed controls. It also recovered cellular immunity, body fat mass and serum leptin levels in fasted gerbils to the values of the fed controls. Blood glucose levels were positively correlated with body fat mass, leptin levels and cellular immune responses. Thymus and spleen masses, and white blood cells in fasted gerbils were not affected by glucose supplement. In general, our data demonstrate that glucose supplement could reverse fasting-induced suppression of cellular immunity in Mongolian gerbils. PMID:21885265

  5. Strain-Specific Protective Effect of the Immunity Induced by Live Malarial Sporozoites under Chloroquine Cover

    PubMed Central

    Wijayalath, Wathsala; Cheesman, Sandra; Tanabe, Kazuyuki; Handunnetti, Shiroma; Carter, Richard; Pathirana, Sisira

    2012-01-01

    The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2–4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2–5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites’ circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the

  6. The Skin Microbiome: Is It Affected by UV-induced Immune Suppression?

    PubMed Central

    Patra, VijayKumar; Byrne, Scott N.; Wolf, Peter

    2016-01-01

    Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation (UV-R) from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin’s microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs) that interfere with UV-induced immune suppression. PMID:27559331

  7. The Skin Microbiome: Is It Affected by UV-induced Immune Suppression?

    PubMed

    Patra, VijayKumar; Byrne, Scott N; Wolf, Peter

    2016-01-01

    Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation (UV-R) from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin's microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs) that interfere with UV-induced immune suppression. PMID:27559331

  8. Immune Cells and Molecular Networks in Experimentally Induced Pulpitis.

    PubMed

    Renard, E; Gaudin, A; Bienvenu, G; Amiaud, J; Farges, J C; Cuturi, M C; Moreau, A; Alliot-Licht, B

    2016-02-01

    Dental pulp is a dynamic tissue able to resist external irritation during tooth decay by using immunocompetent cells involved in innate and adaptive responses. To better understand the immune response of pulp toward gram-negative bacteria, we analyzed biological mediators and immunocompetent cells in rat incisor pulp experimentally inflamed by either lipopolysaccharide (LPS) or saline solution (phosphate-buffered saline [PBS]). Untreated teeth were used as control. Expression of pro- and anti-inflammatory cytokines, chemokine ligands, growth factors, and enzymes were evaluated at the transcript level, and the recruitment of the different leukocytes in pulp was measured by fluorescence-activated cell-sorting analysis after 3 h, 9 h, and 3 d post-PBS or post-LPS treatment. After 3 d, injured rat incisors showed pulp wound healing and production of reparative dentin in both LPS and PBS conditions, testifying to the reversible pulpitis status of this model. IL6, IL1-β, TNF-α, CCL2, CXCL1, CXCL2, MMP9, and iNOS gene expression were significantly upregulated after 3 h of LPS stimulation as compared with PBS. The immunoregulatory cytokine IL10 was also upregulated after 3 h, suggesting that LPS stimulates not only inflammation but also immunoregulation. Fluorescence-activated cell-sorting analysis revealed a significant, rapid, and transient increase in leukocyte levels 9 h after PBS and LPS stimulation. The quantity of dendritic cells was significantly upregulated with LPS versus PBS. Interestingly, we identified a myeloid-derived suppressor cell-enriched cell population in noninjured rodent incisor dental pulp. The percentage of this population, known to regulate immune response, was higher 9 h after inflammation triggered with PBS and LPS as compared with the control. Taken together, these data offer a better understanding of the mechanisms involved in the regulation of dental pulp immunity that may be elicited by gram-negative bacteria. PMID:26472753

  9. Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity.

    PubMed

    Gabitzsch, Elizabeth S; Xu, Younong; Yoshida, Lois H; Balint, Joseph; Amalfitano, Andrea; Jones, Frank R

    2009-10-30

    Recombinant Adenovirus serotype 5 (Ad5) vectors have been used as vaccine platforms in numerous animal and human clinical studies. The immune response induced by Ad5 vaccines can be mitigated due to pre-existing Ad5 immunity. We previously reported the use of a novel Ad5 platform to induce cellular immune responses (CMI) against HIV-1 Gag in Ad5 hyper immune mice. Here, the effectiveness of the Ad5 [E1-, E2b-] vaccine platform was evaluated using a triad mixture of HIV-1 Gag, Pol, and Nef as antigenic transgenes. Broad CMI was induced following vaccination with the HIV-1 expressing vectors in Ad5 naïve and Ad5 immunized mice. A mixture of the three vaccines induced CMI against each transgene product even in the presence of hyper Ad5 immunity. These studies revealed that CMI responses to immunization with Ad5 [E1-, E2b-]-gag, Ad5 [E1-, E2b-]-pol or Ad5 [E1-, E2b-]-nef vectors were transgene specific and did not induce CMI responses against irrelevant antigens such as carcinoembryonic antigen (CEA), herpes simplex virus glycoprotein B (HSV), cytomegalovirus (CMV) or influenza virus antigens. We are evaluating this recombinant triad viral vector as an HIV-1 vaccine in a non-human primate model and the data indicate that the vaccine is worthy of clinical evaluation. PMID:19559110

  10. Polycation-decorated PLA microspheres induce robust immune responses via commonly used parenteral administration routes.

    PubMed

    Chen, Xiaoming; Wang, Lianyan; Liu, Qi; Jia, Jilei; Liu, Yuan; Zhang, Weifeng; Ma, Guanghui; Su, Zhiguo

    2014-12-01

    Recombinant viral subunit-based vaccines have gained increasing attention due to their enhanced safety over the classic live-attenuated or inactivated vaccines. The low immunogenicity of the subunit antigen alone, however, requires the addition of an adjuvant to induce immunity. Particulate-based delivery systems have great potential for developing new vaccine adjuvants, compared to traditional aluminum-based saline adjuvants. The physicochemical properties of particulate vaccines have been extensively investigated; however, few studies have focused on how the administration route of various adjuvant-antigen combinations impacts the efficacy of the immune response. Here, for the first time, the viral Hepatitis B surface antigen (HBsAg) was combined with aluminum-based or cationic-microsphere (MP) based adjuvants to investigate the characteristics of immune responses elicited after immunization via the subcutaneous, intramuscular, or intraperitoneal routes respectively. In vitro, the MP-based vaccine significantly increased dendritic cell (DC) activation with up-regulated CD40 and CD80 expression and IL-12 production compared to alum-based vaccine. After immunization, both MP and alum-based vaccines produced increased IgG titers in mice. The administration route of these vaccines did influenced immune responses. The MP-based vaccine delivered via the intramuscular route yielded the highest levels of the IgG2a isotype. The alum-based vaccine, delivered via the same route, produced an IgG1-dominated humoral immune response. Moreover, subcutaneous and intramuscular immunizations with MP-based vaccine augmented Granzyme B, Th1-type cytokines (IL-2, IL-12, and IFN-γ), and Th2 cytokine IL-4 secretions. These results demonstrate that MP-based vaccines have the capacity to induce higher cellular and humoral immune response especially via an intramuscular administration route than an alum-based vaccine. PMID:25466267

  11. Does Infection-Induced Immune Activation Contribute to Dementia?

    PubMed Central

    Barichello, Tatiana; Generoso, Jaqueline S; Goularte, Jessica A; Collodel, Allan; Pitcher, Meagan R; Simões, Lutiana R; Quevedo, João; Dal-Pizzol, Felipe

    2015-01-01

    The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders. PMID:26425389

  12. 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

  13. Hydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses

    PubMed Central

    Babar, Faizan; Posner, Jeffery N.; Obah, Eugene A.

    2016-01-01

    Hydralazine has been used since the 1950s for the management of hypertension. Evidence for hydralazine-associated vasculitis dates to pre-ANCA (antineutrophil cytoplasmic antibodies) era. This abstract describes two cases of ANCA-positive pauci-immune glomerulonephritis (GN) in challenging scenarios where diagnosis was misconstrued. A comprehensive literature review was done to understand the pathogenesis of drug-induced pauci-immune GN. We have described key diagnostic features that are helpful in distinguishing idiopathic ANCA vasculitis from drug-induced vasculitis. Additionally, we have also described different treatments meant to provide therapy options with the least side effects. PMID:27124161

  14. Neonatal Immunization with Respiratory Syncytial Virus Glycoprotein Fragment Induces Protective Immunity in the Presence of Maternal Antibodies in Mice

    PubMed Central

    Noh, Youran; Shim, Byoung-Shik; Cheon, In Su; Rho, Semi; Kim, Hee Joo; Choi, Youngjoo; Kang, Chang-Yuil; Chang, Jun

    2013-01-01

    Abstract Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly worldwide. The significant morbidity and mortality associated with this infection underscores the urgent need for development of RSV vaccine. In this study, we first show that intranasal administration of RSV glycoprotein core fragment (Gcf) to neonatal mice can induce systemic humoral immune responses and protective immunity against RSV without causing lung eosinophilia, although antibody response was shifted to a Th2 response. Next, we examined whether the presence of maternal anti-RSV antibodies would affect the responsiveness and protection efficacy of Gcf in newborn mice, since infants can possess RSV-specific maternal antibodies due to frequent RSV re-infections to adults. Intranasal administration of Gcf induced antibody response and increased IFNγ secretion and protected mice against RSV challenge without severe lung eosinophilia, even in the presence of high levels of RSV-specific maternal antibodies. Thus, our findings suggest that Gcf may be an effective and safe RSV vaccine during the neonatal period. PMID:23869549

  15. Pertussis immunity and epidemiology: mode and duration of vaccine-induced immunity.

    PubMed

    Magpantay, F M G; Domenech DE Cellès, M; Rohani, P; King, A A

    2016-06-01

    The resurgence of pertussis in some countries that maintain high vaccination coverage has drawn attention to gaps in our understanding of the epidemiological effects of pertussis vaccines. In particular, major questions surround the nature, degree and durability of vaccine protection. To address these questions, we used mechanistic transmission models to examine regional time series incidence data from Italy in the period immediately following the introduction of acellular pertussis (aP) vaccine. Our results concur with recent animal-challenge experiments wherein infections in aP-vaccinated individuals proved as transmissible as those in naive individuals but much less symptomatic. On the other hand, the data provide evidence for vaccine-driven reduction in susceptibility, which we quantify via a synthetic measure of vaccine impact. As to the precise nature of vaccine failure, the data do not allow us to distinguish between leakiness and waning of vaccine immunity, or some combination of these. Across the range of well-supported models, the nature and duration of vaccine protection, the age profile of incidence and the range of projected epidemiological futures differ substantially, underscoring the importance of the remaining unknowns. We identify key data gaps: sources of data that can supply the information needed to eliminate these remaining uncertainties. PMID:26337864

  16. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    PubMed

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. PMID:26278659

  17. Pentabody-mediated antigen delivery induces antigen-specific mucosal immune response.

    PubMed

    Li, Shenghua; Zheng, Wenju; Kuolee, Rhonda; Hirama, Tomoko; Henry, Matthew; Makvandi-Nejad, Shokouh; Fjällman, Ted; Chen, Wangxue; Zhang, Jianbing

    2009-05-01

    An efficient immunization system is essential for the development of mucosal vaccine. Cholera toxin (CT) and Escherichia coli heat labile toxin (LT) are among the strongest adjuvants tested in experimental animals but their use in humans has been hindered by their toxicity. On the other hand, the role of their non-toxic B-subunits, CTB or LTB, in enhancing mucosal immune response is not clear. We propose here a novel strategy for the induction of mucosal immune responses. Single domain antibodies (sdAbs) against a model antigen bovine serum albumin (BSA) were raised from the antibody repertoire of a llama immunized with BSA, pentamerized by fusing the sdAbs to CTB, generating the so-called pentabodies. These pentabodies were used to deliver the antigen by mixing the two components and administering the mixture to mice intranasally. One construct was equivalent to CT in helping induce mucosal immune response. It was also found that this ability was probably due to its high affinity to BSA, providing some insight into the controversial role of CTB in mucosal immunization: at least for BSA, the model antigen BSA employed in this study, CTB has to be tightly linked to the antigen to have adjuvant/immune-enhancing effect. PMID:19269688

  18. Mouse and pig models for studies of natural and vaccine-induced immunity to Bordetella pertussis.

    PubMed

    Mills, Kingston H G; Gerdts, Volker

    2014-04-01

    The increasing incidence of whooping cough in many developed countries has been linked with waning immunity induced after immunization with acellular pertussis (aP) vaccines. The rational design of an improved aP vaccine requires a full understanding of the mechanism of protective immunity and preclinical studies in animal models. Infection of mice and pigs with Bordetella pertussis has many features of the infection seen in humans and has already provided valuable information on the roles of innate and adaptive immune responses in protection. Recent findings in these models have already indicated that it may be possible to develop an improved aP vaccine based on a formulation that includes a Toll-like receptor agonist as an adjuvant. PMID:24626866

  19. Sterilizing the Poor

    ERIC Educational Resources Information Center

    Rothman, Sheila M.

    1977-01-01

    Suggests that freedom for the middle classes may mean vulnerability for the poor. The enthusiasm for sterilization may be so intense as to deprive the poor of their right not to be sterilized. (Author/AM)

  20. Commonly administered bacille Calmette-Guerin strains induce comparable immune response

    PubMed Central

    Wang, Jun-Fang; Dai, Fu-Ying; Gong, Xue-Li; Bao, Lang

    2015-01-01

    Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB), but its protective efficacy in adults is highly variable. This study aimed to compare the immune response induced by two widely used BCG strains: BCG China strain (derivative of BCG Danish strain) in DU2-III group and BCG Pasteur in DU2 -IV group. Healthy BALB/c mice were immunized with BCG China strain or BCG Pasteur strain. Specific IgG, IgG1, and IgG2a antibodies titers, the proliferation of splenocytes, the percentages of splenocyte subsets and the concentrations of induced IFN-γ and IL-4 at 6th, 8th, 10th, and 12th weeks after the immunization were detected. We found that BCG Pasteur strain induced higher specific IgG and IgG1 titers, higher proliferation of splenocytes, higher percentages of CD4+ or CD8+ T cells, and higher concentration of secreted IFN-γ than BCG China strain. However, there were no significant differences in IgG2a titer and IL-4 concentration between both strains. In conclusion, our study shows that immune responses to BCG vaccine differ by strain, which may account for variable outcomes of BCG immunization. PMID:26629084

  1. Apparatus Circulates Sterilizing Gas

    NASA Technical Reports Server (NTRS)

    Cross, John H.; Schwarz, Ray P.

    1991-01-01

    Apparatus circulates sterilizing gas containing ethylene oxide and chlorofluorocarbon through laboratory or medical equipment. Confines sterilizing gas, circulating it only through parts to be treated. Consists of two units. One delivers ethylene oxide/chlorofluorocarbon gas mixture and removes gas after treatment. Other warms, humidifies, and circulates gas through equipment to be treated. Process provides reliable sterilization with negligible residual toxicity from ethylene oxide. Particularly suitable for sterilization of interiors of bioreactors, heart/lung machines, dialyzers, or other equipment including complicated tubing.

  2. Steroid-induced femoral head osteonecrosis in immune thrombocytopenia treatment with osteochondral autograft transplantation.

    PubMed

    Fotopoulos, Vasileios Ch; Mouzopoulos, George; Floros, Themistoklis; Tzurbakis, Matthaios

    2015-09-01

    Osteonecrosis of the femoral head is a devastating complication of steroid administration and has rarely been observed in the treatment of immune thrombocytopenia. The treatment of osteochondral defects in advanced stages of avascular necrosis (AVN), characterized by collapse of the subchondral bone, remains an unsolved burden in orthopedic surgery. In this report, we present a case of a 19-year-old female that was admitted in the Emergency Department with walking disability and painful hip joint movement due to steroid-induced femoral head osteonecrosis. Two years before she was diagnosed with immune thrombocytopenia, for which she received pulse steroid therapy with high dose of dexamethasone and underwent a splenectomy. This case report is the first to describe the use of osteochondral autograft transplantation as a treatment of steroid-induced AVN of the femoral head due to immune thrombocytopenia at the age of 19 years with very good clinical and radiological results 3 years postoperatively. PMID:25173503

  3. Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review.

    PubMed

    Forcello, Nicholas P; Khubchandani, Sapna; Patel, Shrina J; Brahaj, Driola

    2015-04-01

    Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly. PMID:24500808

  4. ISO radiation sterilization standards

    NASA Astrophysics Data System (ADS)

    Lambert, Byron J.; Hansen, Joyce M.

    1998-06-01

    This presentation provides an overview of the current status of the ISO radiation sterilization standards. The ISO standards are voluntary standards which detail both the validation and routine control of the sterilization process. ISO 11137 was approved in 1994 and published in 1995. When reviewing the standard you will note that less than 20% of the standard is devoted to requirements and the remainder is guidance on how to comply with the requirements. Future standards developments in radiation sterilization are being focused on providing additional guidance. The guidance that is currently provided in informative annexes of ISO 11137 includes: device/packaging materials, dose setting methods, and dosimeters and dose measurement, currently, there are four Technical Reports being developed to provide additional guidance: 1. AAMI Draft TIR, "Radiation Sterilization Material Qualification" 2. ISO TR 13409-1996, "Sterilization of health care products — Radiation sterilization — Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches" 3. ISO Draft TR, "Sterilization of health care products — Radiation sterilization Selection of a sterilization dose for a single production batch" li]4. ISO Draft TR, "Sterilization of health care products — Radiation sterilization-Product Families, Plans for Sampling and Frequency of Dose Audits."

  5. Human Pappilomavirus (HPV) induced cancers and prevention by immunization.

    PubMed

    Khaliq, Sheikh Abdul; Shyum Naqvi, Syed Baqir; Fatima, Anab

    2012-10-01

    Incidences of different types of cancer are increasing in Pakistan, among which cancer of Cervix and Respiratory pappilomatosis are of great concern because of their association with human Pappilomavirus (HPV). Cervical cancers typically distress women of middle age or older; however it may affect women in any age after the puberty. Two serotypes of HPV (16 & 18) accounts 70% of cervical cancer cases, while HPV (6 & 11) are considered low-risk viruses associated with genital warts (Condyloma acuminata) and Respiratory pappilomatosis in both gender. Generally, there is transient role of HPV in human body and are removed by immune system in or around 1 year. Data from different Pakistani hospitals provides sound evidence for increasing trends of cervical cancer, which is, being developing country imperative for us. As the cost of cancer management is increasing day by day with poor survival rate and its burden is borne by patient, their family or society in-large, so if screening or prevention is possible then there would be need to identify target population for screening and vaccination. By quality adjusted life year (QALY) measurement, the data from different sources indicates that adolescent age is the appropriate target population and is cost effective for vaccination. Two vaccines manufactured by recombinant DNA technology are licensed in some parts of the world for prevention of HPV related cancers, however both have certain advantage over another, as one of the vaccines contains viral like proteins of two HPV serotypes 16 & 18 and provide additional cross protection against HPV type 13 and 45 with 100% seroprotection, while the other vaccine, being quadrivalent offers protection against four serotypes 6, 11, 16 and 18. Both vaccines tolerability and safety profiles are similar and acceptable, however bivalent vaccine appears to provide long-lasting immunity by the development of memory B-cells hypothetically due to difference of adsorbing agent used by

  6. T-Cell Immune Response Assessment as a Complement to Serology and Intranasal Protection Assays in Determining the Protective Immunity Induced by Acellular Pertussis Vaccines in Mice

    PubMed Central

    Ausiello, C. M.; Lande, R.; Stefanelli, P.; Fazio, C.; Fedele, G.; Palazzo, R.; Urbani, F.; Mastrantonio, P.

    2003-01-01

    The relative value of antibodies and/or T-cell immune responses to Bordetella pertussis antigens in the immunity induced by acellular pertussis (aP) vaccines is still an open issue, probably due to the incomplete knowledge on the mechanisms of protective immunity to pertussis. The relevance of T-cell immune responses in protection from pertussis has been demonstrated in murine and human models of infection; thus, in this study, the ability of different vaccine preparations of three component (pertussis toxin, filamentous hemagglutinin, and pertactin) aP vaccines to induce T-cell responses was investigated in mice. All vaccine preparations examined passed the immunogenicity control test, based on antibody titer assessment, according to European Pharmacopoeia standards, and protected mice from B. pertussis intranasal challenge, but not all preparations were able to prime T cells to pertussis toxin, the specific B. pertussis antigen. In particular, one vaccine preparation was unable to induce proliferation and gamma interferon (IFN-γ) production while the other two gave borderline results. The evaluation of T-cell responses to pertussis toxin antigen may provide information on the protective immunity induced by aP vaccines in animal models. Considering the critical role of the axis interleukin-12-IFN-γ for protection from pertussis, our results suggest that testing the induction of a key protective cytokine such as IFN-γ could be an additional tool for the evaluation of the immune response induced by aP vaccines. PMID:12853397

  7. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    SciTech Connect

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

    2014-01-03

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

  8. Fatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor

    PubMed Central

    Haley, Kristina M; Russell, Thomas B; Boshkov, Lynn; Leger, Regina M; Garratty, George; Recht, Michael; Nazemi, Kellie J

    2014-01-01

    Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy. PMID:24868179

  9. GMCSF-armed vaccinia virus induces an antitumor immune response.

    PubMed

    Parviainen, Suvi; Ahonen, Marko; Diaconu, Iulia; Kipar, Anja; Siurala, Mikko; Vähä-Koskela, Markus; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

    2015-03-01

    Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor-associated hypermetabolism was armed with human granulocyte-macrophage colony-stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene-carrying viruses was similar to unarmed virus. The hGMCSF-encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus-treated tumors. These findings help clarify the mechanism of action of GMCSF-armed vaccinia viruses undergoing clinical trials. PMID:25042001

  10. A VACCINE STRATEGY THAT INDUCES PROTECTIVE IMMUNITY AGAINST HEROIN

    PubMed Central

    Stowe, G. Neil; Vendruscolo, Leandro F.; Edwards, Scott; Schlosburg, Joel E.; Misra, Kaushik K.; Schulteis, Gery; Mayorov, Alexander V.; Zakhari, Joseph S.; Koob, George F.; Janda, Kim D.

    2011-01-01

    Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach though the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten. PMID:21692508

  11. Heterologous Vaccination and Checkpoint Blockade Synergize To Induce Antileukemia Immunity.

    PubMed

    Manlove, Luke S; Schenkel, Jason M; Manlove, Kezia R; Pauken, Kristen E; Williams, Richard T; Vezys, Vaiva; Farrar, Michael A

    2016-06-01

    Checkpoint blockade-based immunotherapies are effective in cancers with high numbers of nonsynonymous mutations. In contrast, current paradigms suggest that such approaches will be ineffective in cancers with few nonsynonymous mutations. To examine this issue, we made use of a murine model of BCR-ABL(+) B-lineage acute lymphoblastic leukemia. Using a principal component analysis, we found that robust MHC class II expression, coupled with appropriate costimulation, correlated with lower leukemic burden. We next assessed whether checkpoint blockade or therapeutic vaccination could improve survival in mice with pre-established leukemia. Consistent with the low mutation load in our leukemia model, we found that checkpoint blockade alone had only modest effects on survival. In contrast, robust heterologous vaccination with a peptide derived from the BCR-ABL fusion (BAp), a key driver mutation, generated a small population of mice that survived long-term. Checkpoint blockade strongly synergized with heterologous vaccination to enhance overall survival in mice with leukemia. Enhanced survival did not correlate with numbers of BAp:I-A(b)-specific T cells, but rather with increased expression of IL-10, IL-17, and granzyme B and decreased expression of programmed death 1 on these cells. Our findings demonstrate that vaccination to key driver mutations cooperates with checkpoint blockade and allows for immune control of cancers with low nonsynonymous mutation loads. PMID:27183622

  12. Antigens linked to synthetic microspheres induce immune responses in primates in the absence of adjuvant.

    PubMed

    Sedlik, C; Perraut, R; Bonnemains, B; Leclerc, C

    1996-01-01

    Although most strategies of vaccination require immunopotentiation to induce efficient immune responses, the development of new adjuvants for human vaccines is highly limited by safety problems. In order to overcome this problem, we developed a new vaccine formulation based on the covalent linkage of protein or peptide to synthetic microspheres. In previous experiments performed in mice, we demonstrated that these particulate antigens induce strong antigen-specific CD4+ T cell proliferative responses in the absence of adjuvant. In the present study, we analyzed the immunogenicity in primate Saimiri sciureus monkeys of two different proteins linked to synthetic microspheres. Immune responses induced by these particulate proteins administered without adjuvant were compared to those stimulated by the soluble antigens injected with alum. We currently demonstrated that, in monkeys, particulate antigens administered without adjuvant, induced good PBMC proliferative response and antibody production. Furthermore, the analysis of antibody responses using mAbs specific for different Saimiri sciureus immunoglobulins showed that the antibody response profiles were different in monkeys immunized with soluble versus particulate form of antigens. Results of this study demonstrate that particulate form of antigen may stimulate qualitatively different immune responses as compared to alum and therefore suggest that this new antigen formulation could be an attractive candidate for the development of vaccines. PMID:8852604

  13. Glycerol-3-phosphate is a critical mobile inducer of systemic immunity in plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glycerol-3-phosphate (G3P) is an important metabolite that contributes to the growth and disease-related physiologies of prokaryotes, plants, animals and humans alike. Here we show that G3P serves as the inducer of an important form of broad-spectrum immunity in plants, termed systemic acquired resi...

  14. Fungal innate immunity induced by bacterial microbe-associated molecular patterns (MAMPs)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plants and animals detect bacterial presence through Microbe-Associated Molecular Patterns (MAMPs) which induce an innate immune response. The field of fungal-bacterial interaction at the molecular level is still in its infancy and very little is known about fungal molecular responses to bacteria, a...

  15. Marek's Disease Virus-Induced Immunosuppression: Array Analysis of Chicken Immune Response Gene Expression Profiling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by a highly cell-associated oncogenic alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latency infection within CD4+ T cells. Host-virus interaction, immune responses to...

  16. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte...

  17. Basophil-derived amphiregulin is essential for UVB irradiation-induced immune suppression.

    PubMed

    Meulenbroeks, Chantal; van Weelden, Huib; Schwartz, Christian; Voehringer, David; Redegeld, Frank A M; Rutten, Victor P M G; Willemse, Ton; Sijts, Alice J A M; Zaiss, Dietmar M W

    2015-01-01

    UVB irradiation (290-320 nm) is used to treat skin diseases like psoriasis and atopic dermatitis, and is known to suppress contact hypersensitivity (CHS) reactions in mouse models. Regulatory T cells (Treg cells) have been shown to be responsible for this UVB-induced suppression of CHS. The epidermal growth factor (EGF)-like growth factor amphiregulin (AREG) engages EGFR on Treg cells and, in different disease models, it was shown that mast cell-derived AREG is essential for optimal Treg cell function in vivo. Here we determined whether AREG has a role in UVB-induced, Treg cell-mediated suppression of CHS reactions in the skin. Our data show that AREG is essential for UVB-induced CHS suppression. In contrast to the general assumption, however, mast cells were dispensable for UVB-induced immune suppression, whereas basophil-derived AREG was essential. These data reveal, to our knowledge, a previously unreported function for basophils in the homeostasis of immune responses in the skin. Basophils thus fulfill a dual function: they contribute to the initiation of effective type 2 immune responses and, by enhancing the suppressive capacity of local Treg cell populations, also to local immune regulation in the skin. PMID:25089660

  18. In vitro activation of rat neutrophils and alveolar macrophages with IgA and IgG immune complexes. Implications for immune complex-induced lung injury.

    PubMed Central

    Warren, J. S.; Kunkel, S. L.; Johnson, K. J.; Ward, P. A.

    1987-01-01

    In the rat, both IgG and IgA immune complexes induce oxygen radical mediated lung injury that is partially complement-dependent. In vivo studies have suggested that the chief sources of oxygen radicals in IgG and IgA immune complex-induced lung injury are neutrophils and tissue macrophages, respectively. The current studies have been designed to provide additional insights into these two models of tissue injury. Preformed monoclonal IgG and IgA immune complexes stimulated dose-dependent O2-. and H2O2 production by alveolar macrophages. In contrast, neutrophils exhibited O2-. production and lysosomal enzyme secretion in response to IgG immune complexes, but not in response to IgA complexes. There is evidence that C5a significantly amplifies these responses. Purified human C5a enhanced the O2-. responses of neutrophils activated with IgG immune complexes and alveolar macrophages activated with either IgG or IgA immune complexes. Addition of C5a alone to neutrophils or alveolar macrophages had no direct stimulatory effect as measured by O2-. production. The observation that O2-. responses of immune complex-activated alveolar macrophages can be significantly enhanced by the presence of C5a and that C5a can also enhance O-2. responses of IgG immune complex-stimulated neutrophils suggests a potential amplification mechanism through which complement may participate in both IgG and IgA immune complex-induced lung injury. The present data corroborate in vivo studies which suggest that IgG immune complex lung injury is primarily neutrophil-mediated, whereas IgA complex lung injury is predominantly macrophage-mediated. PMID:2827492

  19. Immunization with adenovirus LIGHT-engineered dendritic cells induces potent T cell responses and therapeutic immunity in HBV transgenic mice.

    PubMed

    Jiang, Wenzheng; Chen, Ran; Kong, Xiaobo; Long, Fengying; Shi, Yaru

    2014-07-31

    LIGHT, a TNF superfamily member (TNFSF14), is a type II transmembrane protein expressed on activated T cells and immature dendritic cells (DCs). However, the expression of LIGHT on mature DCs is down-regulated. Recent studies demonstrated that LIGHT provides potent costimulatory activity for T cells, enhancing proliferation and the production of Th1 cytokines independently of the B7-CD28 pathway. Here, we evaluated the effectiveness of peptide-pulsed DC-mediated antiviral immunity in HBV transgenic mice and the immunoadjuvant effect of LIGHT. The bone marrow-derived DCs were modified in vitro with an adenovirus (Ad) vector expressing mouse LIGHT (Ad-LIGHT), the expression of costimulatory molecules was up-regulated and the secretion of cytokines IL-12 and IFN-γ increased. LIGHT-modified DCs enhanced allostimulation for T cells in mixed lymphocyte reaction (MLR). HBV peptide-pulsed DCs elicited HBV specific CD8+ T cell response and reduced the level of HBsAg and HBV DNA in sera of HBV transgenic mice. Importantly, LIGHT-modified DCs could induce stronger antiviral immunity. These results support the concept that genetic modification of DCs with a recombinant LIGHT adenovirus vector may be a useful strategy for antiviral immunotherapy. PMID:24951859

  20. Coffea arabica Seed Extract Stimulate the Cellular Immune Function and Cyclophosphamide-induced Immunosuppression in Mice

    PubMed Central

    Rafiul Haque, Mohammad; Ansari, Shahid Hussain; Rashikh, Azhar

    2013-01-01

    In this study, we investigate the immunostimulatory effects of alcoholic extract of the coffee seed on cell-mediated immune response and cyclophosphamide-induced (CP) immunosuppressed mice. The assessment of cellular immune function was carried out by the measurement of delayed-type hypersensitivity (DTH) response. According to the literature survey, cyclophosphamide has only suppressing effect on the lymphoid organ, white blood cell (WBC) and other parts of humoral immunity. Humoral immunity was assessed by the hemagglutination antibody titre. Mice were treated with three doses of extract (50, 150 and 250 mg/Kg body weight per os). Relative organ weight and WBC counts were also studied in these animals. At doses of 50 and 150, a significant increase (p < 0.05) in relative organ weight of spleen and thymus was observed but there was no effect on kidney and liver weights. WBC counts was also increased significantly (p < 0.001) in all doses of the plant extract. Coffea arabica extract elicited a significant (p < 0.001) increase in the DTH response at doses of 50 and 150 mg/Kg, but the change at higher dose of 250 mg/Kg was not statistically significant. In the HT test, plant extract also showed modulatory effect at all doses groups. Over all, coffee seed showed the stimulatory effect on cellular immune function and cyclophosphamide induced immunosuppression in mice. PMID:24250577

  1. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    SciTech Connect

    Streeter, P.R.; Fortner, G.W.

    1986-03-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes.

  2. Mucosal and systemic immune responses induced by a single time vaccination strategy in mice.

    PubMed

    González Aznar, Elizabeth; Romeu, Belkis; Lastre, Miriam; Zayas, Caridad; Cuello, Maribel; Cabrera, Osmir; Valdez, Yolanda; Fariñas, Mildrey; Pérez, Oliver

    2015-08-01

    Vaccination is considered by the World Health Organization as the most cost-effective strategy for controlling infectious diseases. In spite of great successes with vaccines, many infectious diseases are still leading killers, because of the inadequate coverage of many vaccines. Several factors have been responsible: number of doses, high vaccine reactogenicity, vaccine costs, vaccination policy, among others. Contradictorily, few vaccines are of single dose and even less of mucosal administration. However, more common infections occur via mucosa, where secretory immunoglobulin A plays an essential role. As an alternative, we proposed a novel protocol of vaccination called Single Time Vaccination Strategy (SinTimVaS) by immunizing 2 priming doses at the same time: one by mucosal route and the other by parenteral route. Here, the mucosal and systemic responses induced by Finlay adjuvants (AF Proteoliposome 1 and AF Cochleate 1) implementing SinTimVaS in BALB/c mice were evaluated. One intranasal dose of AF Cochleate 1 and an intramuscular dose of AF Proteoliposome 1 adsorbed onto aluminum hydroxide, with bovine serum albumin or tetanus toxoid as model antigens, administrated at the same time, induced potent specific mucosal and systemic immune responses. Also, we demonstrated that SinTimVaS using other mucosal routes like oral and sublingual, in combination with the subcutaneous route elicits immune responses. SinTimVaS, as a new immunization strategy, could increase vaccination coverage and reduce time-cost vaccines campaigns, adding the benefits of immune response in mucosa. PMID:26140382

  3. Immunity against Boophilus annulatus induced by the Bm86 (Tick-GARD) vaccine.

    PubMed

    Pipano, Eugene; Alekceev, Eugene; Galker, Felicia; Fish, Lea; Samish, Michael; Shkap, Varda

    2003-01-01

    Friesian cattle were immunized with two inoculations of anti-tick Bm86 (Tick-GARD) vaccine and were challenged 30 or 90 d later with Boophilus annulatus larvae derived from 1.2 g of eggs. No nymphs or adult ticks were found on the immunized cattle during four weeks after challenge. Repeated infestations (2 to 4) with larvae on three other calves during a period of 160 and 390 d after the immunization did not result in development of nymphal and adult stages. In control, non-immunized cattle infested with corresponding batches of larvae 1380 to 4653 replete adult female ticks were collected. Larvae issued from Babesia bovis-infected female ticks transmitted the infection to Bm86-immunized cattle, but the progeny of B. bigemina-infected females did not. Since B. bigemina is transmitted exclusively by nymphal stages of Bo. annulatus these results support the observation that immunity induced by Bm86 affects the larval stage of this tick. PMID:14580066

  4. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation

    PubMed Central

    Wong, Carmen P.; Rinaldi, Nicole A.; Ho, Emily

    2015-01-01

    Scope Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. Methods and results An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency up-regulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, that coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Conclusion Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation. PMID:25656040

  5. High physical activity in young children suggests positive effects by altering autoantigen-induced immune activity.

    PubMed

    Carlsson, E; Ludvigsson, J; Huus, K; Faresjö, M

    2016-04-01

    Physical activity in children is associated with several positive health outcomes such as decreased cardiovascular risk factors, improved lung function, enhanced motor skill development, healthier body composition, and also improved defense against inflammatory diseases. We examined how high physical activity vs a sedentary lifestyle in young children influences the immune response with focus on autoimmunity. Peripheral blood mononuclear cells, collected from 55 5-year-old children with either high physical activity (n = 14), average physical activity (n = 27), or low physical activity (n = 14), from the All Babies In Southeast Sweden (ABIS) cohort, were stimulated with antigens (tetanus toxoid and beta-lactoglobulin) and autoantigens (GAD65 , insulin, HSP60, and IA-2). Immune markers (cytokines and chemokines), C-peptide and proinsulin were analyzed. Children with high physical activity showed decreased immune activity toward the autoantigens GAD65 (IL-5, P < 0.05), HSP60 and IA-2 (IL-10, P < 0.05) and also low spontaneous pro-inflammatory immune activity (IL-6, IL-13, IFN-γ, TNF-α, and CCL2 (P < 0.05)) compared with children with an average or low physical activity. High physical activity in young children seems to have positive effects on the immune system by altering autoantigen-induced immune activity. PMID:25892449

  6. Lipopolysaccharide Induces Immune Activation and SIV Replication in Rhesus Macaques of Chinese Origin

    PubMed Central

    Bao, Rong; Zhuang, Ke; Liu, Jinbiao; Wu, Jianguo; Li, Jieliang; Wang, Xu; Ho, Wen-Zhe

    2014-01-01

    Background Chronic immune activation is a hallmark of progressive HIV infection and a key determinant of immunodeficiency in HIV-infected individuals. Bacterial lipopolysaccharide (LPS) in the circulation has been implicated as a key factor in HIV infection-related systemic immune activation. We thus investigate the impact of LPS on systemic immune activation in simian immunodeficiency virus (SIV)-infected rhesus macaques of Chinese origin. Methods The animals were inoculated intravenously with SIVmac239. The levels of plasma viral load and host inflammatory cytokines in PBMC were measured by real-time RT-PCR. CD4/CD8 ratio and systemic immune activation markers were examined by flow cytometric analysis of PBMCs. White blood cell and neutrophil counts and C Reactive Protein levels were determined using biochemistry analyzer. The plasma levels of LPS were determined by Tachypleus Amebocyte Lysate (TAL) test. Results The animals inoculated with SIVmac239 became infected as evidenced by the increased plasma levels of SIV RNA and decreased CD4/CD8 ratio. LPS administration of SIV-infected animals induced a transient increase of plasma SIV RNA and immune activation, which was indicated by the elevated expression of the inflammatory cytokines and CD4+HLA-DR+ T cells in PBMCs. Conclusions These data support the concept that LPS is a driving factor in systemic immune activation of HIV disease. PMID:24918575

  7. Brief Report: Immune Microenvironment Determines the Immunogenicity of Induced Pluripotent Stem Cell Derivatives.

    PubMed

    Todorova, Dilyana; Kim, Jinchul; Hamzeinejad, Sara; He, Jingjin; Xu, Yang

    2016-02-01

    The breakthrough of induced pluripotent stem cells (iPSCs) has raised the possibility that patient-specific iPSCs can provide autologous cells for cell therapy without the concern for immune rejection. However, the immunogenicity of iPSC-derived cells remains controversial. Using syngeneic C57BL/6 (B6) mouse transplantation model, several studies indicate that B6 iPSC-derived cells exhibit some levels of immunogenicity when transplanted into B6 mice subcutaneously. In contrast, one recent study has concluded that various lineages of B6 iPSC-derived cells exhibit no immunogenicity when transplanted under the kidney capsule of B6 mice. To resolve the controversy concerning this critical issue of iPSC biology, we used the same B6 transplantation model to demonstrate that the immune response toward antigens is dependent on the immune environment of the transplantation site. Immunogenic antigen-expressing B6 embryonic stem cells (ESCs) as well as B6 iPSCs and their terminally differentiated cells survived under the kidney capsule but are immune rejected when transplanted subcutaneously or intramuscularly. The cotransplantation of mature B6 dendritic cells under the kidney capsule leads to immune rejection of B6 iPSC-derived grafts but not B6 ESC-derived grafts, indicating that the lack of detectable immune response to iPSC-derived grafts under the kidney capsule is due to the lack of functional antigen presenting cells. PMID:26439188

  8. Commercial sunscreen lotions prevent ultraviolet-radiation-induced immune suppression of contact hypersensitivity.

    PubMed

    Roberts, L K; Beasley, D G

    1995-09-01

    Ultraviolet (UV) radiation suppresses certain immunologic responses, such as contact hypersensitivity (CH). Some previous studies, using sunlamps emitting nonsolar-spectrum UV or excessive UV doses, have questioned the ability of sunscreens to prevent UV-induced immune suppression. Our study evaluated the immune protection capacities of commercial sunscreen lotions in relation to the effects of UV spectrum and dose. C3H mice were exposed to a fixed UV dose from Kodacel-filtered FS sunlamps that caused maximum Langerhans cell depletion and suppression of CH. Kodacel film blocks UV energy below 290 nm, thus eliminating immune-suppressive effects of UVC (200-290 nm) not present in sunlight. CH was equally suppressed in unprotected and placebo-lotion-treated, UV-exposed mice. Mice protected with sun protection factor (SPF)-15 and SPF-30 sunscreens mounted normal CH responses. SPF-4 and SPF-8 sunscreen-protected mice had CH responses significantly greater than those of unprotected mice. Direct effects of UV spectral differences on the immune protection value of an SPF-15 sunscreen were determined by exposing mice to UV radiation from unfiltered and Kodacel-filtered sunlamps and a 1000-W xenon lamp solar simulator (UV spectrum nearly equivalent to sunlight). The sunscreen immune protection value was 30 times the minimum immune suppression dose for the solar simulator, while being 7.5 times this dose for Kodacel-filtered and 2 times the dose for unfiltered sunlamps. These results demonstrate that commercial sunscreen lotions prevent UV-induced immune suppression at a level exceeding the labeled SPF when tested with an environmentally relevant UV source. PMID:7665909

  9. Repeated stress-induced stimulation of catecholamine response is not followed by altered immune cell redistribution.

    PubMed

    Imrich, Richard; Tibenska, Elena; Koska, Juraj; Ksinantova, Lucia; Kvetnansky, Richard; Bergendiova-Sedlackova, Katarina; Blazicek, Pavol; Vigas, Milan

    2004-06-01

    Stress response is considered an important factor in the modulation of immune function. Neuroendocrine hormones, including catecholamines, affect the process of immune cell redistribution, important for cell-mediated immunity. This longitudinal investigation was aimed at evaluating the effect of repeated stress-induced elevation of catecholamines on immune cell redistribution and expression of adhesive molecules. We assessed the responses of epinephrine (EPI), norepinephrine (NE), cortisol, changes in lymphocytes subpopulations, and percentages of CD11a+, CD11b+, and CD62L+ lymphocytes to a 20-min treadmill exercise of an intensity equal to 80% of the individual's Vo(2)max. The exercise was performed before and after 6 weeks of endurance training consisting of a 1-h run 4 times a week (ET) and after 5 days of bed rest (HDBR) in 10 healthy males. We did not observe any significant changes in the basal levels of EPI, NE, and cortisol in the plasma, nor in the immune parameters after ET and HDBR. The exercise test led to a significant (P <.001) elevation of EPI and NE levels after both ET and HDBR, a significant elevation (P <.01) of cortisol after HDBR, an increase in the absolute numbers of leukocytes, granulocytes, monocytes, CD3+, CD4+, CD8+, CD16+, CD19+ lymphocytes, percentage of CD11a+ and CD11b+ lymphocytes, and to a decrease of CD62L1 before, after ET, and after HDBR. We found comparable changes in all measured immune parameters after ET and HDBR. In conclusion, repeated stress-induced elevation of EPI and NE was not associated with an alteration in immune cell redistribution found in response to the single bout of exercise. PMID:15240377

  10. Electron paramagnetic resonance analyses of surface radical chemistries of gamma-sterilized orthopedic materials: implications pointing to cytotoxicity via wear debris-induced inflammation.

    PubMed

    DiCicco, Michael; Compton, Ryan; Duong, Thanh; Jansen-Varnum, Susan A

    2005-10-01

    In this research, electron paramagnetic resonance (EPR) spin-trapping was utilized to determine if surface radical chemistries occur for gamma (gamma)-sterilized orthopedic materials-ultra-high molecular weight polyethylene (UHMWPE) and the novel, hybrid, diurethane dimethacrylate (DUDMA)-based RHAKOSS. The materials' ability to competitively chelate catalytic ferrous ions (Fe(2+)) or readily reduce ferric ions (Fe(3+)), and hydrogen peroxide (H(2)O(2)) directly, in facilitating the Fenton reaction (FR), is indicative of cytotoxicity. Validations with a radical scavenger aids to confirm a radical mechanism. In conjunction, materials were thermally annealed and characterized by attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy in order to explore accelerated oxidative degradation induced by residual radicals evolving from gamma-sterilization. Particularly, there was a significant decrease in spin-adduct peak areas obtained from the reduction of H(2)O(2) in the presence of RHAKOSS or UHMWPE, evaluated against their respective controls. Additionally, chelated Fe(2+) accelerated the rate of FR. This phenomenon suggests that the materials are not better chelators than the Fe-activating chelator, edta. Neither material had the propensity to readily reduce Fe(3+) to the relevant Fe(2+), as certified by a nonradical mechanism. Alternatively, the false spin-adduct signal acquired when chelated Fe(3+) is employed arises via the nucleophilic addition of water onto the DMPO spin trap. Residual radicals in UHMWPE did not recombine/terminate following thermal annealing in an inert atmosphere. The radicals in RHAKOSS, however, did recombine under mild heating in an oxidizing or inert atmosphere. Both materials displayed quenching of ( )OH; however, for UHMWPE, this mechanism was jointly accountable for its accelerated degradation, evidenced by ATR-FTIR. Quenching of ( )OH by the silica found in RHAKOSS manifested in a competing effect that

  11. Trivalent Combination Vaccine Induces Broad Heterologous Immune Responses to Norovirus and Rotavirus in Mice

    PubMed Central

    Tamminen, Kirsi; Lappalainen, Suvi; Huhti, Leena; Vesikari, Timo; Blazevic, Vesna

    2013-01-01

    Rotavirus (RV) and norovirus (NoV) are the two major causes of viral gastroenteritis (GE) in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1) derived virus-like particles (VLPs) of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6), the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50%) as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs) and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes. PMID:23922988

  12. Combining mapping of physiological quantitative trait loci and transcriptome for cold tolerance for counteracting male sterility induced by low temperatures during reproductive stage in rice.

    PubMed

    Shimono, Hiroyuki; Abe, Akira; Aoki, Naohiro; Koumoto, Takemasa; Sato, Masahiro; Yokoi, Shuji; Kuroda, Eiki; Endo, Takashi; Saeki, Ken-Ich; Nagano, Kuniaki

    2016-06-01

    Male sterility induced by low temperatures (LTs) during the reproductive stage is a major constraint for temperate zone rice. To detect physiological quantitative trait loci (QTLs), we modeled genotypic variation in the physiological processes involved in low temperature spikelet sterility on the basis of anther length (AL), a proxy for microspore and pollen grain number per anther. The model accounted for 83% of the genotypic variation in potential AL at normal temperature and the ability to maintain AL at LT. We tested the model on 208 recombinant inbred lines of cold-tolerant 'Tohoku-PL3' (PL3) × cold-sensitive 'Akihikari' (AH) for 2 years. QTLs for spikelet fertility (FRT) at LT were detected on chromosomes 5 (QTL for Cold Tolerance at Reproductive stage, qCTR5) and 12 (qCTR12). qCTR12 was annotated with the ability to maintain AL under LTs. qCTR5 was in a region shared with QTLs for culm length and heading date. Genome-wide expression analysis showed 798 genes differentially expressed in the spikelets between the parents at LTs. Of these, 12 were near qCTR5 and 23 were near qCTR12. Gene expression analysis confirmed two candidate genes for qCTR5 (O-methyltransferase ZRP4, Os05g0515600; beta-1,3-glucanase-like protein, Os05g0535100) and one for qCTR12 (conserved hypothetical protein, Os12g0550600). Nucleotide polymorphisms (21 deletions, 2 insertions and 10 single nucleotide polymorphisms) in PL3 were found near the candidate conserved hypothetical protein (Os12g0550600) and upstream in PL3, but not in AH. Haplotype analysis revealed that this gene came from 'Kuchum'. The combination of mapping physiological QTLs with gene expression analysis can be extended to identify other genes for abiotic stress response in cereals. PMID:26607766

  13. Polysaccharides Isolated from Açaí Fruit Induce Innate Immune Responses

    PubMed Central

    Holderness, Jeff; Schepetkin, Igor A.; Freedman, Brett; Kirpotina, Liliya N.; Quinn, Mark T.; Hedges, Jodi F.; Jutila, Mark A.

    2011-01-01

    The Açaí (Acai) fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease. PMID:21386979

  14. Agents that reverse UV-induced immune suppression and photocarcinogenesis affect DNA repair

    PubMed Central

    Sreevidya, Coimbatore S.; Fukunaga, Atsushi; Khaskhely, Noor M.; Masaki, Taro; Ono, Ryusuke; Nishigori, Chikako; Ullrich, Stephen E.

    2010-01-01

    UV exposure induces skin cancer, in part by inducing immune suppression. Repairing DNA damage, neutralizing the activity of cis-urocanic acid (cis-UCA), and reversing oxidative stress abrogates UV-induced immune suppression and skin cancer induction, suggesting the DNA, UCA and lipid photo-oxidation serves as UV photoreceptors. What is not clear is whether signaling through each of these different photoreceptors activates independent pathways to induce biological effects or whether there is a common checkpoint where these pathways converge. Here we show that agents known to reverse photocarcinogenesis and photoimmune suppression, such as platelet activating factor (PAF) and serotonin (5-HT) receptor antagonists regulate DNA repair. Pyrimidine dimer repair was accelerated in UV-irradiated mice injected with PAF and 5-HT receptor antagonists. Nucleotide excision repair, as measured by unscheduled DNA synthesis, was accelerated by PAF and 5-HT receptor antagonists. Injecting PAF and 5-HT receptor antagonists into UV-irradiated Xeroderma pigmentosum complementation group A (XPA) deficient mice, which lack the enzymes responsible for nucleotide excision repair, did not accelerate photoproduct repair. Similarly, UV-induced formation of 8-oxo-deoxyguanosine (8-oxo-dG) was reduced by PAF and 5-HT receptor antagonists. We conclude that PAF and 5-HT receptor antagonists accelerate DNA repair caused by UV radiation, which prevents immune suppression and interferes with photocarcinogenesis. PMID:19829299

  15. TLR 9 involvement in early protection induced by immunization with rPb27 against Paracoccidioidomycosis.

    PubMed

    Morais, Elis Araujo; Chame, Daniela Ferreira; Melo, Eliza Mathias; de Carvalho Oliveira, Junnia Alvarenga; de Paula, Ana Cláudia Chagas; Peixoto, Andiara Cardoso; da Silva Santos, Lílian; Gomes, Dawidson Assis; Russo, Remo Castro; de Goes, Alfredo Miranda

    2016-02-01

    Paracoccidioidomycosis is caused by fungi of the Paracoccidioides genus and constitutes the most prevalent deep mycosis in Latin America. Toll-like receptors promote immune response against infectious agents. Recently, it was reported that TLR9 is crucial for mice survival during the first 48 h of P. brasiliensis infection. In this study, we used CPG oligodeoxynucleotide motif as an adjuvant with and without rPb27 to immunize mice against Paracoccidioidomycosis. CPG adjuvant induced differential recruitment of lymphocytes in the inflammatory process and a lower recruitment of neutrophils. In addition, CPG induced the production of pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-12; increased phagocytic ability and microbicidal activity by macrophages; and induced differential production of lgG2a and lgG2b, subtypes of Ig. Knockout mice for TLR9 and IL-12 showed higher fungal loads and rates of mortality compared to control mice after 30 days of infection. The association between CPG and rPb27 induced a high level of protection against Paracoccidioidomycosis after the first 30 days of infection but not at 60 days. Our findings demonstrate that TLR 9 plays a role in the protection induced by immunization with rPb27 and confirms the importance of TLR9 in the initial protection against Paracoccidioidomycosis. PMID:26597327

  16. Cell mediated immunity to corn starch in starch-induced granulomatous peritonitis.

    PubMed

    Goodacre, R L; Clancy, R L; Davidson, R A; Mullens, J E

    1976-03-01

    Two patients with histologically diagnosed starch induced granulomatous peritonitis (SGP) have been shown to have cell mediated immunity to corn starch using the techniques of macrophage migration inhibition and lymphocyte DNA synthesis. Control groups of normal subjects, patients with uncomplicated laparotomy, and patients with Crohn's disease were negative in both tests. Lymphocytes from two patients with band adhesions, one of whom had biopsy evidence of a granulomatous reaction to starch, were sensitized to starch. Cell mediated immunity to starch may contribute to the pathogenesis of SGP, and some band adhesions may be a chronic low grade manifestation of this disorder. PMID:1269987

  17. Drug-induced immune hemolytic anemia associated with albumin-bound paclitaxel.

    PubMed

    Thomas, Roby; Shillingburg, Alexandra

    2015-08-01

    Drug-induced immune hemolytic anemia (DIIHA) is rare, with only 1 patient in 1 million affected by the condition.1 Garratty identified 125 drugs indicated in DIIHA of which 11% were antineoplastic agents, and neither paclitaxel nor albumin-bound paclitaxel were included.2 In addition, we did not find any reports in our own search of the literature. Taxanes are known to cause anemia as a result of their myelosuppressive effects, but an immune hemolysis is rare. To our knowledge, we present here the first case of DIIHA with nab-paclitaxel. PMID:26859672

  18. The first report of cabergoline-induced immune hemolytic anemia in an adolescent with prolactinoma.

    PubMed

    Gürbüz, Fatih; Yağcı-Küpeli, Begül; Kör, Yılmaz; Yüksel, Bilgin; Zorludemir, Suzan; Gürbüz, Berrak Bilginer; Küpeli, Serhan

    2014-01-01

    Prolactinomas are common pituitary tumors that can cause gonadal dysfunction and infertility related to hyperprolactinemia. Dopamine agonists are the first-line treatment in these patients. Cabergoline leads to significant reduction in serum prolactin levels and tumor size in patients with prolactinoma. Dopamine agonists have been associated with adverse effects such as nausea, vomiting and psychosis. We report here a case with cabergoline-induced immune hemolytic anemia. The patient had cabergoline treatment history for prolactinoma and presented with weakness, fatigue, nausea, and paleness. Laboratory findings revealed severe anemia-related immune hemolysis. There were no causes identified to explain hemolytic anemia except cabergoline. Therefore, cabergoline therapy was stopped and subsequently hemolytic anemia resolved and did not occur again. This is the first reported pediatric case with prolactinoma and cabergoline-induced hemolytic anemia. Clinicians should be watchful for this rare side effect induced by cabergoline. PMID:23945126

  19. NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay.

    PubMed

    Ridnour, Lisa A; Cheng, Robert Y S; Weiss, Jonathan M; Kaur, Sukhbir; Soto-Pantoja, David R; Basudhar, Debashree; Heinecke, Julie L; Stewart, C Andrew; DeGraff, William; Sowers, Anastasia L; Thetford, Angela; Kesarwala, Aparna H; Roberts, David D; Young, Howard A; Mitchell, James B; Trinchieri, Giorgio; Wiltrout, Robert H; Wink, David A

    2015-07-15

    Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) squamous cell carcinoma tumor-bearing mice treated post-IR with the constitutive NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In support of this observation, tumor irradiation induced a rapid increase in the immunosuppressive Th2 cytokine IL10, which was abated by post-IR administration of L-NAME. In vivo suppression of IL10 using an antisense IL10 morpholino also extended the tumor growth delay induced by radiation in a manner similar to L-NAME. Further examination of this mechanism in cultured Jurkat T cells revealed L-NAME suppression of IR-induced IL10 expression, which reaccumulated in the presence of exogenous NO donor. In addition to L-NAME, the guanylyl cyclase inhibitors ODQ and thrombospondin-1 also abated IR-induced IL10 expression in Jurkat T cells and ANA-1 macrophages, which further suggests that the immunosuppressive effects involve eNOS. Moreover, cytotoxic Th1 cytokines, including IL2, IL12p40, and IFNγ, as well as activated CD8(+) T cells were elevated in tumors receiving post-IR L-NAME. Together, these results suggest that post-IR NOS inhibition improves radiation tumor response via Th1 immune polarization within the tumor microenvironment. PMID:25990221

  20. CsBAFF, a Teleost B Cell Activating Factor, Promotes Pathogen-Induced Innate Immunity and Vaccine-Induced Adaptive Immunity

    PubMed Central

    Sun, Yun; Sun, Li

    2015-01-01

    B cell activating factor (BAFF) is a member of the tumor necrosis factor family that is known to play an important role in B cell activation, proliferation, and differentiation in mammals. However, studies of BAFF in teleosts are very limited and its function, in particular that under in vivo conditions, is essentially unknown. In this study, we conducted in vivo as well as in vitro functional analyses of a BAFF homologue (CsBAFF) from the teleost fish tongue sole (Cynoglossus semilaevis). CsBAFF is composed of 261 residues and shares moderate sequence identities with known BAFFs of other teleosts. CsBAFF expression was most abundant in immune organs and was upregulated during bacterial infection. Purified recombinant CsBAFF (rCsBAFF) bound to tongue sole lymphocytes and promoted cellular proliferation and survival. The results of an in vivo study showed that CsBAFF overexpression in tongue sole significantly enhanced macrophage activation and reduced bacterial infection in fish tissues, whereas knockdown of CsBAFF expression resulted in increased bacterial dissemination and colonization in fish tissues. Furthermore, vaccination studies showed that CsBAFF enhanced the immunoprotection of a DNA vaccine and augmented the production of specific serum antibodies. Taken together, these results provide the first in vivo evidence to indicate that teleost BAFF is an immunostimulator that significantly contributes to the innate antibacterial immune response and vaccine-induced adaptive immune response. PMID:26295165

  1. DNA vaccination using expression vectors carrying FIV structural genes induces immune response against feline immunodeficiency virus.

    PubMed

    Cuisinier, A M; Mallet, V; Meyer, A; Caldora, C; Aubert, A

    1997-07-01

    Following inactivated virus vaccination trials, the surface glycoprotein gp120 of the feline immunodeficiency virus (FIV) was considered as one of the determinants for protection. However, several vaccination trials using recombinant Env protein or some peptides failed to induce protection. To understand the role of the gp120 protein in vivo, we vaccinated cats with naked DNA coding for FIV structural proteins gp120 and p10. We analyzed the ability of these vaccinations to induce immune protection and to influence the onset of infection. Injection in cat muscles of expression vectors coding for the FIV gp120 protein induced a humoral response. Cats immunized twice with the gp120 gene showed different patterns after challenge. Two cats were, like the control cats, infected from the second week after infection onwards. The two others maintained a low proviral load with no modification of their antibody pattern. The immune response induced by gp120 DNA injection could control the level of viral replication. This protective-like immune response was not correlated to the humoral response. All the cats immunized with the gp120 gene followed by the p10 gene were infected, like the control cats, from the second week but they developed a complete humoral response against viral proteins after challenge. Furthermore, they showed a sudden but transient drop of the proviral load at 4 weeks after infection. Under these conditions, one injection of the p10 gene after one injection of the gp120 gene was not sufficient to stimulate protection. On the contrary, after a period, it seems to facilitate virus replication. PMID:9269051

  2. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    PubMed

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID:26754788

  3. New sterilization technologies alternative to ethylene oxide

    NASA Astrophysics Data System (ADS)

    Tabrizian, Maryam; Lerouge, Sophie; Debrie, Anne; Yahia, L'Hocine

    1997-06-01

    Sterilization of biomedical devices may induce bulk and surface modification, responsible for the decrease or loss of their biofunctionality. Pure ethylene oxide (EO) at low temperature and new alternative techniques such as cold gas plasma sterilization have been developed for heat-sensitive polymers. There is a lack of the knowledge concerning their safety in terms of materials damage and consequences on the biofunctionality of sterilized devices. The objective of our work consists in studying bulk and surface changes in biomedical devices induced by these two sterilization techniques. Samples from PVC, Polyurethane, Polyacrylate and Polyethylene-based medical devices are subjected to 1, 5, and 10 sterilization cycles by Steri-Vac-3M (pure EO), Sterrad-100$TM, J&J (gas plasma + H2O2), and studied by X-rays photoelectron spectroscopy. Preliminary results show an increasing in Oxygen/Carbon ratio by a factor of 1.3 to 4.4 between the first and tenth cycle indicating the surface oxidation by gas plasma sterilization processes. Some changes in C-C chemical bounding are associated with EO sterilization.

  4. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice.

    PubMed

    Hammerschmidt, Swantje I; Friedrichsen, Michaela; Boelter, Jasmin; Lyszkiewicz, Marcin; Kremmer, Elisabeth; Pabst, Oliver; Förster, Reinhold

    2011-08-01

    Diarrheal diseases represent a major health burden in developing countries. Parenteral immunization typically does not induce efficient protection against enteropathogens because it does not stimulate migration of immune cells to the gut. Retinoic acid (RA) is critical for gut immunity, inducing upregulation of gut-homing receptors on activated T cells. In this study, we have demonstrated that RA can redirect immune responses elicited by s.c. vaccination of mice from skin-draining inguinal LNs (ingLNs) to the gut. When present during priming, RA induced robust upregulation of gut-homing receptors in ingLNs, imprinting gut-homing capacity on T cells. Concurrently, RA triggered the generation of gut-tropic IgA+ plasma cells in ingLNs and raised the levels of antigen-specific IgA in the intestinal lumen and blood. RA applied s.c. in vivo induced autonomous RA production in ingLN DCs, further driving efficient induction of gut-homing molecules on effector cells. Importantly, RA-supplemented s.c. immunization elicited a potent immune response in the small intestine that protected mice from cholera toxin–induced diarrhea and diminished bacterial loads in Peyer patches after oral infection with Salmonella. Thus, the use of RA as a gut-homing navigator represents a powerful tool to induce protective immunity in the intestine after s.c. immunization, offering what we believe to be a novel approach for vaccination against enteropathogens. PMID:21737878

  5. Beryllium-induced immune response in C3H mice

    SciTech Connect

    Benson, J.M.; Bice, D.E.; Nikula, K.J.

    1995-12-01

    Studies conducted at ITRI over the past several years have investigated whether Beagle dogs, monkeys, and mice are suitable models for human chronic beryllium-induced lung disease (CBD). Recent studies have focused on the histopathological and immunopathological changes occurring in A/J and C3H/HeJ mice acutely exposed by inhalation to Be metal. Lung lesions in both strains of mice included focal lymphocyte aggregates comprised primarily of B lymphocytes and lesser amounts of T-helper lymphocytes and microgranulomas consisting chiefly of macrophages and T-helper lymphocytes. The distribution of proliferating cells within the microgranulomas was similar to the distribution of T-helper cells. These results strongly suggested that A/J and C3H/HeJ mice responded to inhaled Be metal in a fashion similar to humans in terms of pulmonary lesions and the apparent in situ proliferation of T-helper cells. Results of these studies confirm lymphocyte involvement in the pulmonary response to inhaled Be metal.

  6. Molecular Components of the Sporothrix schenckii Complex that Induce Immune Response.

    PubMed

    Alba-Fierro, Carlos A; Pérez-Torres, Armando; Toriello, Conchita; Romo-Lozano, Yolanda; López-Romero, Everardo; Ruiz-Baca, Estela

    2016-08-01

    Sporotrichosis is a fungal disease caused by the Sporothrix schenckii complex that includes species such as S. brasiliensis, S. schenckii sensu stricto, S. globosa, S. luriei, S. mexicana, and S. pallida, which exhibit different potentially antigenic molecular components. The immune response of susceptible hosts to control infection and disease caused by these fungi has been little studied. Besides, the fungus-host interaction induces the activation of different types of immune response. This mini-review analyzes and discusses existing reports on the identification and functional characterization of molecules from species of the S. schenckii complex with clinical relevance, and the mechanisms that mediate the type and magnitude of the immune response in experimental models in vivo and in vitro. This knowledge is expected to contribute to the development of protective and therapeutic strategies against sporotrichosis and other mycoses. PMID:27117164

  7. Dissecting Polyclonal Vaccine-Induced Humoral Immunity against HIV Using Systems Serology.

    PubMed

    Chung, Amy W; Kumar, Manu P; Arnold, Kelly B; Yu, Wen Han; Schoen, Matthew K; Dunphy, Laura J; Suscovich, Todd J; Frahm, Nicole; Linde, Caitlyn; Mahan, Alison E; Hoffner, Michelle; Streeck, Hendrik; Ackerman, Margaret E; McElrath, M Juliana; Schuitemaker, Hanneke; Pau, Maria G; Baden, Lindsey R; Kim, Jerome H; Michael, Nelson L; Barouch, Dan H; Lauffenburger, Douglas A; Alter, Galit

    2015-11-01

    While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive. PMID:26544943

  8. Characterization of the immune response induced by pertussis OMVs-based vaccine.

    PubMed

    Bottero, D; Gaillard, M E; Zurita, E; Moreno, G; Martinez, D Sabater; Bartel, E; Bravo, S; Carriquiriborde, F; Errea, A; Castuma, C; Rumbo, M; Hozbor, D

    2016-06-14

    For the development of a third generation of pertussis vaccine that could improve the control of the disease, it was proposed that the immune responses induced by the classic whole cell vaccine (wP) or after infection should be used as a reference point. We have recently identified a vaccine candidate based on outer membrane vesicles (OMVs) derived from the disease etiologic agent that have been shown to be safe and protective in mice model of infection. Here we characterized OMVs-mediated immunity and the safety of our new candidate. We also deepen the knowledge of the induced humoral response contribution in pertussis protection. Regarding the safety of the OMVs based vaccine (TdapOMVsBp,) the in vitro whole blood human assay here performed, showed that the low toxicity of OMVs-based vaccine previously detected in mice could be extended to human samples. Stimulation of splenocytes from immunized mice evidenced the presence of IFN-γ and IL-17-producing cells, indicated that OMVs induces both Th1 and Th17 response. Interestingly TdapOMVsBp-raised antibodies such as those induced by wP and commercial acellular vaccines (aP) which contribute to induce protection against Bordetella pertussis infection. As occurs with wP-induced antibodies, the TdapOMVsBp-induced serum antibodies efficiently opsonized B. pertussis. All the data here obtained shows that OMVs based vaccine is able to induce Th1/Th17 and Th2 mixed profile with robust humoral response involved in protection, positioning this candidate among the different possibilities to constitute the third generation of anti-pertussis vaccines. PMID:27151884

  9. Antigen-oriented T cell migration contributes to myelin peptide induced-EAE and immune tolerance.

    PubMed

    Zheng, Peiguo; Fu, Hanxiao; Wei, Gaohui; Wei, Zhongwei; Zhang, Junhua; Ma, Xuehan; Rui, Dong; Meng, Xianchun; Ming, Liang

    2016-08-01

    Treatment with soluble myelin peptide can efficiently and specifically induce tolerance to demyelination autoimmune diseases including multiple sclerosis, however the mechanism underlying this therapeutic effect remains to be elucidated. In actively induced mouse model of experimental autoimmune encephalomyelitis (EAE) we analyzed T cell and innate immune cell responses in the central nervous system (CNS) and spleen after intraperitoneal (i.p.) infusion of myelin oligodendrocyte glycoprotein (MOG). We found that i.p. MOG infusion blocked effector T cell recruitment to the CNS and protected mice from EAE and lymphoid organ atrophy. Innate immune CD11b(+) cells preferentially recruited MOG-specific effector T cells, particularly when activated to become competent antigen presenting cells (APCs). During EAE development, mature APCs were enriched in the CNS rather than in the spleen, attracting effector T cells to the CNS. Increased myelin antigen exposure induced CNS-APC maturation, recruiting additional effector T cells to the CNS, causing symptoms of disease. MOG triggered functional maturation of splenic APCs. MOG presenting APCs interacted with MOG-specific T cells in the spleen, aggregating to cluster around CD11b(+) cells, and were trapped in the periphery. This process was MHC II dependent as an MHC II directed antibody blocked CD4(+) T cell cluster formation. These findings highlight the role of myelin peptide-loaded APCs in myelin peptide-induced EAE and immune tolerance. PMID:27327113

  10. Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response.

    PubMed

    Lau, Corinna; Olstad, Ole Kristoffer; Holden, Marit; Nygård, Ståle; Fure, Hilde; Lappegård, Knut Tore; Brekke, Ole-Lars; Espevik, Terje; Hovig, Eivind; Mollnes, Tom Eirik

    2015-09-01

    Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia-reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis biomarkers and biomarker pathways, as well as to test the efficacy of combined inhibition of innate immunity key players complement and Toll-like receptor co-receptor CD14 as a possible therapeutic regimen for sepsis. We performed whole blood gene expression analyses using microarray in order to profile Gram-negative bacteria-induced inflammatory responses in an ex vivo human whole blood model. The experiments were performed in the presence or absence of inhibitors of complement proteins (C3 and CD88 (C5a receptor 1)) and CD14, alone or in combination. In addition, we used blood from a C5-deficient donor. Anti-coagulated whole blood was challenged with heat-inactivated Escherichia coli for 2 h, total RNA was isolated and microarray analyses were performed on the Affymetrix GeneChip Gene 1.0 ST Array platform. The initial experiments were performed in duplicates using blood from two healthy donors. C5-deficiency is very rare, and only one donor could be recruited. In order to increase statistical power, a technical replicate of the C5-deficient samples was run. Subsequently, log2-transformed intensities were processed by robust multichip analysis and filtered using a threshold of four. In total, 73 microarray chips were run and analyzed. The normalized and filtered raw data have been deposited in NCBI's Gene Expression Omnibus (GEO) and are accessible with GEO Series accession number GSE55537. Linear models for microarray data were applied to estimate fold changes between data sets and the respective multiple testing adjusted p-values (FDR q-values). The interpretation of the

  11. Delayed adaptive immunity is related to higher MMR vaccine-induced antibody titers in children

    PubMed Central

    Strömbeck, Anna; Lundell, Anna-Carin; Nordström, Inger; Andersson, Kerstin; Adlerberth, Ingegerd; Wold, Agnes E; Rudin, Anna

    2016-01-01

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles–mumps–rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-induced antibody titers were measured in plasma samples obtained at 36 months of age. Infants' blood samples obtained at birth, 3–5 days and at 4 and 18 months of age were analyzed for T- and B-cell numbers, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells. Multivariate factor analyses show that higher anti-MMR antibody titers were associated with a lower degree of adaptive immune maturation, that is, lower proportions of memory T cells and a lower capacity of mononuclear cells to produce cytokines, but with higher proportions of putative regulatory T cells. Further, children born by cesarean section (CS) had significantly higher anti-measles titers than vaginally-born children; and CS was found to be associated with delayed adaptive immunity. Also, girls presented with significantly higher anti-mumps and anti-rubella antibody levels than boys at 36 months of age. These results indicate that delayed adaptive immune maturation before and in close proximity to immunization seems to be advantageous for the ability of children to respond with higher anti-MMR antibody levels after vaccination. PMID:27195118

  12. Effect of adjuvants on immunization with dengue virus-induced cytotoxic factor.

    PubMed Central

    Mukerjee, R; Chaturvedi, U C

    1995-01-01

    Specific active immunization with dengue type 2 virus (DV)-induced cytokine, cytotoxic factor (CF), prevents CF-mediated pathology in mice. The present study was undertaken to determine the optimum dose of CF and the effect of different adjuvants on the immune response as assessed by the study of anti-CF antibody titre by ELISA and protection against increase in capillary permeability to challenging dose of 3 micrograms CF. The maximum protection of 94 +/- 4% against increase in capillary permeability was observed at week 4 after immunization with 5 micrograms dose of CF mixed with Freund's incomplete adjuvant (FIA), which gradually decreased to 21 +/- 10% on week 24. With a dose of 10 micrograms the protection obtained was 79 +/- 5%, but persisted for a longer time at a higher level. The response was poor with 1 microgram dose of CF. The mean anti-CF antibody titres gradually decreased after reaching the peak at week 4 after immunization. Mice immunized with different adjuvants emulsified with 5 micrograms CF were challenged at different intervals with 3 micrograms CF. Maximum protection observed with CF + tetanus toxoid (TT) and 84/246 was about 93 +/- 2% and 97 +/- 2%, while that with alhydrogel was 33 +/- 12% and with bacille Calmette-Guérin (BCG) was 67 +/- 4%. At week 24 after immunization, however, the best response was obtained with 10 micrograms of adjuvant 84/246. Intracerebral challenge with 10 or 100 LD50 dose of dengue type 2 virus showed significantly prolonged mean survival time and delayed onset of signs of sickness in immunized mice compared with normal mice. The maximum survival time was with adjuvant 84/246 even at week 24. The findings thus show that the optimum dose of CF is 5 micrograms and the adjuvant of choice is 84/246. PMID:8536363

  13. Delayed adaptive immunity is related to higher MMR vaccine-induced antibody titers in children.

    PubMed

    Strömbeck, Anna; Lundell, Anna-Carin; Nordström, Inger; Andersson, Kerstin; Adlerberth, Ingegerd; Wold, Agnes E; Rudin, Anna

    2016-04-01

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles-mumps-rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-induced antibody titers were measured in plasma samples obtained at 36 months of age. Infants' blood samples obtained at birth, 3-5 days and at 4 and 18 months of age were analyzed for T- and B-cell numbers, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells. Multivariate factor analyses show that higher anti-MMR antibody titers were associated with a lower degree of adaptive immune maturation, that is, lower proportions of memory T cells and a lower capacity of mononuclear cells to produce cytokines, but with higher proportions of putative regulatory T cells. Further, children born by cesarean section (CS) had significantly higher anti-measles titers than vaginally-born children; and CS was found to be associated with delayed adaptive immunity. Also, girls presented with significantly higher anti-mumps and anti-rubella antibody levels than boys at 36 months of age. These results indicate that delayed adaptive immune maturation before and in close proximity to immunization seems to be advantageous for the ability of children to respond with higher anti-MMR antibody levels after vaccination. PMID:27195118

  14. Surfactant protein D induces immune quiescence and apoptosis of mitogen-activated peripheral blood mononuclear cells.

    PubMed

    Pandit, Hrishikesh; Thakur, Gargi; Koippallil Gopalakrishnan, Aghila Rani; Dodagatta-Marri, Eswari; Patil, Anushree; Kishore, Uday; Madan, Taruna

    2016-02-01

    Surfactant protein D (SP-D) is an integral molecule of the innate immunity secreted by epithelial cells lining the mucosal surfaces. The C-type lectin domain of SP-D performs pattern recognition functions while it binds to putative receptors on immune cells to modify cellular functions. Activation of immune cells and increased serum SP-D is observed in a range of patho-physiological conditions including infections. We speculated if SP-D can modulate systemic immune response via direct interaction with activated PBMCs. In this study, we examined interaction of a recombinant fragment of human SP-D (rhSP-D) on PHA-activated PBMCs. We report a significant downregulation of activation receptors such as TLR2, TLR4, CD11c and CD69 upon rhSP-D treatment. rhSP-D inhibited production of Th1 (TNF-α and IFN-γ) and Th17 (IL-17A) cytokines along with IL-6. Interestingly, levels of IL-2, Th2 (IL-4) and regulatory (IL-10 and TGF-β) cytokines remained unaltered. Analysis of co-stimulatory CD28 and co-inhibitory CTLA4 receptors along with their ligands CD80 and CD86 revealed a selective up-regulation of CTLA4 in the lymphocyte subset. rhSP-D induced apoptosis in the activated but not in non-activated lymphocytes. Blockade of CTLA4 inhibited rhSP-D mediated apoptosis of activated lymphocytes, confirming involvement of CTLA4. We conclude that SP-D restores immune homeostasis. It regulates expression of immunomodulatory receptors and cytokines, which is followed by induction of apoptosis in activated lymphocytes. These findings suggest a critical role of SP-D in immune surveillance against activated immune cells. PMID:26563748

  15. Protective immunity induced by recombinant protein CPSIT_p8 of Chlamydia psittaci.

    PubMed

    Liang, Mingxing; Wen, Yating; Ran, Ou; Chen, Liesong; Wang, Chuan; Li, Li; Xie, Yafeng; Zhang, Yang; Chen, Chaoqun; Wu, Yimou

    2016-07-01

    Chlamydia psittaci is a zoonotic pathogen with a broad host range that can lead to severe respiratory and systemic disease in humans. Currently, an effective commercial vaccine against C. psittaci infection is not available. The chlamydial plasmid is an important virulence factor and encodes plasmid proteins that play important roles in chlamydial infection and the corresponding immune response. In this study, we assessed the efficacy of vaccination with plasmid proteins at preventing C. psittaci lung infection in a murine model. BALB/c mice were immunized intraperitoneally, three times at 2-week intervals, with purified recombinant CPSIT_p8 protein and then infected with C. psittaci. Immunization significantly decreased chlamydial load in the lungs of infected mice, resulted in a lower level of IFN-γ, and reduced the extent of inflammation. In vivo or in vitro neutralization of C. psittaci with sera collected from immunized mice did not reduce the amount of viable C. psittaci in the lungs of mice, indicating that CPSIT_p8-specific antibodies do not have neutralizing capacity. Furthermore, confocal fluorescence microscopy using a mouse anti-CPSIT_p8 antibody revealed that CPSIT_p8 was localized inside the inclusion of C. psittaci 6BC-infected cells. Our results demonstrate that CPSIT_p8 protein induces significant protective immunity against challenge with C. psittaci in mice and represents a promising new vaccine candidate for the prevention of C. psittaci infection. PMID:27052378

  16. Efficient Qualitative and Quantitative Determination of Antigen-induced Immune Responses*

    PubMed Central

    2016-01-01

    To determine the effectiveness of immunization strategies used in therapeutic antibody or vaccine development, it is critical to assess the quality of immunization-induced polyclonal antibody responses. Here, we developed a workflow that uses sensitive methods to quantitatively and qualitatively assess immune responses against foreign antigens with regard to antibody binding affinity and epitope diversity. The application of such detailed assessments throughout an immunization campaign can significantly reduce the resources required to generate highly specific antibodies. Our workflow consists of the following two steps: 1) the use of surface plasmon resonance to quantify antigen-specific antibodies and evaluate their apparent binding affinities, and 2) the recovery of serum IgGs using an automated small scale purification system, followed by the determination of their epitope diversity using hydrogen deuterium exchange coupled with mass spectrometry. We showed that these methods were sensitive enough to detect antigen-specific IgGs in the nanogram/μl range and that they provided information for differentiating the antibody responses of the various immunized animals that could not be obtained by conventional methods. We also showed that this workflow can guide the selection of an animal that produces high affinity antibodies with a desired epitope coverage profile, resulting in the generation of potential therapeutic monoclonal antibody clones with desirable functional profiles. We postulate that this workflow will be an important tool in the development of effective vaccines to combat the highly sophisticated evasion mechanisms of pathogens. PMID:27288409

  17. Immunity against heterosubtypic influenza virus induced by adenovirus and MVA expressing nucleoprotein and matrix protein-1.

    PubMed

    Lambe, Teresa; Carey, John B; Li, Yuanyuan; Spencer, Alexandra J; van Laarhoven, Arjan; Mullarkey, Caitlin E; Vrdoljak, Anto; Moore, Anne C; Gilbert, Sarah C

    2013-01-01

    Alternate prime/boost vaccination regimens employing recombinant replication-deficient adenovirus or MVA, expressing Influenza A virus nucleoprotein and matrix protein 1, induced antigen-specific T cell responses in intradermally (ID) vaccinated mice; with the strongest responses resulting from Ad/MVA immunization. In BALB/C mice the immunodominant response was shifted from the previously identified immunodominant epitope to a novel epitope when the antigen was derived from A/Panama/2007/1999 rather than A/PR/8. Alternate immunization routes did not affect the magnitude of antigen-specific systemic IFN-γ response, but higher CD8(+) T-cell IFN-γ immune responses were seen in the bronchoalveolar lavage following intransal (IN) boosting after intramuscular (IM) priming, whilst higher splenic antigen-specific CD8(+) T cell IFN-γ was seen following IM boosting. Partial protection against heterologous influenza virus challenge was achieved following either IM/IM or IM/IN but not ID/ID immunization. These data may be of relevance for the design of optimal immunization regimens for human influenza vaccines, especially for influenza-naïve infants. PMID:23485942

  18. Efficient Qualitative and Quantitative Determination of Antigen-induced Immune Responses.

    PubMed

    Yang, Danlin; Frego, Lee; Lasaro, Marcio; Truncali, Kristopher; Kroe-Barrett, Rachel; Singh, Sanjaya

    2016-07-29

    To determine the effectiveness of immunization strategies used in therapeutic antibody or vaccine development, it is critical to assess the quality of immunization-induced polyclonal antibody responses. Here, we developed a workflow that uses sensitive methods to quantitatively and qualitatively assess immune responses against foreign antigens with regard to antibody binding affinity and epitope diversity. The application of such detailed assessments throughout an immunization campaign can significantly reduce the resources required to generate highly specific antibodies. Our workflow consists of the following two steps: 1) the use of surface plasmon resonance to quantify antigen-specific antibodies and evaluate their apparent binding affinities, and 2) the recovery of serum IgGs using an automated small scale purification system, followed by the determination of their epitope diversity using hydrogen deuterium exchange coupled with mass spectrometry. We showed that these methods were sensitive enough to detect antigen-specific IgGs in the nanogram/μl range and that they provided information for differentiating the antibody responses of the various immunized animals that could not be obtained by conventional methods. We also showed that this workflow can guide the selection of an animal that produces high affinity antibodies with a desired epitope coverage profile, resulting in the generation of potential therapeutic monoclonal antibody clones with desirable functional profiles. We postulate that this workflow will be an important tool in the development of effective vaccines to combat the highly sophisticated evasion mechanisms of pathogens. PMID:27288409

  19. Identification of immune inducible genes from the velvet worm Epiperipatus biolleyi (Onychophora).

    PubMed

    Altincicek, Boran; Vilcinskas, Andreas

    2008-01-01

    Onychophora are the next relatives of Arthropoda and, hence, represent an important taxon to unravel relationships among Insecta, Crustacea, Arachnida, and Myriapoda. Here, we screened for immune inducible genes from the onychophoran Epiperipatus biolleyi (Peripatidae) by injecting crude bacterial LPS and applying the suppression subtractive hybridization technique. Our analysis of 288 cDNAs resulted in identification of 36 novel genes in E. biolleyi whose potential homologues from other animals are known to mediate immune-related signaling (e.g. mitogen-activated protein kinase kinase 1 and immunoglobulin enhancer binding protein), to be involved in cellular processes (e.g. perilipin and myosin light chain), or to act as immune effector molecules (e.g. lysosomal beta-galactosidase, a putative antimicrobial peptide and a potential thiolester containing protein). Comparisons with homologous genes from other animals including the two most favored ecdysozoan model organisms of innate immunity research, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, provide further insights into the origin and evolution of Arthropoda immunity. PMID:18598713

  20. PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis

    PubMed Central

    Zinselmeyer, Bernd H.; Heydari, Sara; Sacristán, Catarina; Nayak, Debasis; Cammer, Michael; Herz, Jasmin; Cheng, Xiaoxiao; Davis, Simon J.; Dustin, Michael L.

    2013-01-01

    Immune responses to persistent viral infections and cancer often fail because of intense regulation of antigen-specific T cells—a process referred to as immune exhaustion. The mechanisms that underlie the induction of exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined the dynamics of virus-specific CD8+ and CD4+ T cells in the living spleen by two-photon microscopy (TPM) during the establishment of an acute or persistent viral infection. We demonstrate that immune exhaustion during viral persistence maps anatomically to the splenic marginal zone/red pulp and is defined by prolonged motility paralysis of virus-specific CD8+ and CD4+ T cells. Unexpectedly, therapeutic blockade of PD-1–PD-L1 restored CD8+ T cell motility within 30 min, despite the presence of high viral loads. This result was supported by planar bilayer data showing that PD-L1 localizes to the central supramolecular activation cluster, decreases antiviral CD8+ T cell motility, and promotes stable immunological synapse formation. Restoration of T cell motility in vivo was followed by recovery of cell signaling and effector functions, which gave rise to a fatal disease mediated by IFN-γ. We conclude that motility paralysis is a manifestation of immune exhaustion induced by PD-1 that prevents antiviral CD8+ T cells from performing their effector functions and subjects them to prolonged states of negative immune regulation. PMID:23530125

  1. The immune tolerance network: a new paradigm for developing tolerance-inducing therapies.

    PubMed

    Rotrosen, Daniel; Matthews, Jeff B; Bluestone, Jeffrey A

    2002-07-01

    Immune tolerance therapies are designed to reprogram immune cells in a highly specific fashion to eliminate pathogenic responses while preserving protective immunity. A concept that has tantalized immunologists for decades, the development of tolerance-inducing therapies, would revolutionize the management of a wide range of chronic and often debilitating diseases by obviating the need for lifelong immunosuppressive regimens. The advances of the past decade have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Building on these advances, immunologists have demonstrated the feasibility of various tolerance-inducing approaches in small- and large-animal models of autoimmunity, allergy, and transplant graft rejection. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. To capitalize on these advances, the National Institutes of Health recently established the Immune Tolerance Network (ITN), an international consortium of more than 70 basic and clinical immunologists dedicated to the evaluation of novel tolerance-inducing therapies and associated studies of immunologic mechanisms. By using a unique interactive approach to accelerate the development of clinical tolerance therapies, the ITN is partnering with the biotechnology and pharmaceutical industries to examine innovative tolerogenic approaches in a range of allergic and autoimmune diseases and to prevent graft rejection after transplantation. Two years since its inception, the ITN now has approximately 2 dozen clinical trials or tolerance assays studies ongoing or in later stages of protocol development. This report summarizes the rationale for emphasizing clinical research on immune tolerance and highlights the progress of the ITN. PMID:12110811

  2. Single-layer tungsten oxide as intelligent photo-responsive nanoagents for permanent male sterilization.

    PubMed

    Liu, Zhen; Liu, Xianjun; Ran, Xiang; Ju, Enguo; Ren, Jinsong; Qu, Xiaogang

    2015-11-01

    Permanent male sterilization has been recognized as useful tools for the development of neuter experimental animals and fattening livestock, as well as efficient control of pet overpopulation. Traditional routes such as surgical ways, chemical injections, and anti-fertility vaccines have addressed these crucial problems with idea outcomes. However, these routes usually bring out serious pain and infection towards animals, as well as induce long-term adverse reaction and immune suppression. Thus, a convenient, but non-surgical strategy for male sterilization under a mild manner is highly desirable. Here, for the first time, we demonstrate a novel platform for male sterilization by using single-layer WO2.72 nanosheets as smart photo-responsive sterilants. Upon a 980 nm irradiation, these nanoagents can possess intrinsic NIR-induced hyperthermia and sensitize the formation of singlet oxygen due to the cooperation of photothermal and photodynamic effects. Mechanism of cellular injury can be attributed to the denaturation of protein and apoptosis-related death. Moreover, long-term toxicity and possible metabolism route after testicular injection are discussed, indicating the neglectable systemic toxicity and high bio-compatibility of our nanoagents. Overall, our strategy can extremely overcome the shortcomings in various routine routes and suggest the new biological application of nanomaterials. PMID:26280950

  3. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.

    PubMed

    Schölch, Sebastian; Rauber, Conrad; Tietz, Alexandra; Rahbari, Nuh N; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A; Lipson, Kenneth E; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E

    2015-03-10

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  4. Inducible factors with antimicrobial activity after immune challenge in the haemolymph of Red Palm Weevil (Insecta).

    PubMed

    Mastore, Maristella; Binda Rossetti, Simona; Giovannardi, Stefano; Scarì, Giorgio; Brivio, Maurizio F

    2015-05-01

    Insects are capable of innate immune responses elicited after microbial infection. In this process, the receptor-mediated recognition of foreign bodies and the subsequent activation of immunocompetent cells lead to the synthesis ex novo of a peptide pool with antimicrobial activity. We investigated the inducible immune response of a coleopteran, Rhynchophorus ferrugineus, challenged with both Gram-negative and Gram-positive bacteria. After immunization, we evaluated the presence of antimicrobial peptides using either biochemical analyses or microbiological techniques. The antimicrobial properties of the newly synthesized protein pool, detectable in haemolymph fractions of low molecular mass, showed strong antibacterial activity against various bacterial strains (Escherichia coli, Pseudomonas sp. OX1, Bacillus subtilis and Micrococcus luteus). In addition to the preliminary study of the mechanism of action of the pool of antimicrobial peptides, we also investigated its effects on bacterial cell walls by means of fluorescence microscopy and scanning electron microscopy. The data suggest that the main effects seem to be directed at destabilizing and damaging the bacterial wall. This study provides data that help us to understand some aspects of the inducible innate immunity in a system model that lacks anticipatory responses. However, the weevil has finely tuned its defensive strategies to counteract effectively microbial infection. PMID:25114180

  5. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

    PubMed Central

    Tietz, Alexandra; Rahbari, Nuh N.; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A.; Lipson, Kenneth E.; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E.

    2015-01-01

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  6. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine.

    PubMed

    Kim, Kwang Soon; Hong, Sung-Wook; Han, Daehee; Yi, Jaeu; Jung, Jisun; Yang, Bo-Gie; Lee, Jun Young; Lee, Minji; Surh, Charles D

    2016-02-19

    Dietary antigens are normally rendered nonimmunogenic through a poorly understood "oral tolerance" mechanism that involves immunosuppressive regulatory T (Treg) cells, especially Treg cells induced from conventional T cells in the periphery (pTreg cells). Although orally introducing nominal protein antigens is known to induce such pTreg cells, whether a typical diet induces a population of pTreg cells under normal conditions thus far has been unknown. By using germ-free mice raised and bred on an elemental diet devoid of dietary antigens, we demonstrated that under normal conditions, the vast majority of the small intestinal pTreg cells are induced by dietary antigens from solid foods. Moreover, these pTreg cells have a limited life span, are distinguishable from microbiota-induced pTreg cells, and repress underlying strong immunity to ingested protein antigens. PMID:26822607

  7. Effects of serostatus and gender on the HRV-16-induced local immune response.

    PubMed

    Koch, Rebecca M; Kox, Matthijs; Pickkers, Peter; de Jonge, Marien I

    2016-07-29

    The "experimental cold model" is widely used to investigate effects of HRV infection. However, effects of serostatus and gender on the HRV-induced immune response have not been clarified. 40 healthy seropositive and seronegative (1:1) male and female (1:1) subjects were inoculated with HRV-16. HRV infection increased viral load in nasal wash, which tended to be more pronounced in seronegative subjects. Furthermore, HRV infection increased levels of IP-10, IL-6, and IL-10 and leukocyte numbers in nasal wash of seronegative, but not of seropositive subjects. No differences in any of the parameters were found between both sexes. The HRV-induced local immune response is diminished in seropositive subjects compared with seronegative subjects, while gender does not influence this response. These results have important implications for the design of future experimental cold studies: seronegative subjects, from both sexes can be included. PMID:27389172

  8. Nonimmunogenic radiation-induced lymphoma: immunity induction by a somatic cell hybrid

    SciTech Connect

    Yefenof, E.; Goldapfel, M.; Ber, R.

    1982-05-01

    The cell line designated PIR-2 is a nonimmunogenic X-ray-induced thymoma of C57BL/6 origin that is unable to induce antitumor immunity in syngeneic lymphocytes in vitro and in mice in vivo. Fusion of PIR-2 with an allogeneic universal fuser A9HT (clone 3c) resulted in the establishment of a somatic cell hybrid designated A9/PIR. C57BL/6 lymphocytes sensitized in vitro with A9/PIR could lyse parental PIR-2 cells, as well as other syngeneic tumors. However, immunization of mice with the hybrid significantly enhanced PIR-2 tumor takes while it partially protected the animals against a challenge with unrelated syngeneic tumors. The results imply that somatic cell hybridization can increase the immunogenicity of an otherwise nonimmunogenic tumor. However, in view of the enhancing effects of hybrid preimmunization on parental tumor cell growth, the possible application of this approach for immunotherapy is questionable.

  9. White spot syndrome virus strains of different virulence induce distinct immune response in Cherax quadricarinatus.

    PubMed

    Gao, Meiling; Li, Fang; Xu, Limei; Zhu, Xiaoming

    2014-07-01

    In this study, we identified three white spot syndrome virus (WSSV) strains (WSSV-CN01, WSSV-CN02 and WSSV-CN03) with significant differences in virulence. Among them, WSSV-CN01 caused significant higher and earlier mortality in redclaw crayfish Cherax quadricarinatus, thus was determined as high-virulent, while WSSV-CN02 and WSSV-CN03 were moderate-virulent and low-virulent. By investigating the total number of the circulating haemocytes and the activity of immune relative enzymes, we demonstrated that the different virulent WSSV strains induced distinct immune response in the host. Notably, a dramatic reduction of circulating haemocytes was observed in the crayfish infected with WSSV-CN01 and WSSV-CN02 but not WSSV-CN03. Further analysis revealed that cell death induced by WSSV-CN01 and WSSV-CN02 might be responsible for the decrease of circulating haemocytes. PMID:24795080

  10. Female Tubal Sterilization

    PubMed Central

    Rowe, Timothy C.; Pabuccu, Recai

    1986-01-01

    Tubal ligation has become the second most popular method of contraception in Canada, after oral contraception. Refinement of techniques has resulted in sterilization procedures which have minimal potential for failure and high potential for reversibility. Laparoscopic and minilaparatomy techniques allow outpatient “Band-Aid” sterilizations with less risk of complications than more destructive procedures. Laparoscopic application of tubal clips or rings is highly effective, with minimal tubal destruction. Tubal ligation following a pregnancy is more often regretted than is interval sterilization. The search continues for a satisfactory transcervical sterilization procedure. PMID:21267115

  11. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers.

    PubMed

    Ubillos, Luis; Freire, Teresa; Berriel, Edgardo; Chiribao, María Laura; Chiale, Carolina; Festari, María Florencia; Medeiros, Andrea; Mazal, Daniel; Rondán, Mariella; Bollati-Fogolín, Mariela; Rabinovich, Gabriel A; Robello, Carlos; Osinaga, Eduardo

    2016-04-01

    Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48(-) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth. PMID:26519949

  12. Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

    PubMed

    Nag, D; Koley, H; Sinha, R; Mukherjee, P; Sarkar, C; Withey, J H; Gachhui, R

    2016-02-01

    An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1β and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future. PMID:26478541

  13. Maize Prolamins Could Induce a Gluten-Like Cellular Immune Response in Some Celiac Disease Patients

    PubMed Central

    Ortiz-Sánchez, Juan P.; Cabrera-Chávez, Francisco; Calderón de la Barca, Ana M.

    2013-01-01

    Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet. PMID:24152750

  14. Immune response induced by candidate Sarcoptes scabiei var. cuniculi DNA vaccine encoding paramyosin in mice.

    PubMed

    Gu, Xiaobin; Xie, Yue; Wang, Shuxian; Peng, Xuerong; Lai, Songjia; Yang, Guangyou

    2014-07-01

    Sarcoptes scabiei is the causal agent of the highly contagious disease sarcoptic mange (scabies) that affects animals and humans worldwide. An increasing number of cases of treatment failure is being reported because of drug resistance. The development of a specific vaccine would be a sustainable option for control of this disease. In this study, we cloned and expressed a S. scabiei gene encoding paramyosin (PAR) and investigated the immune response elicited by DNA encoding PAR in mice. The ability of the DNA vaccine to express antigen in COS-7 cells was confirmed by RT-PCR and IFA. The immune response induced by DNA vaccine was investigated by ELISA, splenocyte proliferation assay, and cytokine production assay. Compared to the pVAX1 control group, the PAR DNA vaccination group showed the higher levels of IgG, IgG1, IgG2a, IgE, IgM, stronger lymphocyte proliferation in mouse spleen, and larger production of IL-2, IL-4, IL-5, and IFN-γ in the supernatant of cultures from splenocytes. These results indicated that the PAR DNA vaccine induced a mixed Th1/Th2 response in mice. In conclusion, our results revealed that the S. scabiei PAR DNA vaccine induced both a humoral and cellular immune response, which would provide basic data for the further study to develop an effective vaccine against sarcoptic mange. PMID:24729069

  15. Native cellulose nanofibrills induce immune tolerance in vitro by acting on dendritic cells.

    PubMed

    Tomić, Sergej; Kokol, Vanja; Mihajlović, Dušan; Mirčić, Aleksandar; Čolić, Miodrag

    2016-01-01

    Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs. In a co-culture with CD4(+)T cells, CNF-treated mo-DCs possessed a weaker allostimulatory and T helper (Th)1 and Th17 polarizing capacity, but a stronger capacity to induce Th2 cells and CD4(+)CD25(hi)FoxP3(hi) regulatory T cells. This correlated with an increased immunoglobulin-like transcript-4 and indolamine dioxygenase-1 expression by CNF-treated mo-DCs, following the partial internalization of CNFs and the accumulation of CD209 and actin bundles at the place of contacts with CNFs. Cumulatively, we showed that CNFs are able to induce an active immune tolerance by inducing tolerogenic DCs, which could be beneficial for the application of CNFs in wound healing and chronic inflammation therapies. PMID:27558765

  16. Toxoplasma gondii GRA7-Induced TRAF6 Activation Contributes to Host Protective Immunity

    PubMed Central

    Yuk, Jae-Min; Lee, Young-Ha; Jo, Eun-Kyeong

    2015-01-01

    The intracellular parasite Toxoplasma gondii has unique dense granule antigens (GRAs) that are crucial for host infection. Emerging evidence suggests that GRA7 of T. gondii is a promising serodiagnostic marker and an effective toxoplasmosis vaccine candidate; however, little is known about the intracellular regulatory mechanisms involved in the GRA7-induced host responses. Here we show that GRA7-induced MyD88 signaling through the activation of TRAF6 and production of reactive oxygen species (ROS) is required for the induction of NF-κB-mediated proinflammatory responses by macrophages. GRA7 stimulation resulted in the rapid activation of mitogen-activated protein kinases and an early burst of ROS in macrophages in a MyD88-dependent manner. GRA7 induced a physical association between GRA7 and TRAF6 via MyD88. Remarkably, the C terminus of GRA7 (GRA7-V) was sufficient for interaction with and ubiquitination of the RING domain of TRAF6, which is capable of inflammatory cytokine production. Interestingly, the generation of ROS and TRAF6 activation are mutually dependent on GRA7/MyD88-mediated signaling in macrophages. Furthermore, mice immunized with GRA7-V showed markedly increased Th1 immune responses and protective efficacy against T. gondii infection. Collectively, these results provide novel insight into the crucial role of GRA7-TRAF6 signaling in innate immune responses. PMID:26553469

  17. Interleukin-5 is necessary for eosinophilia induced by cyclophosphamide in immunized mice.

    PubMed Central

    Mu, H H; Penny, R; Sewell, W A

    1993-01-01

    Interleukin-5 (IL-5) has an important role in the induction of eosinophilia, which is associated with parasitic infestations and with allergic conditions, and which can be induced in a number of experimental systems. One of these model systems involves the administration of cyclophosphamide (CY) to immunized animals. In order to assess the role of IL-5 in this model, eosinophilia was induced in vivo and cell suspensions of spleens or lymph nodes were stimulated in vitro. IL-5 protein secretion was detected by bioassay using an IL-5-dependent cell line (T88-m), and mRNA was assessed by reverse transcription and polymerase chain reaction (RT-PCR). The production of IL-5 protein and mRNA were greatly enhanced in the cells from mice given CY with ovalbumin (OVA), compared with mice given either agent alone. IL-5 protein and mRNA were increased both in spleen and in lymph node cells, and in response either to OVA or to polyclonal stimuli. Further evidence for the importance of IL-5 in this model of eosinophilia was provided by experiments with monoclonal antibodies (mAb) in vivo. A single injection of an IL-5-specific mAb at the time of immunization completely abolished the eosinophilia. By contrast, a monoclonal antibody to IL-4 had no effect. These experiments indicate that IL-5 is required for the eosinophilia induced by CY in immunized mice. Images Figure 3 PMID:8406572

  18. Native cellulose nanofibrills induce immune tolerance in vitro by acting on dendritic cells

    PubMed Central

    Tomić, Sergej; Kokol, Vanja; Mihajlović, Dušan; Mirčić, Aleksandar; Čolić, Miodrag

    2016-01-01

    Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs. In a co-culture with CD4+T cells, CNF-treated mo-DCs possessed a weaker allostimulatory and T helper (Th)1 and Th17 polarizing capacity, but a stronger capacity to induce Th2 cells and CD4+CD25hiFoxP3hi regulatory T cells. This correlated with an increased immunoglobulin-like transcript-4 and indolamine dioxygenase-1 expression by CNF-treated mo-DCs, following the partial internalization of CNFs and the accumulation of CD209 and actin bundles at the place of contacts with CNFs. Cumulatively, we showed that CNFs are able to induce an active immune tolerance by inducing tolerogenic DCs, which could be beneficial for the application of CNFs in wound healing and chronic inflammation therapies. PMID:27558765

  19. Escherichia coli O157:H7 Induces Stronger Plant Immunity than Salmonella enterica Typhimurium SL1344

    PubMed Central

    Roy, Debanjana; Panchal, Shweta; Rosa, Bruce A

    2014-01-01

    Consumption of fresh produce contaminated with bacterial human pathogens has resulted in various, sometimes deadly, disease outbreaks. In this study, we assessed plant defense responses induced by the fully pathogenic bacteria Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium SL1344 in both Arabidopsis thaliana and lettuce (Lactuca sativa). Unlike SL1344, O157:H7 induced strong plant immunity at both pre-invasion and post-invasion steps of infection. For instance, O157:H7 triggered stomatal closure even under high relative humidity (RH); an environmental condition that generally weakens plant defenses against bacteria in the field and laboratory conditions. SL1344 instead induced a transient stomatal immunity. We also observed that PR1 gene expression was significantly higher in Arabidopsis leaves infected with O157:H7 as compared to SL1344. These results suggest that plants may recognize and respond to some human pathogens more effectively than others. Furthermore, stomatal immunity can diminish the penetration of human pathogens through the leaf epidermis resulting in low bacterial titers in the plant apoplast suggesting that additional control measures can be employed to prevent food contamination. The understanding of how plant responses can diminish bacterial contamination is paramount in preventing outbreaks and improving the safety of food supplies. PMID:23301812

  20. Comparison of structural changes in skin and amnion tissue grafts for transplantation induced by gamma and electron beam irradiation for sterilization.

    PubMed

    Mrázová, H; Koller, J; Kubišová, K; Fujeríková, G; Klincová, E; Babál, P

    2016-06-01

    Sterilization is an important step in the preparation of biological material for transplantation. The aim of the study is to compare morphological changes in three types of biological tissues induced by different doses of gamma and electron beam radiation. Frozen biological tissues (porcine skin xenografts, human skin allografts and human amnion) were irradiated with different doses of gamma rays (12.5, 25, 35, 50 kGy) and electron beam (15, 25, 50 kGy). Not irradiated specimens served as controls. The tissue samples were then thawn and fixed in 10 % formalin, processed by routine paraffin technique and stained with hematoxylin and eosin, alcian blue at pH 2.5, orcein, periodic acid Schiff reaction, phosphotungstic acid hematoxylin, Sirius red and silver impregnation. The staining with hematoxylin and eosin showed vacuolar cytoplasmic changes of epidermal cells mainly in the samples of xenografts irradiated by the lowest doses of gamma and electron beam radiation. The staining with orcein revealed damage of fine elastic fibers in the xenograft dermis at the dose of 25 kGy of both radiation types. Disintegration of epithelial basement membrane, especially in the xenografts, was induced by the dose of 15 kGy of electron beam radiation. The silver impregnation disclosed nuclear chromatin condensation mainly in human amnion at the lowest doses of both radiation types and disintegration of the fine collagen fibers in the papillary dermis induced by the lowest dose of electron beam and by the higher doses of gamma radiation. Irradiation by both, gamma rays and the electron beam, causes similar changes on cells and extracellular matrix, with significant damage of the basement membrane and of the fine and elastic and collagen fibers in the papillary dermis, the last caused already by low dose electron beam radiation. PMID:26649556

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

    PubMed Central

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

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)–based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. PMID:26505634

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

    PubMed

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

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. PMID:26505634

  3. Immune response induced by conjunctival immunization with polymeric antigen BLSOmp31 using a thermoresponsive and mucoadhesive in situ gel as vaccine delivery system for prevention of ovine brucellosis.

    PubMed

    Díaz, Alejandra Graciela; Quinteros, Daniela Alejandra; Gutiérrez, Silvina Elena; Rivero, Mariana Alejandra; Palma, Santiago Daniel; Allemandi, Daniel Alberto; Pardo, Romina Paola; Zylberman, Vanesa; Goldbaum, Fernando Alberto; Estein, Silvia Marcela

    2016-10-01

    Control of ovine brucellosis with subcellular vaccines can solve some drawbacks associated with the use of Brucella melitensis Rev.1. Previous studies have demonstrated that the polymeric antigen BLSOmp31 administered by parenteral route was immunogenic and conferred significant protection against B. ovis in rams. Immunization with BLSOmp31 by conjunctival route could be efficient for the induction of mucosal and systemic immune responses. In this work, we evaluated the conjunctival immunization using a thermoresponsive and mucoadhesive in situ gel composed of Poloxamer 407 (P407) and chitosan (Ch) as vaccine delivery system for BLSOmp31 in rams. Serum samples, saliva, lacrimal, preputial and nasal secretions were analyzed to measure specific IgG and IgA antibodies. Cellular immune response was evaluated in vivo and in vitro. Immunization with BLSOmp31-P407-Ch induced high IgG antibody levels in serum and preputial secretions which remained at similar levels until the end of the experiment. Levels of IgG in saliva, lacrimal and nasal secretions were also higher compared to unvaccinated control group but decreased more rapidly. IgA antibodies were only detected in nasal and preputial secretions. BLSOmp31-P407-Ch stimulated a significant cellular immune response in vivo and in vitro. The induction of systemic and local immune responses indicates a promising potential of P407-Ch for the delivery of BLSOmp31 by conjunctival route. PMID:27496742

  4. Effect of Phlebodium Decumanum on the Immune Response Induced by Training in Sedentary University Students

    PubMed Central

    Gonzalez-Jurado, Jose A.; Pradas, Francisco; Molina, Edgardo S.; de Teresa, Carlos

    2011-01-01

    Exercise training is considered a good model to provoke different degrees of immune dysfunction affecting physical performance and some physiological responses related to oxidative stress and low grade inflammation. Phlebodium decumanum is a polypodiaceae may induce shown immunomodulating effects, specifically directed to the release of proinflammatory cytokines by macrophages in response to various stimuli, as reported different in vitro studies. The aim of this study was to evaluate the modulating effect of phlebodium decumanum, on the immune response induced by physical exercise. Thirty-one subjects (males only) were randomly divided into two groups: Group PD (n = 18); age: 22.1 ± 1.81, weight 74.21 ± 8.74 kg) that was treated with phlebodium decumanum; Group P (n = 13); age: 22.5 ± 1.63, weight 78 ± 12.5 kg) that was treated with a placebo. Before and after one month training program performed by both groups (three times a week), the following performance parameters and immune response variables were measured: Dynamic Maximum Force; Interval-Training; Tennis test; pro-inflammatory (TNF , IL6) and anti-inflammatory (TNFα-IIrs, IL1-ra) cytokines levels. Data were statistically analyzed with Mann- Whitney U test and Wilcoxon paired test (p < 0.05). Statistically significant differences were recorded within groups before and after the training program. PD group showed a significant improvement in the performance parameters (Strength Muscle Test: dorsal: p < 0.002; deltoids: p < 0.03; and pectorals: p < 0.07; Interval Training: p < 0.06; Tennis Test: p < 0.02). Cytokine levels resulted in a more positive profile in the PD group rather than in the P group, in which higher levels of IL-6 (p < 0.02) and a reduction of TNF-IIrs (p < 0.003) and IL1-ra (p < 0.03) were recorded. In this study the use of phlebodium decumanum demonstrated beneficial effects in the modulation of the immune response during physical performance. Key points Practicing sport or physical

  5. Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin-induced allergic airway inflammation

    PubMed Central

    Zhong, Wenwei; Su, Wen; Zhang, Yanjie; Liu, Qi; Wu, Jinhong; Di, Caixia; Zhang, Zili; Xia, Zhenwei

    2014-01-01

    Antigen-induced allergic airway inflammation is mediated by T helper type 2 (Th2) cells and their cytokines, but the mechanism that initiates the Th2 immunity is not fully understood. Recent studies show that basophils play important roles in initiating Th2 immunity in some inflammatory models. Here we explored the role of basophils in ovalbumin (OVA) -induced airway allergic inflammation in BALB/c mice. We found that OVA sensitization and challenge resulted in a significant increase in the amount of basophils in blood and lung, along with the up-regulation of activation marker of CD200R. However, depletion of basophils with MAR-1 or Ba103 antibody attenuated airway inflammation, represented by the significantly decreased amount of the Th2 subset in spleen and draining lymph nodes, interlukin-4 level in lung and OVA-special immunoglobulin E (sIgE) levels in serum. On the other hand, adoptive transfer of basophils from OVA-challenged lung tissue to naive BALB/c mice provoked the Th2 immune response. In addition, pulmonary basophils from OVA-challenged mice were able to uptake DQ-OVA and express MHC class II molecules and CD40 in vivo, as well as to release interleukin-4 following stimulation by IgE–antigen complexes and promote Th2 polarization in vitro. These findings demonstrate that basophils may participate in Th2 immune responses in antigen-induced allergic airway inflammation and that they do so through facilitating antigen presentation and providing interleukin-4. PMID:24383680

  6. Prospects for vector control through sterilization procedures

    PubMed Central

    Smith, Carroll N.

    1963-01-01

    Interest in sterilization as a possible method for controlling insects of public health importance can be said to have arisen first in the mid-fifties, when the screw-worm fly was successfully eradicated from the island of Curaçao by the release over the entire island of large numbers of male flies sterilized by gamma-radiation. Since then, many studies on the sterilization of various insect vectors of disease have been carried out. This paper reviews these studies and discusses the present position regarding vector control by sterilization procedures, with special reference to the use of chemosterilants. These compounds have certain advantages over radiation since they can be used not only as a substitute for X-rays or gamma-rays in the sterilization of insects specially reared for release in large numbers, but also as a means of inducing sterility in natural populations of insects. The author emphasizes that chemosterilants cannot at present be recommended as a practical control or eradication procedure for any vector species of insect, but considers that this extension of the sterilization method holds great promise and merits intensive investigation. PMID:20604181

  7. Partially Protective Immunity Induced by a 20 kDa Protein Secreted by Trichinella spiralis Stichocytes

    PubMed Central

    Wang, Lei; Gu, Yuan; Zhan, Bin; Zhu, Xinping

    2015-01-01

    Background Trichinella spiralis infection induces protective immunity against re-infection in animal models. Identification of the antigens eliciting acquired immunity during infection is important for vaccine development against Trichinella infection and immunodiagnosis. Methods and Findings The T. spiralis adult cDNA library was immunoscreened with sera from pigs experimentally infected with 20,000 infective T. spiralis larvae. Total 43 positive clones encoding for 28 proteins were identified; one of the immunodominant proteins was 20 kDa Ts-ES-1 secreted by Trichinella stichocytes and existing in the excretory/secretory (ES) products of T. spiralis adult and muscle larval worms. Ts-ES-1 contains 172 amino acids with a typical signal peptide in the first 20 amino acids. The expression of Ts-ES-1 was detected in both the adult and muscle larval stages at the mRNA and protein expression levels. Mice immunized with recombinant Ts-ES-1 (rTs-ES-1) formulated with ISA50v2 adjuvant exhibited a significant worm reduction in both the adult worm (27%) and muscle larvae burden (42.1%) after a challenge with T. spiralis compared to the adjuvant control group (p<0.01). The rTs-ES-1-induced protection was associated with a high level of specific anti-Ts-ES-1 IgG antibodies and a Th1/Th2 mixed immune response. Conclusion The newly identified rTs-ES-1 is an immunodominant protein secreted by Trichinella stichocytes during natural infection and enables to the induction of partial protective immunity in vaccinated mice against Trichinella infection. Therefore, rTs-ES-1 is a potential candidate for vaccine development against trichinellosis. PMID:26288365

  8. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells

    PubMed Central

    Cohen, Evan N.; Gao, Hui; Anfossi, Simone; Mego, Michal; Reddy, Neelima G.; Debeb, Bisrat; Giordano, Antonio; Tin, Sanda; Wu, Qiong; Garza, Raul J.; Cristofanilli, Massimo; Mani, Sendurai A.; Croix, Denise A.; Ueno, Naoto T.; Woodward, Wendy A.; Luthra, Raja; Krishnamurthy, Savitri; Reuben, James M.

    2015-01-01

    Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction. PMID:26207636

  9. Effective antibody therapy induces host protective antitumor immunity that is augmented by TLR4 agonist treatment

    PubMed Central

    Wang, Shangzi; Astsaturov, Igor A.; Bingham, Catherine A.; McCarthy, Kenneth M.; von Mehren, Margaret; Xu, Wei; Alpaugh, R. Katherine; Tang, Yong; Littlefield, Bruce A.; Hawkins, Lynn D.; Ishizaka, Sally T.; Weiner, Louis M.

    2012-01-01

    Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a toll-like receptor agonist and an anti-tumor monoclonal antibody is effective and induces host-protective anti-tumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2 tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2 targeted therapeutics. Here we show that E6020, a toll like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against re-challenge with human HER2 transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct anti-tumor effects but also induces a host-protective human HER2-directed adaptive immune response indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer. PMID:21842208

  10. Nasal immunization with M cell-targeting ligand-conjugated ApxIIA toxin fragment induces protective immunity against Actinobacillus pleuropneumoniae infection in a murine model.

    PubMed

    Park, Jisang; Seo, Ki-Weon; Kim, Sae-Hae; Lee, Ha-Yan; Kim, Bumseok; Lim, Chae Woong; Kim, Jin-Hee; Yoo, Han Sang; Jang, Yong-Suk

    2015-05-15

    Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia and severe economic loss in the swine industry has been caused by the infection. Therefore, the development of an effective vaccine against the bacteria is necessary. ApxII toxin, among several virulence factors expressed by the bacteria, is considered to be a promising vaccine candidate because ApxII toxin not only accompanies cytotoxic and hemolytic activities, but is also expressed in all 15 serotypes of bacteria except serotypes 10 and 14. In this study, we identified the peptide ligand capable of targeting the ligand-conjugated ApxIIA #5 fragment antigen to nasopharynx-associated lymphoid tissue. It was found that nasal immunization with ligand-conjugated ApxIIA #5 induced efficient mucosal and systemic immune responses measured at the levels of antigen-specific antibodies, cytokine-secreting cells after antigen exposure, and antigen-specific lymphocyte proliferation. More importantly, the nasal immunization induced protective immunity against nasal challenge infection of the bacteria, which was confirmed by histopathological studies and bacterial clearance after challenge infection. Collectively, we confirmed that the ligand capable of targeting the ligand-conjugated antigen to nasopharynx-associated lymphoid tissue can be used as an effective nasal vaccine adjuvant to induce protective immunity against A. pleuropneumoniae infection. PMID:25818577

  11. Killer B Lymphocytes and Their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

    PubMed Central

    Klinker, Matthew W.; Fox, David A.

    2015-01-01

    Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL), and their ability to kill T helper (TH) lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV) consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed major histocompatibility complex (MHC) class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes. PMID:25852690

  12. Theoretical evaluation of induced radioactivity in food products by electron — or X-ray beam sterilization

    NASA Astrophysics Data System (ADS)

    Leboutet, H.; Aucouturier, J.

    We evaluate first the energy density for electrons or X-ray beams necessary to produce a reference level of 1 kilogray at the maximum of dose, as a function of energy, for electrons and bremsstrahlung photons ( BX rays), based on experimental data obtained on radio-therapy beams, from 4 to 32 MeV, and irradiation beams from production plant CARIC. Then from the production of neutrons on the tungsten target and from (γ n) reactions on the deuterium content of the irradiated food, the slowing down and capture of these neutrons is estimated. Radioisotopes can be produced by (γ n) reactions on iodine, and to a lesser extent on tin, lead, barium, etc., but the major contribution is neutron activation, where the more critical elements are sodium, chlorine, potassium, magnesium, phosphorus, calcium. Induced activity is compared to natural activity coming from potassium 40, carbon 14 and radium, contained in all foods. We conclude that for electrons up to 1 Mrad the induced activity remains of the order of a few percent of natural activity, for energies below 10-11 MeV. Bremsstrahlung X-ray irradiations can give comparable levels as soon as the energy of the generating electron beam is above 3 MeV. The induced activity decays within a few days. There is only a small increase of induced activity as the energy changes from 5 to 10 MeV, for the same total applied dose.

  13. Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut.

    PubMed

    Chamcha, Venkateswarlu; Jones, Andrew; Quigley, Bernard R; Scott, June R; Amara, Rama Rao

    2015-11-15

    The induction of a potent humoral and cellular immune response in mucosal tissue is important for the development of an effective HIV vaccine. Most of the current HIV vaccines under development use the i.m. route for immunization, which is relatively poor in generating potent and long-lived mucosal immune responses. In this article, we explore the ability of an oral vaccination with a probiotic organism, Lactococcus lactis, to elicit HIV-specific immune responses in the mucosal and systemic compartments of BALB/c mice. We expressed the HIV-1 Gag-p24 on the tip of the T3 pilus of Streptococcus pyogenes as a fusion to the Cpa protein (LL-Gag). After four monthly LL-Gag oral immunizations, we observed strong Gag-specific IgG and IgA responses in serum, feces, and vaginal secretions. However, the Gag-specific CD8 T cell responses in the blood were at or below our detection limit. After an i.m. modified vaccinia Ankara/Gag boost, we observed robust Gag-specific CD8 T cell responses both in systemic and in mucosal tissues, including intraepithelial and lamina propria lymphocytes of the small intestine, Peyer's patches, and mesenteric lymph nodes. Consistent with strong immunogenicity, the LL-Gag induced activation of CD11c(+) CD11b(+) dendritic cells in the Peyer's patches after oral immunization. Our results demonstrate that oral immunization with L. lactis expressing an Ag on the tip of the group A Streptococcus pilus serves as an excellent vaccine platform to induce strong mucosal humoral and cellular immunity against HIV. PMID:26482408

  14. Sterilization for Women and Men

    MedlinePlus

    ... are rare. Can sterilization be reversed? Sterilization is permanent birth control and is not meant to be reversible. Before ... that can fertilize a female egg. Sterilization: A permanent method of birth control. Testes: Two male organs that produce sperm and ...

  15. Allogeneic IgG combined with dendritic cell stimuli induces anti-tumor T cell immunity

    PubMed Central

    Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Burt, Bryan M; Prestwood, Tyler R.; Perlman, Nikola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Pusapati, Ganesh V.; Bhattacharya, Nupur; Engleman, Edgar G.

    2015-01-01

    While cancers grow in their hosts and evade host immunity through immunoediting and immunosuppression1–5, tumors are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumors are reliably rejected by host T cells, even when the tumor and host share the same major histocompatibility complex (MHC) alleles, the most potent determinants of transplant rejection6–10. How such tumor-eradicating immunity is initiated remains unknown, though elucidating this process could provide a roadmap for inducing similar responses against naturally arising tumors. We found that allogeneic tumor rejection is initiated by naturally occurring tumor-binding IgG antibodies, which enable dendritic cells (DC) to internalize tumor antigens and subsequently activate tumor-reactive T cells. We exploited this mechanism to successfully treat autologous and autochthonous tumors. Either systemic administration of DC loaded with allogeneic IgG (alloIgG)-coated tumor cells or intratumoral injection of alloIgG in combination with DC stimuli induced potent T cell mediated anti-tumor immune responses, resulting in tumor eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumors and metastases, as well as the injected primary tumors. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumor antigens after culture with alloIgG-loaded DC, recapitulating our findings in mice. These results reveal that tumor-binding alloIgG can induce powerful anti-tumor immunity that can be exploited for cancer immunotherapy. PMID:25924063

  16. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

    PubMed

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Engle, Dannielle; Miller, George

    2016-04-14

    Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells

  17. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8+ T cell priming in response to intravaginal immunization

    PubMed Central

    Seavey, Matthew M.; Mosmann, Tim R.

    2010-01-01

    Although vaginal immunization has been explored as a strategy to induce mucosal immunity in the female reproductive tract, this site displays unique immunological features that probably evolved to inhibit anti-paternal T cell responses after insemination to allow successful pregnancy. We previously demonstrated that estradiol, which induces an estrus-like state, prevented CD8+ T cell priming during intravaginal immunization of mice. We now show that estradiol prevented antigen loading of vaginal antigen presenting cells (APC) after intravaginal immunization. Histological examination confirmed that estradiol prevented penetration of peptide antigen into the vaginal wall. Removal of the estradiol-induced mucus barrier by mucinase partially restored antigen loading of vaginal APC and CD8+ T cell proliferation in vivo. The estradiol-induced mucus barrier may thus prevent exposure to antigens delivered intravaginally, supplementing additional estradiol-dependent mechanism(s) that inhibit CD8+ T cell priming after insemination or vaginal vaccination. PMID:19428849

  18. Sterile post-traumatic immunosuppression.

    PubMed

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-04-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  19. Sterile post-traumatic immunosuppression

    PubMed Central

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-01-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  20. Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry

    PubMed Central

    Williams, Gareth R.; Fierens, Kaat; Preston, Stephen G.; Lunn, Daniel; Rysnik, Oliwia; De Prijck, Sofie; Kool, Mirjam; Buckley, Hannah C.; O’Hare, Dermot; Austyn, Jonathan M.

    2014-01-01

    There is currently no paradigm in immunology that enables an accurate prediction of how the immune system will respond to any given agent. Here we show that the immunological responses induced by members of a broad class of inorganic crystalline materials are controlled purely by their physicochemical properties in a highly predictable manner. We show that structurally and chemically homogeneous layered double hydroxides (LDHs) can elicit diverse human dendritic cell responses in vitro. Using a systems vaccinology approach, we find that every measured response can be modeled using a subset of just three physical and chemical properties for all compounds tested. This correlation can be reduced to a simple linear equation that enables the immunological responses stimulated by newly synthesized LDHs to be predicted in advance from these three parameters alone. We also show that mouse antigen–specific antibody responses in vivo and human macrophage responses in vitro are controlled by the same properties, suggesting they may control diverse responses at both individual component and global levels of immunity. This study demonstrates that immunity can be determined purely by chemistry and opens the possibility of rational manipulation of immunity for therapeutic purposes. PMID:24799501

  1. ALD1 Regulates Basal Immune Components and Early Inducible Defense Responses in Arabidopsis.

    PubMed

    Cecchini, Nicolás M; Jung, Ho Won; Engle, Nancy L; Tschaplinski, Timothy J; Greenberg, Jean T

    2015-04-01

    Robust immunity requires basal defense machinery to mediate timely responses and feedback cycles to amplify defenses against potentially spreading infections. AGD2-LIKE DEFENSE RESPONSE PROTEIN 1 (ALD1) is needed for the accumulation of the plant defense signal salicylic acid (SA) during the first hours after infection with the pathogen Pseudomonas syringae and is also upregulated by infection and SA. ALD1 is an aminotransferase with multiple substrates and products in vitro. Pipecolic acid (Pip) is an ALD1-dependent bioactive product induced by P. syringae. Here, we addressed roles of ALD1 in mediating defense amplification as well as the levels and responses of basal defense machinery. ALD1 needs immune components PAD4 and ICS1 (an SA synthesis enzyme) to confer disease resistance, possibly through a transcriptional amplification loop between them. Furthermore, ALD1 affects basal defense by controlling microbial-associated molecular pattern (MAMP) receptor levels and responsiveness. Vascular exudates from uninfected ALD1-overexpressing plants confer local immunity to the wild type and ald1 mutants yet are not enriched for Pip. We infer that, in addition to affecting Pip accumulation, ALD1 produces non-Pip metabolites that play roles in immunity. Thus, distinct metabolite signals controlled by the same enzyme affect basal and early defenses versus later defense responses, respectively. PMID:25372120

  2. 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.

  3. [Prolactin and sterility (author's transl)].

    PubMed

    Santeler, P; Martin, J; Daxenbichler, G

    1980-07-01

    From July 1975 to December 1979 at the Univ.-Klinik für Frauenheilkunde, Innsbruck, 91 female sterile patients were examined due to hyperprolactinaemia. Since hyperprolactin presents common symptoms of different diseases, we established a differentiated clarification and therapy scheme using the guidelines of the W.H.O. and all new knowledge. After disqualification of patients with corresponding tubular sterility, we induced in 24 patients 32 pregnancies with medication or operative therapy. After birth or abortion a prolactin-caused dysfunction reappeared in the reproductive system. With a gradual prolactin increasion in the serum level, the grade of this dysfunction in the reproductive system was worsened. A reduction of the prolactin serum level to 40 ng/ml seems to be the basis for spontaneous ovulation. Present therapeutic possibilities and as a result the reversibility of this disturbance after interruption of prolactin inhibitors, we find that long-therm therapy is necessary. PMID:6933737

  4. Simulating sterilization, vaccination, and test-and-remove as brucellosis control measures in bison

    USGS Publications Warehouse

    Ebinger, M.; Cross, P.; Wallen, Rick; White, P.J.; Treanor, John

    2011-01-01

    Brucella abortus, the causative agent of bovine brucellosis, infects wildlife, cattle, and humans worldwide, but management of the disease is often hindered by the logistics of controlling its prevalence in wildlife reservoirs. We used an individually based epidemiological model to assess the relative efficacies of three management interventions (sterilization, vaccination, and test-and-remove). The model was parameterized with demographic and epidemiological data from bison in Yellowstone National Park, USA. Sterilization and test-and-remove were most successful at reducing seroprevalence when they were targeted at young seropositive animals, which are the most likely age and sex category to be infectious. However, these approaches also required the most effort to implement. Vaccination was less effective (even with a perfect vaccine) but also required less effort to implement. For the treatment efforts we explored (50–100 individuals per year or 2.5–5% of the female population), sterilization had little impact upon the bison population growth rate when selectively applied. The population growth rate usually increased by year 25 due to the reduced number of Brucella-induced abortions. Initial declines in seroprevalence followed by rapid increases (>15% increase in 5 years) occurred in 3–13% of simulations with sterilization and test-and-remove, but not vaccination. We believe this is due to the interaction of superspreading events and the loss of herd immunity in the later stages of control efforts as disease prevalence declines. Sterilization provided a mechanism for achieving large disease reductions while simultaneously limiting population growth, which may be advantageous in some management scenarios. However, the field effort required to find the small segment of the population that is infectious rather than susceptible or recovered will likely limit the utility of this approach in many free-ranging wildlife populations. Nevertheless, we encourage

  5. Plasmepsin 4-Deficient Plasmodium berghei Are Virulence Attenuated and Induce Protective Immunity against Experimental Malaria

    PubMed Central

    Spaccapelo, Roberta; Janse, Chris J.; Caterbi, Sara; Franke-Fayard, Blandine; Bonilla, J. Alfredo; Syphard, Luke M.; Di Cristina, Manlio; Dottorini, Tania; Savarino, Andrea; Cassone, Antonio; Bistoni, Francesco; Waters, Andrew P.; Dame, John B.; Crisanti, Andrea

    2010-01-01

    Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Δpm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Real-time in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines. PMID:20019192

  6. Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

    PubMed Central

    Liikanen, Ilkka; Ahtiainen, Laura; Hirvinen, Mari LM; Bramante, Simona; Cerullo, Vincenzo; Nokisalmi, Petri; Hemminki, Otto; Diaconu, Iulia; Pesonen, Sari; Koski, Anniina; Kangasniemi, Lotta; Pesonen, Saila K; Oksanen, Minna; Laasonen, Leena; Partanen, Kaarina; Joensuu, Timo; Zhao, Fang; Kanerva, Anna; Hemminki, Akseli

    2013-01-01

    Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum—a possible indicator of immune response—increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy. PMID:23546299

  7. Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients.

    PubMed

    Liikanen, Ilkka; Ahtiainen, Laura; Hirvinen, Mari L M; Bramante, Simona; Cerullo, Vincenzo; Nokisalmi, Petri; Hemminki, Otto; Diaconu, Iulia; Pesonen, Sari; Koski, Anniina; Kangasniemi, Lotta; Pesonen, Saila K; Oksanen, Minna; Laasonen, Leena; Partanen, Kaarina; Joensuu, Timo; Zhao, Fang; Kanerva, Anna; Hemminki, Akseli

    2013-06-01

    Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy. PMID:23546299

  8. Phytotoxicity and Innate Immune Responses Induced by Nep1-Like Proteins[W

    PubMed Central

    Qutob, Dinah; Kemmerling, Birgit; Brunner, Frédéric; Küfner, Isabell; Engelhardt, Stefan; Gust, Andrea A.; Luberacki, Borries; Seitz, Hanns Ulrich; Stahl, Dietmar; Rauhut, Thomas; Glawischnig, Erich; Schween, Gabriele; Lacombe, Benoit; Watanabe, Naohide; Lam, Eric; Schlichting, Rita; Scheel, Dierk; Nau, Katja; Dodt, Gabriele; Hubert, David; Gijzen, Mark; Nürnberger, Thorsten

    2006-01-01

    We show that oomycete-derived Nep1 (for necrosis and ethylene-inducing peptide1)–like proteins (NLPs) trigger a comprehensive immune response in Arabidopsis thaliana, comprising posttranslational activation of mitogen-activated protein kinase activity, deposition of callose, production of nitric oxide, reactive oxygen intermediates, ethylene, and the phytoalexin camalexin, as well as cell death. Transcript profiling experiments revealed that NLPs trigger extensive reprogramming of the Arabidopsis transcriptome closely resembling that evoked by bacteria-derived flagellin. NLP-induced cell death is an active, light-dependent process requiring HSP90 but not caspase activity, salicylic acid, jasmonic acid, ethylene, or functional SGT1a/SGT1b. Studies on animal, yeast, moss, and plant cells revealed that sensitivity to NLPs is not a general characteristic of phospholipid bilayer systems but appears to be restricted to dicot plants. NLP-induced cell death does not require an intact plant cell wall, and ectopic expression of NLP in dicot plants resulted in cell death only when the protein was delivered to the apoplast. Our findings strongly suggest that NLP-induced necrosis requires interaction with a target site that is unique to the extracytoplasmic side of dicot plant plasma membranes. We propose that NLPs play dual roles in plant pathogen interactions as toxin-like virulence factors and as triggers of plant innate immune responses. PMID:17194768

  9. Immune Modulatory Effects of IL-22 on Allergen-Induced Pulmonary Inflammation

    PubMed Central

    Fang, Ping; Zhou, Li; Zhou, Yuqi; Kolls, Jay K.; Zheng, Tao; Zhu, Zhou

    2014-01-01

    IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma. PMID:25254361

  10. Dermatophytes Activate Skin Keratinocytes via Mitogen-Activated Protein Kinase Signaling and Induce Immune Responses

    PubMed Central

    Achterman, Rebecca R.; Moyes, David L.; Thavaraj, Selvam; Smith, Adam R.; Blair, Kris M.

    2015-01-01

    Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation. PMID:25667269

  11. The role of the immune system in hexachlorobenzene-induced toxicity.

    PubMed Central

    Michielsen, C C; van Loveren, H; Vos, J G

    1999-01-01

    Hexachlorobenzene (HCB) is a persistent environmental pollutant. The toxicity of HCB has been extensively studied after an accidental human poisoning in Turkey and more recently it has been shown that HCB has immunotoxic properties in laboratory animals and probably also in man. Oral exposure of rats to HCB showed stimulatory effects on spleen and lymph node weights and histology, increased serum IgM levels, and an enhancement of several parameters of immune function. Moreover, more recent studies indicate that HCB-induced effects in the rat may be related to autoimmunity. In Wistar rats exposed to HCB, IgM antibodies against several autoantigens were elevated; in the Lewis rat, HCB differently modulated two experimental models of autoimmune disease. Oral exposure of rats to HCB induces skin and lung pathology in the rat. Recently several studies have been conducted to investigate whether these skin and lung lesions can be related to HCB-induced immunomodulation, and these studies will be discussed in this review. HCB-induced skin and lung lesions probably have a different etiology; pronounced strain differences and correlation of skin lesions with immune parameters suggest a specific involvement of the immune system in HCB-induced skin lesions. The induction of lung lesions by HCB was thymus independent. Thymus-dependent T cells were not likely to be required for the induction of skin lesions, although T cells enhanced the rate of induction and the progression of the skin lesions. No deposition of autoantibodies was observed in nonlesional or lesional skin of HCB-treated rats. Therefore, we concluded that it is unlikely that the mechanism by which most allergic or autoimmunogenic chemicals work, i.e., by binding to macromolecules of the body and subsequent T- and B-cell activation, is involved in the HCB-induced immunopathology in the rat. Such a thymus-independent immunopathology is remarkable, as HCB strongly modulates T-cell-mediated immune parameters. This

  12. Fungal Innate Immunity Induced by Bacterial Microbe-Associated Molecular Patterns (MAMPs)

    PubMed Central

    Ipcho, Simon; Sundelin, Thomas; Erbs, Gitte; Kistler, H. Corby; Newman, Mari-Anne; Olsson, Stefan

    2016-01-01

    Plants and animals detect bacterial presence through Microbe-Associated Molecular Patterns (MAMPs) which induce an innate immune response. The field of fungal–bacterial interaction at the molecular level is still in its infancy and little is known about MAMPs and their detection by fungi. Exposing Fusarium graminearum to bacterial MAMPs led to increased fungal membrane hyperpolarization, a putative defense response, and a range of transcriptional responses. The fungus reacted with a different transcript profile to each of the three tested MAMPs, although a core set of genes related to energy generation, transport, amino acid production, secondary metabolism, and especially iron uptake were detected for all three. Half of the genes related to iron uptake were predicted MirA type transporters that potentially take up bacterial siderophores. These quick responses can be viewed as a preparation for further interactions with beneficial or pathogenic bacteria, and constitute a fungal innate immune response with similarities to those of plants and animals. PMID:27172188

  13. Fungal Innate Immunity Induced by Bacterial Microbe-Associated Molecular Patterns (MAMPs).

    PubMed

    Ipcho, Simon; Sundelin, Thomas; Erbs, Gitte; Kistler, H Corby; Newman, Mari-Anne; Olsson, Stefan

    2016-01-01

    Plants and animals detect bacterial presence through Microbe-Associated Molecular Patterns (MAMPs) which induce an innate immune response. The field of fungal-bacterial interaction at the molecular level is still in its infancy and little is known about MAMPs and their detection by fungi. Exposing Fusarium graminearum to bacterial MAMPs led to increased fungal membrane hyperpolarization, a putative defense response, and a range of transcriptional responses. The fungus reacted with a different transcript profile to each of the three tested MAMPs, although a core set of genes related to energy generation, transport, amino acid production, secondary metabolism, and especially iron uptake were detected for all three. Half of the genes related to iron uptake were predicted MirA type transporters that potentially take up bacterial siderophores. These quick responses can be viewed as a preparation for further interactions with beneficial or pathogenic bacteria, and constitute a fungal innate immune response with similarities to those of plants and animals. PMID:27172188

  14. Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice.

    PubMed

    Blank, M; Faden, D; Tincani, A; Kopolovic, J; Goldberg, I; Gilburd, B; Allegri, F; Balestrieri, G; Valesini, G; Shoenfeld, Y

    1994-08-01

    Beta-2-GPI is a 50 kDa glycoprotein which is known to be a serum co-factor, with a role in determining the binding of pathogenic anticardiolipin antibodies to phospholipids. Immunization of naive mice with beta-2-GPI resulted in elevated levels of antibodies directed against negatively charged phospholipids (cardiolipin, phosphotidylserine, phosphatidylinositol). The presence of increased titres of antiphospholipid antibodies in the sera of the mice was later followed by prolonged activated partial thromboplastin time (APTT), thrombocytopenia, and when the mice were mated, by a high percentage of fetal resorptions in the uterus. These data point to the ability of beta-2-GPI to induce pathogenic anti-cardiolipin antibodies following active immunization. PMID:7980847

  15. Inactivation of conserved genes induces microbial aversion, drug detoxification, and innate immunity in C.elegans

    PubMed Central

    Melo, Justine A.; Ruvkun, Gary

    2012-01-01

    Summary The nematode C. elegans consumes benign bacteria such as E. coli and is repelled by pathogens and toxins. Here we show that RNAi and toxin-mediated disruption of core cellular activities, including translation, respiration, and protein turnover, stimulates behavioral avoidance of attractive E. coli. RNAi of such essential processes also induces expression of detoxification and innate immune response genes in the absence of toxins or pathogens. Disruption of core processes in non-neuronal tissues can stimulate aversion behavior, revealing a neuroendocrine axis of control. Microbial avoidance requires serotonergic and Jnk kinase signaling. We propose that surveillance pathways oversee critical cellular activities to detect pathogens, many of which deploy toxins and virulence factors to disrupt these same host pathways. Variation in cellular surveillance and endocrine pathways controlling behavior, detoxification and immunity selected by past toxin or microbial interactions could underlie aberrant responses to foods, medicines, and microbes. PMID:22500807

  16. Targeting with bovine CD154 enhances humoral immune responses induced by a DNA vaccine in sheep.

    PubMed

    Manoj, Sharmila; Griebel, Philip J; Babiuk, Lorne A; van Drunen Littel-van den Hurk, Sylvia

    2003-01-15

    CD40-CD154 interactions play an important role in regulating humoral and cell-mediated immune responses. Recently, these interactions have been exploited for the development of therapeutic and preventive treatments. The objective of this study was to test the ability of bovine CD154 to target a plasmid-encoded Ag to CD40-expressing APCs. To achieve this, a plasmid coding for bovine CD154 fused to a truncated secreted form of bovine herpesvirus 1 glycoprotein D (tgD), pSLIAtgD-CD154, was constructed. The chimeric tgD-CD154 was expressed in vitro in COS-7 cells and reacted with both glycoprotein D- and CD154-specific Abs. Both tgD and tgD-CD154 were capable of binding to epithelial cells, whereas only tgD-CD154 bound to B cells. Furthermore, dual-labeling of ovine PBMCs revealed that tgD-CD154 was bound by primarily B cells. The functional integrity of the tgD-CD154 chimera was confirmed by the induction of both IL-4-dependent B cell proliferation and tgD-specific lymphoproliferative responses in vitro. Finally, sheep immunized with pSLIAtgD-CD154 developed a more rapid primary tgD-specific Ab response and a significantly stronger tgD-specific secondary response when compared with animals immunized with pSLIAtgD and control animals. Similarly, virus-neutralizing Ab titers were significantly higher after secondary immunization with pSLIAtgD-CD154. These results demonstrate that using CD154 to target plasmid-expressed Ag can significantly enhance immune responses induced by a DNA vaccine. PMID:12517965

  17. Biofilm Matrix Exoproteins Induce a Protective Immune Response against Staphylococcus aureus Biofilm Infection

    PubMed Central

    Gil, Carmen; Solano, Cristina; Burgui, Saioa; Latasa, Cristina; García, Begoña; Toledo-Arana, Alejandro

    2014-01-01

    The Staphylococcus aureus biofilm mode of growth is associated with several chronic infections that are very difficult to treat due to the recalcitrant nature of biofilms to clearance by antimicrobials. Accordingly, there is an increasing interest in preventing the formation of S. aureus biofilms and developing efficient antibiofilm vaccines. Given the fact that during a biofilm-associated infection, the first primary interface between the host and the bacteria is the self-produced extracellular matrix, in this study we analyzed the potential of extracellular proteins found in the biofilm matrix to induce a protective immune response against S. aureus infections. By using proteomic approaches, we characterized the exoproteomes of exopolysaccharide-based and protein-based biofilm matrices produced by two clinical S. aureus strains. Remarkably, results showed that independently of the nature of the biofilm matrix, a common core of secreted proteins is contained in both types of exoproteomes. Intradermal administration of an exoproteome extract of an exopolysaccharide-dependent biofilm induced a humoral immune response and elicited the production of interleukin 10 (IL-10) and IL-17 in mice. Antibodies against such an extract promoted opsonophagocytosis and killing of S. aureus. Immunization with the biofilm matrix exoproteome significantly reduced the number of bacterial cells inside a biofilm and on the surrounding tissue, using an in vivo model of mesh-associated biofilm infection. Furthermore, immunized mice also showed limited organ colonization by bacteria released from the matrix at the dispersive stage of the biofilm cycle. Altogether, these data illustrate the potential of biofilm matrix exoproteins as a promising candidate multivalent vaccine against S. aureus biofilm-associated infections. PMID:24343648

  18. Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

    PubMed

    Synhaeve, Nicholas; Musilli, Stefania; Stefani, Johanna; Nicolas, Nour; Delissen, Olivia; Dublineau, Isabelle; Bertho, Jean-Marc

    2016-03-01

    Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout. PMID:26930377

  19. Interleukin-17 mediated inflammatory responses are required for ultraviolet radiation-induced immune suppression.

    PubMed

    Li, Hui; Prasad, Ram; Katiyar, Santosh K; Yusuf, Nabiha; Elmets, Craig A; Xu, Hui

    2015-01-01

    Ultraviolet radiation (UVR) induces immunosuppression and is a major factor for development of skin cancer. Numerous efforts have been made to determine mechanisms for UVR-induced immunosuppression and to develop strategies for prevention and treatment of UVR-induced cancers. In the current study, we use IL-17 receptor (IL-17R) deficient mice to examine whether IL-17 mediated responses have a role in UVB (290-320)-induced immunosuppression of contact hypersensitivity responses. Results demonstrate that IL-17 mediated responses are required for UVB-induced immunosuppression of contact hypersensitivity responses. The systemic immune suppression and development of regulatory T cells are inhibited in UVB-treated IL-17R deficient mice compared to wild-type animals. The deficiency in IL-17R inhibits the infiltration and development of a tolerogenic myeloid cell population in UVB-treated skin, which expresses CD11b and Gr-1 and produces reactive oxygen species. We speculate that the development of the tolerogenic myeloid cells is dependent on IL-17-induced chemokines and inflammatory mediators in UVB-treated skin. The inhibition of the tolerogenic myeloid cells may be attributed to the suppression of regulatory T cells in UVR-treated IL-17R(-/-) mice. The findings may be exploited to new strategies for prevention and treatment of UVR-induced skin diseases and cancers. PMID:25250896

  20. Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity.

    PubMed

    Kowalczyk, Aleksandra; Doener, Fatma; Zanzinger, Kai; Noth, Janine; Baumhof, Patrick; Fotin-Mleczek, Mariola; Heidenreich, Regina

    2016-07-19

    mRNA represents a new platform for the development of therapeutic and prophylactic vaccines with high flexibility with respect to production and application. We have previously shown that our two component self-adjuvanted mRNA-based vaccines (termed RNActive® vaccines) induce balanced immune responses comprising both humoral and cellular effector as well as memory responses. Here, we evaluated the early events upon intradermal application to gain more detailed insights into the underlying mode of action of our mRNA-based vaccine. We showed that the vaccine is taken up in the skin by both non-leukocytic and leukocytic cells, the latter being mostly represented by antigen presenting cells (APCs). mRNA was then transported to the draining lymph nodes (dLNs) by migratory dendritic cells. Moreover, the encoded protein was expressed and efficiently presented by APCs within the dLNs as shown by T cell proliferation and immune cell activation, followed by the induction of the adaptive immunity. Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the sera of the immunized mice indicating a favorable safety profile of the mRNA-based vaccines. Notably, a substantial boostability of the immune responses was observed, indicating that mRNA can be used effectively in repetitive immunization schedules. The evaluation of the immunostimulation following prime and boost vaccination revealed no signs of exhaustion as demonstrated by comparable levels of cytokine production at the injection site and immune cell activation within dLNs. In summary, our data provide mechanistic insight into the mode of action and a rational for the use of mRNA-based vaccines as a promising immunization platform. PMID:27269061

  1. [Sterilization and eugenics].

    PubMed

    Shasha, Shaul M

    2011-04-01

    The term "eugenics" was coined by Francis Galton in 1883 and was defined as the science of the improvement of the human race by better breeding. "Positive eugenics" referred to methods of encouraging the "most fit" to reproduce more often, while "negative eugenics" was related to ways of discouraging or preventing the "less fit" from reproducing by birth control and sterilization. Many western countries adopted eugenics programs including Britain, Canada, Norway, Australia, Switzerland and others. In Sweden more then 62,000 "unfits" were forcibly sterilized. Many states in the U.S.A. had adopted marriage laws with eugenics criteria including forced sterilization. Approximately 64,000 individuals were sterilized. Eugenics considerations also lay behind the adoption of the Immigration Restriction Act of 1924. The Largest plan on eugenics was adopted by the Nazi regime in Germany. Hundreds of thousands of people, who were viewed as being "unfit", were forcibly sterilized by different methods: Surgical sterilization or castration with severe complications and high mortality rates. X-ray irradiation. The method was suggested by Brack, and tested by Schuman using prisoners in Block No. 10 in Auschwitz and Birkenau. Experiments were also performed by Brack on prisoners using the "window method". "Klauberg method"--injection of irritating materials into the uterus. Experiments were conducted using the plant Caladium Seguinum which was believed to have sterilization and castration properties. PMID:22164927

  2. HPV16L1-attenuated Shigella recombinant vaccine induced strong vaginal and systemic immune responses in guinea pig model

    PubMed Central

    Yan, Xiaofei; Wang, Depu; Liang, Fengli; Fu, Ling; Guo, Cheng

    2014-01-01

    Though human papillomavirus (HPV) vaccines based on L1 virus-like particles (VLPs) have excellent protective effect against HPV-induced cervical cancer, they are too expensive to be afforded by the developing countries, where most cases of cervical cancer occur. A live bacterial-based vaccine could be an inexpensive alternative. The aim of this study was to evaluate the potential value of live attenuated Shigella. flexneri 2a sc602 strain-based HPV16L1 as a high-efficiency, low-cost HPV16L1 mucosal vaccine. Recombinant sc602/L1 vaccine induced high L1-specific systemic and mucosal immune responses as well as cell-mediated Th1 and Th2 immune responses in guinea pig model. Sc602/L1 vaccine induced higher L1-specific IgG and IgA antibodies as well as HPV16-neutralizing antibodies in genital region in sc602/L1 mucosal immunized animals than in L1 intramuscular immunized animals. Though both are via mucosal delivery, immunized sc602/L1 vaccine by rectum route induced higher L1-specific IgA and IgG titers in genital region than by conjunctiva route. In addition, sc602/L1 also strongly increased L1-specific IFN-γ and IL-4 expression, implying its effect on cell-mediated immune response. HPV16L1 was expressed in sc602 bacteria and their biologic characteristics were detected by immunoblot, electron microscope and HeLa cell invasion assay. Guinea pigs were immunized with sc602L1 through conjunctiva (i.c.) or rectum (i.r.). Mucosal and systemic immune responses were detected by ELISA, ELISPOT and Neutralization activity assays. Strong mucosal and systemic immune responses were induced by sc602/L1 vaccine. This study provides evidence that sc602/L1 vaccine may have protective effect on HPV infection. PMID:25483698

  3. Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor.

    PubMed

    Jaiswal, Mukesh K; Agrawal, Varkha; Mallers, Timothy; Gilman-Sachs, Alice; Hirsch, Emmet; Beaman, Kenneth D

    2013-12-01

    An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 h after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN; a TLR 2 agonist) and polyinosinic-polycytidylic acid [poly(I:C); a TLR3 agonist], modeling Gram-positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C)-induced preterm labor. Expression of inducible NO synthase was significantly upregulated in PGN+poly(I:C)-treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via an extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblasts. F4/80(+) macrophages were increased and polarization was skewed in PGN+poly(I:C)-treated uterus toward double-positive CD11c(+) (M1) and CD206(+) (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 were increased in PGN+poly(I:C)-treated uterus, which could induce pyroptosis. These results suggest that the double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes. PMID:24163412

  4. Study of the BCG Vaccine-Induced Cellular Immune Response in Schoolchildren in Antananarivo, Madagascar

    PubMed Central

    Ranaivomanana, Paulo; Raharimanga, Vaomalala; Dubois, Patrice M.; Richard, Vincent; Rasolofo Razanamparany, Voahangy

    2015-01-01

    Objective Although the Bacillus Calmette-Guérin vaccine (BCG) protects young children against serious forms of TB, protection against pulmonary TB is variable. We assessed BCG vaccine-induced cellular immune responses and determined for how long they could be detected during childhood in Antananarivo, Madagascar. Methods We assessed BCG vaccine-induced cellular immune responses by TST and IGRA (in-house ELISPOT assay) using BCG and PPD as stimulation antigen, and compared results between vaccinated and non-vaccinated schoolchildren of two age groups, 6-7 and 13-14 years old. Results Three hundred and sixty-three healthy schoolchildren were enrolled. TST was performed on 351 children and IGRA on 142. A high proportion (66%; 229/343) of the children had no TST reactivity (induration size 0 mm). TST-positive responses (≥15 mm) were more prevalent among 13-14 year-old (31.7%) than 6-7 year old (16.5%) children, both in the non-vaccinated (43% vs. 9%, p<0.001) and vaccinated (29% vs. 13%, p=0.002) subgroups. There were no significant differences in TST responses between vaccinated and non-vaccinated children in either of the age groups. The IGRA response to BCG and to PPD stimulation was not significantly different according to BCG vaccination record or to age group. A high rate (15.5%; 22/142) of indeterminate IGRA responses was observed. There was very poor agreement between TST and IGRA-PPD findings (k= 0.08) and between TST and IGRA-BCG findings (k= 0.02) Conclusion Analysis of TST and IGRA response to stimulation with BCG and PPD revealed no difference in immune response between BCG-vaccinated and non-vaccinated children; also no decrease of the BCG vaccine-induced cellular immune response over time was observed. We conclude that TST and IGRA have limitations in assessing a role of BCG or tuberculosis-related immunity. PMID:26214514

  5. Food irradiation and sterilization

    NASA Astrophysics Data System (ADS)

    Josephson, Edward S.

    Radiation sterilization of food (radappertization) requires exposing food in sealed containers to ionizing radiation at absorbed doses high enough (25-70 kGy) to kill all organisms of food spoilage and public health significance. Radappertization is analogous to thermal canning is achieving shelf stability (long term storage without refrigeration). Except for dry products in which autolysis is negligible, the radappertization process also requires that the food be heated to an internal temperature of 70-80°C (bacon to 53°C) to inactivate autolytic enzymes which catalyze spoilage during storage without refrigeration. To minimize the occurence of irradiation induced off-flavors and odors, undesirable color changes, and textural and nutritional losses from exposure to the high doses required for radappertization, the foods are vacuum sealed and irradiated frozen (-40°C to -20°C). Radappertozed foods have the characteristic of fresh foods prepared for eating. Radappertization can substitute in whole or in part for some chemical food additives such as ethylene oxide and nitrites which are either toxic, carcinogenic, mutagenic, or teratogenic. After 27 years of testing for "wholesomeness" (safety for consumption) of radappertized foods, no confirmed evidence has been obtained of any adverse effecys of radappertization on the "wholesomeness" characteristics of these foods.

  6. Dietary histidine increases mouse skin urocanic acid levels and enhances UVB-induced immune suppression of contact hypersensitivity.

    PubMed

    Reilly, S K; De Fabo, E C

    1991-04-01

    Urocanic Acid (UCA) exists in mammalian skin primarily as the trans isomer and is photoisomerized to cis UCA upon UVB absorption. Our previous studies indicated that the photoisomerization of UCA is the initiating event in UBV-induced suppression of cell-mediated immunity (tUCA----cUCA----immune suppression). The purpose of this study was to verify the role of UCA in UV-induced immune suppression of contact hypersensitivity (CHS) in BALB/c mice. Since UCA is a metabolite of the amino acid L-histidine, we reasoned that increased dietary levels of histidine should raise skin tUCA levels. If skin tUCA is the UVB photoreceptor for immune suppression, this increase should enhance UV-induced suppression of CHS. HPLC analysis of skin from BALB/c mice given a histidine-rich diet (10%) showed that the total amount of UCA is significantly higher in these animals than in mice fed a normal diet. Further, levels of suppression of CHS of 3% and 49% in control fed mice, induced by 4.8 and 7.2 kJ/m2 UVB were significantly increased to 21% and 71% respectively in histidine-fed animals at these same UVB doses. These findings provide additional support for the UCA model for immune suppression, and provide the first evidence that UV-induced immune suppression can be enhanced by a dietary component, L-histidine. PMID:1857737

  7. A micro-sterile inflammation array as an adjuvant for influenza vaccines.

    PubMed

    Wang, Ji; Shah, Dilip; Chen, Xinyuan; Anderson, R Rox; Wu, Mei X

    2014-01-01

    There is an urgent need of adjuvants for cutaneous vaccination. Here, we report that micro-sterile inflammation induced at inoculation sites can augment immune responses to influenza vaccines in animal models. The inoculation site is briefly illuminated with a handheld, non-ablative fractional laser before the vaccine is intradermally administered, which creates an array of self-healing microthermal zones (MTZs) in the skin. The dying cells in the MTZs send 'danger' signals that attract a large number of antigen-presenting cells, in particular, plasmacytoid dendritic cells (pDCs) around each MTZ forming a micro-sterile inflammation array. A pivotal role for pDCs in the adjuvanticity is ascertained by significant abrogation of the immunity after systemic depletion of pDCs, local application of a TNF-α inhibitor or null mutation of IFN regulatory factor7 (IRF7). In contrast to conventional adjuvants that cause persistent inflammation and skin lesions, micro-sterile inflammation enhances efficacy of influenza vaccines, yet with diminished adverse effects. PMID:25033973

  8. CD8+ T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia

    PubMed Central

    Qiu, Jihua; Liu, Xuena; Li, Xiaoqing; Zhang, Xu; Han, Panpan; Zhou, Hai; Shao, Linlin; Hou, Yu; Min, Yanan; Kong, Zhangyuan; Wang, Yawen; Wei, Yu; Liu, Xinguang; Ni, Heyu; Peng, Jun; Hou, Ming

    2016-01-01

    In addition to antiplatelet autoantibodies, CD8+ cytotoxic T lymphocytes (CTLs) play an important role in the increased platelet destruction in immune thrombocytopenia (ITP). Recent studies have highlighted that platelet desialylation leads to platelet clearance via hepatocyte asialoglycoprotein receptors (ASGPRs). Whether CD8+ T cells induce platelet desialylation in ITP remains unclear. Here, we investigated the cytotoxicity of CD8+ T cells towards platelets and platelet desialylation in ITP. We found that the desialylation of fresh platelets was significantly higher in ITP patients with positive cytotoxicity of CD8+ T cells than those without cytotoxicity and controls. In vitro, CD8+ T cells from ITP patients with positive cytotoxicity induced significant platelet desialylation, neuraminidase-1 expression on the platelet surface, and platelet phagocytosis by hepatocytes. To study platelet survival and clearance in vivo, CD61 knockout mice were immunized and their CD8+ splenocytes were used. Platelets co-cultured with these CD8+ splenocytes demonstrated decreased survival in the circulation and increased phagocytosis in the liver. Both neuraminidase inhibitor and ASGPRs competitor significantly improved platelet survival and abrogated platelet clearance caused by CD8+ splenocytes. These findings suggest that CD8+ T cells induce platelet desialylation and platelet clearance in the liver in ITP, which may be a novel mechanism of ITP. PMID:27321376

  9. Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

    PubMed

    Rieber, Nikolaus; Singh, Anurag; Öz, Hasan; Carevic, Melanie; Bouzani, Maria; Amich, Jorge; Ost, Michael; Ye, Zhiyong; Ballbach, Marlene; Schäfer, Iris; Mezger, Markus; Klimosch, Sascha N; Weber, Alexander N R; Handgretinger, Rupert; Krappmann, Sven; Liese, Johannes; Engeholm, Maik; Schüle, Rebecca; Salih, Helmut Rainer; Marodi, Laszlo; Speckmann, Carsten; Grimbacher, Bodo; Ruland, Jürgen; Brown, Gordon D; Beilhack, Andreas; Loeffler, Juergen; Hartl, Dominik

    2015-04-01

    Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense. PMID:25771792

  10. CD8(+) T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia.

    PubMed

    Qiu, Jihua; Liu, Xuena; Li, Xiaoqing; Zhang, Xu; Han, Panpan; Zhou, Hai; Shao, Linlin; Hou, Yu; Min, Yanan; Kong, Zhangyuan; Wang, Yawen; Wei, Yu; Liu, Xinguang; Ni, Heyu; Peng, Jun; Hou, Ming

    2016-01-01

    In addition to antiplatelet autoantibodies, CD8(+) cytotoxic T lymphocytes (CTLs) play an important role in the increased platelet destruction in immune thrombocytopenia (ITP). Recent studies have highlighted that platelet desialylation leads to platelet clearance via hepatocyte asialoglycoprotein receptors (ASGPRs). Whether CD8(+) T cells induce platelet desialylation in ITP remains unclear. Here, we investigated the cytotoxicity of CD8(+) T cells towards platelets and platelet desialylation in ITP. We found that the desialylation of fresh platelets was significantly higher in ITP patients with positive cytotoxicity of CD8(+) T cells than those without cytotoxicity and controls. In vitro, CD8(+) T cells from ITP patients with positive cytotoxicity induced significant platelet desialylation, neuraminidase-1 expression on the platelet surface, and platelet phagocytosis by hepatocytes. To study platelet survival and clearance in vivo, CD61 knockout mice were immunized and their CD8(+) splenocytes were used. Platelets co-cultured with these CD8(+) splenocytes demonstrated decreased survival in the circulation and increased phagocytosis in the liver. Both neuraminidase inhibitor and ASGPRs competitor significantly improved platelet survival and abrogated platelet clearance caused by CD8(+) splenocytes. These findings suggest that CD8(+) T cells induce platelet desialylation and platelet clearance in the liver in ITP, which may be a novel mechanism of ITP. PMID:27321376

  11. Involvement of excretion-secretion products from Fasciola hepatica inducing suppression of the cellular immune responses.

    PubMed

    Cervi, L; Rubinstein, H; Masih, D T

    1996-01-01

    Normal rats i.p. injected with Fasciola hepatica excretor-secretor antigen (ESA) induced a population of spleen mononuclear (SpM) cells, which suppressed the delayed type hypersensitivity (DTH) response to parasite antigens as well as to non-related antigens (human serum albumin) by adoptive transfer. A similar effect was observed when the cell transfer was performed with SpM cells non-adherent to nylon wool. The DTH was not modified by cells transfer adherent to nylon wool in syngeneic receptor animals. The observed suppression depended on the concentration and inoculation moment of the antigen; 1.8 mg of protein ESA being enough to suppress the DTH response at the different days studied, before and after immunization with whole F. hepatica antigens. A marked suppression was observed when ESA was injected on day 7 pre-immunization. On the other hand, inoculation of ESA treated with 0.01 M sodium periodate (carbohydrate oxidant) diminished the suppressor effect found after the native ESA inoculation, indicating participation of ESA glucidic components in induced suppression. Inoculation of ESA fractions obtained from polyacrylamide gel elution with different MW range, showed that components between 12 and 23 kDa actively induced suppression to the DTH response to parasite antigens. PMID:8750687

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

    NASA Astrophysics Data System (ADS)

    Viswanathan, Kavitha; Dhabhar, Firdaus S.

    2005-04-01

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

  13. A recombinant pseudotyped lentivirus expressing the envelope glycoprotein of Hantaan virus induced protective immunity in mice

    PubMed Central

    2013-01-01

    Background Hantaviruses cause acute hemorrhagic fever with renal syndrome (HFRS). Currently, several types of inactivated HFRS vaccines are widely used, however the limited ability of these immunogen to elicit neutralizing antibodies restricts vaccine efficacy. Development of an effective vaccine to overcome this weakness is must. Methods In the present study, a recombinant pseudotyped lentivirus bearing the hantaan virus (HTNV) envelope glycoproteins (GP), rLV-M, was constructed. C57BL/6 mice were immunized with the rLV-M and a series of immunological assays were conducted to determine the immunogenicity of the recombinant pseudotyped lentivirus. The humoral and cell-mediated immune responses induced by rLV-M were compared with those of the inactivated HFRS vaccine. Results Indirect immunofluorescence assay (IFA) showed the rLV-M expressed target proteins in HEK-293cells. In mice, the rLV-M efficiently induced GP-specific humoral responses and protection against HTNV infection. Furthermore, the rLV-M induced higher neutralizing antibody titers than the inactivated HFRS vaccine control. Conclusions The results indicated the potential of using a pseudotyped lentivirus as a delivery vector for a hantavirus vaccine immunogen. PMID:24093752

  14. Composition of the Surface Proteome of Anaplasma marginale and Its Role in Protective Immunity Induced by Outer Membrane Immunization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Surface proteins of tick-borne, intracellular bacterial pathogens mediate functions essential for invasion and colonization. Consequently, the surface proteome of these organisms is specifically relevant from two biological perspectives, induction of protective immunity in the mammalian host and un...

  15. Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats

    NASA Astrophysics Data System (ADS)

    Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

    2014-02-01

    Hypobaric hypoxia (HH) induces oxidative stress (OS) and is associated with the generation of reactive oxygen species (ROS). Vitamin C is an efficient antioxidant, and it is used in a high-altitude environment to reduce the OS. The present study explores the role of vitamin C on some HH-induced changes of immune parameters in rats which were exposed to HHc condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days with and without vitamin C administration at three different doses (200, 400, and 600 mg/kg body wt). The phagocytic activity of circulating blood WBC was increased, and the cytotoxic activity of splenic mononuclear cell (MNC) and the delayed type of hypersensitivity (DTH) responses to bovine serum albumin (BSA) were decreased in rats exposed to HHc condition, but these immune changes were blocked after administration of vitamin C at 400 mg/kg body wt. The leukocyte adhesive inhibition index (LAI) was not altered either in HHc condition or after administration of vitamin C in HHc condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HHc condition which was blocked after administration of vitamin C (400 mg/kg body wt). The immune parameters and serum CORT concentration, however, did not show any recovery after administration of vitamin C at the dose of 200 and 600 mg/kg body wt. The present study indicates that administration of vitamin C at a dose of 400 mg/kg body wt may prevent the HH-induced immunological changes but not at the lower dose (200 mg/kg body wt) or higher dose (600 mg/kg body wt) in rats.

  16. Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats.

    PubMed

    Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

    2014-11-01

    Hypobaric hypoxia (HH) induces oxidative stress (OS) and is associated with the generation of reactive oxygen species (ROS). Vitamin C is an efficient antioxidant, and it is used in a high-altitude environment to reduce the OS. The present study explores the role of vitamin C on some HH-induced changes of immune parameters in rats which were exposed to HHc condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days with and without vitamin C administration at three different doses (200, 400, and 600 mg/kg body wt). The phagocytic activity of circulating blood WBC was increased, and the cytotoxic activity of splenic mononuclear cell (MNC) and the delayed type of hypersensitivity (DTH) responses to bovine serum albumin (BSA) were decreased in rats exposed to HHc condition, but these immune changes were blocked after administration of vitamin C at 400 mg/kg body wt. The leukocyte adhesive inhibition index (LAI) was not altered either in HHc condition or after administration of vitamin C in HHc condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HHc condition which was blocked after administration of vitamin C (400 mg/kg body wt). The immune parameters and serum CORT concentration, however, did not show any recovery after administration of vitamin C at the dose of 200 and 600 mg/kg body wt. The present study indicates that administration of vitamin C at a dose of 400 mg/kg body wt may prevent the HH-induced immunological changes but not at the lower dose (200 mg/kg body wt) or higher dose (600 mg/kg body wt) in rats. PMID:24562878

  17. Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity.

    PubMed

    Kudo-Saito, Chie; Fuwa, Takafumi; Kawakami, Yutaka

    2016-07-01

    Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM(+) cells including CD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derived suppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM(+) cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8(+) T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM(+) cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer. PMID:27208904

  18. The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance.

    PubMed

    Dougherty, P M; Harper, C; Dafny, N

    1986-12-01

    An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids. PMID:3784774

  19. Compositional analysis of grain and forage from MON 87427, an inducible male sterile and tissue selective glyphosate-tolerant maize product for hybrid seed production.

    PubMed

    Venkatesh, Tyamagondlu V; Breeze, Matthew L; Liu, Kang; Harrigan, George G; Culler, Angela H

    2014-02-26

    Conventional maize hybrid seed production has historically relied upon detasseling using either manual methods or semiautomated processes to ensure the purity of the hybrid cross. Monsanto Co. has developed biotechnology-derived MON 87427 maize with tissue-selective glyphosate tolerance to facilitate the production of hybrid maize seed. MON 87427 utilizes a specific promoter and intron combination to drive expression of CP4 EPSPS protein in vegetative and female reproductive tissues, conferring tolerance to glyphosate. This specific combination of regulatory elements also results in limited or no production of CP4 EPSPS protein in two key male reproductive tissues: pollen microspores, which develop into pollen grains, and tapetum cells that supply nutrients to the pollen. Thus, MON 87427 induces a male sterile phenotype after appropriately timed glyphosate applications. To confer additional benefits of herbicide tolerance and/or insect resistance, MON 87427 was combined with MON 89034 and NK603 by conventional breeding to develop MON 87427 × MON 89034 × NK603. The work described here is an assessment of the nutrient, antinutrient, and secondary metabolite levels in grain and forage tissues of MON 87427 and MON 87427 × MON 89034 × NK603. Results demonstrated that MON 87427 is compositionally equivalent to a near-isogenic conventional comparator. Results from this analysis established that the compositional equivalence observed for the single-event product MON 87427 is extendable to the combined-trait product, MON 87427 × MON 89034 × NK603. With increasing global demand for food production, the development of more efficient seed production strategies is important to sustainable agriculture. The study reported here demonstrated that biotechnology can be applied to simplify hybrid maize seed production without affecting crop composition. PMID:24397242

  20. Evidence against the existence of specific Schistosoma mansoni subpopulations which are resistant to irradiated vaccine-induced immunity

    SciTech Connect

    Lewis, F.A.; Hieny, S.; Sher, A.

    1985-01-01

    When mice are immunized with irradiated Schistosoma mansoni cercariae a proportion of the subsequent cercarial challenge always escapes killing and matures to egg-laying adults. This report investigates the possibility that incomplete immunity in this system is governed by a genetically-determined insusceptibility of a particular schistosome subpopulation. To do this the authors tested whether more immunoresistant schistosomes would develop following successive passages of progeny of the resistant worms through immunized mice. Mice were immunized with 500 50 Krad-irradiated cercariae, and challenged with normal cercariae when immunity was at its peak. After five successive passages through snails and immune mice, progeny of those parasites which escaped immune killing were no more refractory to vaccine-induced resistance than the original stock maintained in nonimmune mice. Additionally, the passaged isolates did not differ from the original stock in their ability to induce protection following irradiation. The results indicate that with this model of acquired resistance incomplete immunity is unlikely to be due to a subpopulation of the parasites possessing a genetically-determined insusceptibility to killing.

  1. Neutron-induced latch-up immunity in metal gate CMOS integrated circuits

    SciTech Connect

    Barnes, C.E.; Rollins, J.G.; Hachey, D.

    1987-12-01

    Neutron-induced latch-up immunity has been studied in metal gate CMOS integrated circuits as a function of neutron fluence by measuring both the current gain products (beta product) of parasitic NPN and PNP transistors, and the flash x-ray latch-up thresholds prior to and following irradiation and subsequent stabilization anneal. Correlations between the actual latch-up thresholds and the measured beta products are established for the three part types investigated. These correlations indicate that the measurement of beta products on judiciously chosen parasitic transistors is a viable technique for estimating latch-up susceptibility when the observed margin is substantial.

  2. Aerosol Vaccination Induces Robust Protective Immunity to Homologous and Heterologous Influenza Infection in Mice

    PubMed Central

    Smith, Jennifer Humberd; Brooks, Paula; Johnson, Scott; Tompkins, S. Mark; Custer, Koren M.; Haas, Debra L.; Mair, Raydel; Papania, Mark; Tripp, Ralph A.

    2011-01-01

    Live-attenuated influenza vaccine (LAIV) delivered by large droplet intranasal spray is efficacious against infection. However, many of the large droplets are trapped in the external nares and do not reach the target nasal airway tissues. Smaller droplets might provide better distribution yielding similar protection with lower doses. We evaluated 20 and 30 micron aerosol delivery of influenza virus in mice. A 15 second aerosol exposure optimally protected against homologous and heterologous influenza infection and induced a robust immune response. These results demonstrate the feasibility of nasal vaccination using aerosolized particles, providing a strategy to improve vaccine efficacy and delivery. PMID:21300100

  3. Passive adoptive transfer of antitumor immunity induced by laser-dye-immunoadjuvant treatment in a rat metastatic breast cancer model

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Singhal, Anil K.; Nordquist, Robert E.

    2000-06-01

    The ideal cancer treatment modalities should not only cause tumor regression and eradication but also induce a systemic anti-tumor immunity. This is essential for control of metastatic tumors and for long-term tumor resistance. Laser immunotherapy using a laser, a laser-absorbing dye and an immunoadjuvant has induced such a long-term immunity in treatment of a mammary metastatic tumor. The successfully treated rats established total resistance to multiple subsequent tumor challenges. For further mechanistic studies of the antitumor immunity induced by this novel treatment modality, passive adoptive transfer was performed using splenocytes as immune cells. The spleen cells harvested from successfully treated tumor-bearing rats provided 100% immunity in the naive recipients. The passively protected first cohort rats were immune to tumor challenge with an increased tumor dose; their splenocytes also prevented the establishment of tumor in the second cohort of naive recipient rats. This immunity transfer was accomplished without the usually required T-cell suppression in recipients.

  4. A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract.

    PubMed

    Ruane, D; Do, Y; Brane, L; Garg, A; Bozzacco, L; Kraus, T; Caskey, M; Salazar, A; Trumpheller, C; Mehandru, S

    2016-09-01

    Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4(+) T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4(+) T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4(+) and CD8(+) T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections. PMID:26732678

  5. Identification of molecular markers linked to a new nuclear male-sterility gene ms7 in sunflower (Helianthus annuus L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear male sterility (NMS) is an important alternative system to the cytoplasm male sterility (CMS) in hybrid breeding programs because of its stable male sterility and abundant available restorer resources. For sunflower (Helianthus annuus L.), NMS 89-552, a nuclear male-sterile mutant induced by...

  6. Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic

    PubMed Central

    Pelte, Nadège; Robertson, Andrew S.; Zou, Zhen; Belorgey, Didier; Dafforn, Timothy R.; Jiang, Haobo; Lomas, David; Reichhart, Jean-Marc; Gubb, David

    2007-01-01

    The Drosophila Necrotic protein is a serine proteinase inhibitor, which regulates the Toll-mediated innate immune response. Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle. Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure. We show here that cleavage of this N-terminal extension occurs following immune challenge. This modification is blocked in PGRP-SAsemmelweiss mutants after Gram-positive bacterial challenge and in persephone mutants after fungal or Gram-positive bacterial challenge, indicating that activation of either of the Toll pathway upstream branches induces N-terminal cleavage of the serpin. The absolute requirement of persephone gene product for this cleavage indicates that Gram-positive bacteria activate a redundant set of proteinases upstream of Toll. Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases. We found a 13-fold increase in the specificity of the core serpin over that of full-length Necrotic for one of the tested proteinases (porcine pancreatic elastase). This finding indicates that cleavage of the Necrotic amino-terminal extension might modulate Toll activation following the initial immune response. PMID:16360948

  7. Disruption of Rpp1-mediated soybean rust immunity by virus-induced gene silencing

    PubMed Central

    Cooper, Bret; Campbell, Kimberly B; McMahon, Michael B; Luster, Douglas G

    2013-01-01

    Phakopsora pachyrhizi, a fungus that causes rust disease on soybean, has potential to impart significant yield loss and disrupt food security and animal feed production. Rpp1 is a soybean gene that confers immunity to soybean rust, and it is important to understand how it regulates the soybean defense system and to use this knowledge to protect commercial crops. It was previously discovered that some soybean proteins resembling transcription factors accumulate in the nucleus of Rpp1 soybeans. To determine if they contribute to immunity, Bean pod mottle virus was used to attenuate or silence the expression of their genes. Rpp1 plants subjected to virus-induced gene silencing exhibited reduced amounts of RNA for 5 of the tested genes, and the plants developed rust-like symptoms after subsequent inoculation with fungal spores. Symptoms were associated with the accumulation of rust fungal RNA and protein. Silenced plants also had reduced amounts of RNA for the soybean Myb84 transcription factor and soybean isoflavone O-methyltransferase, both of which are important to phenylpropanoid biosynthesis and lignin formation, crucial components of rust resistance. These results help resolve some of the genes that contribute to Rpp1-mediated immunity and improve upon the knowledge of the soybean defense system. It is possible that these genes could be manipulated to enhance rust resistance in otherwise susceptible soybean cultivars. PMID:24401541

  8. Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

    PubMed Central

    McGray, A J Robert; Hallett, Robin; Bernard, Dannie; Swift, Stephanie L; Zhu, Ziqiang; Teoderascu, Florentina; VanSeggelen, Heather; Hassell, John A; Hurwitz, Arthur A; Wan, Yonghong; Bramson, Jonathan L

    2014-01-01

    Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. PMID:24196579

  9. Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis

    PubMed Central

    Khounlotham, Manirath; Kim, Wooki; Peatman, Eric; Nava, Porfirio; Medina-Contreras, Oscar; Addis, Caroline; Koch, Stefan; Fournier, Benedicte; Nusrat, Asma; Denning, Timothy L.; Parkos, Charles A.

    2012-01-01

    SUMMARY Mice lacking Junctional Adhesion Molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r-/-Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury induced colitis. These data establish a role for adaptive immune mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise. PMID:22981539

  10. Borrelia burgdorferi clinical isolates induce human innate immune responses that are not dependent on genotype.

    PubMed

    Mason, Lauren M K; Herkes, Eduard A; Krupna-Gaylord, Michelle A; Oei, Anneke; van der Poll, Tom; Wormser, Gary P; Schwartz, Ira; Petzke, Mary M; Hovius, Joppe W R

    2015-10-01

    Borrelia burgdorferi can be categorized based on restriction fragment length polymorphism analysis into ribosomal spacer type (RST) 1, 2 and 3. A correlation between RST type and invasiveness of Borrelia isolates has been demonstrated in clinical studies and experimental models, and RST 1 isolates are more likely to cause disseminated disease than RST 3 isolates. We hypothesized that this could partially be due to increased susceptibility of RST 3 isolates to killing by the innate immune system early in infection. Thus, we investigated the interaction of five RST 1 and five RST 3 isolates with various components of the human innate immune system in vitro. RST 3 isolates induced significantly greater upregulation of activation markers in monocyte-derived dendritic cells compared to RST 1 isolates at a low multiplicity of infection. However, RST 1 isolates stimulated greater interleukin-6 production. At a high multiplicity of infection no differences in dendritic cell activation or cytokine production were observed. In addition, we observed no differences in the ability of RST 1 and RST 3 isolates to activate monocytes or neutrophils and all strains were phagocytosed at a comparable rate. Finally, all isolates tested were equally resistant to complement-mediated killing, as determined by dark-field microscopy and a growth inhibition assay. In conclusion, we demonstrate that the RST 1 and 3 isolates showed no distinction in their susceptibility to the various components of the human immune system studied here, suggesting that other factors are responsible for their differential invasiveness. PMID:26093919

  11. Yulangsan polysaccharide improves redox homeostasis and immune impairment in D-galactose-induced mimetic aging.

    PubMed

    Doan, Van Minh; Chen, Chunxia; Lin, Xing; Nguyen, Van Phuc; Nong, Zhihuan; Li, Weisi; Chen, Qingquan; Ming, Jianjun; Xie, Qiuqiao; Huang, Renbin

    2015-05-01

    Yulangsan polysaccharide (YLSP) is a traditional Chinese medicine used in long-term treatment as a modulator of brain dysfunction and immunity. In this study, we evaluated the protective effect of YLSP against D-galactose-induced impairment of oxidative stress and the immune system and evaluated its possible mechanism of action. D-galactose was subcutaneously injected into the dorsal neck of mice daily for 8 weeks to establish the aging model. YLSP was simultaneously administered once daily. The results indicate that YLSP significantly improves the general appearance of the aging mice. YLSP significantly increased the levels of antioxidant enzymes, such as super oxide dismutase, glutathione peroxidase, catalase and total anti-oxidation capability, while decreasing the content of malondialdehyde in different tissues, including the liver, brain, and serum. YLSP also increased the interleukin-2 level while decreasing the interleukin-6 level. Moreover, YLSP significantly inhibited advanced glycation end product formation. Furthermore, YLSP decreased p21 and p53 gene expressions in the liver and brain of D-galactose-treated mice. These results suggest that YLSP may have a protective effect suppressing the aging process by enhancing antioxidant activity and immunity, as well as modulating aging-related gene expression. PMID:25920068

  12. Cyclosporine-induced immune suppression alters establishment of HTLV-1 infection in a rabbit model

    PubMed Central

    Haynes, Rashade A. H.; Ware, Evan; Premanandan, Christopher; Zimmerman, Bevin; Yu, Lianbo; Phipps, Andrew J.

    2010-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia and several lymphocyte-mediated inflammatory diseases. Persistent HTLV-1 infection is determined by a balance between host immune responses and virus spread. Immunomodulatory therapy involving HTLV-1–infected patients occurs in a variety of clinical settings. Knowledge of how these treatments influence host-virus relationships is not understood. In this study, we examined the effects of cyclosporine A (CsA)–induced immune suppression during early infection of HTLV-1. Twenty-four New Zealand white rabbits were split into 4 groups. Three groups were treated with either 10 or 20 mg/kg CsA or saline before infection. The fourth group was treated with 20 mg/kg CsA 1 week after infection. Immune suppression, plasma CsA concentration, ex vivo lymphocyte HTLV-1 p19 production, anti–HTLV-1 serologic responses, and proviral load levels were measured during infection. Our data indicated that CsA treatment before HTLV-1 infection enhanced early viral expression compared with untreated HTLV-1–infected rabbits, and altered long-term viral expression parameters. However, CsA treatment 1 week after infection diminished HTLV-1 expression throughout the 10-week study course. Collectively, these data indicate immunologic control is a key determinant of early HTLV-1 spread and have important implications for therapeutic intervention during HTLV-1–associated diseases. PMID:19965683

  13. Immunotherapy-induced CD8+ T cells instigate immune suppression in the tumor.

    PubMed

    McGray, A J Robert; Hallett, Robin; Bernard, Dannie; Swift, Stephanie L; Zhu, Ziqiang; Teoderascu, Florentina; Vanseggelen, Heather; Hassell, John A; Hurwitz, Arthur A; Wan, Yonghong; Bramson, Jonathan L

    2014-01-01

    Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. PMID:24196579

  14. Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

    NASA Astrophysics Data System (ADS)

    Hu, Zhenlin; Yang, Xiao Yi; Liu, Yunbo; Morse, Michael A.; Lyerly, H. Kim; Clay, Timothy M.; Zhong, Pei

    2006-05-01

    To determine whether HIFU treatment can elicit a systemic, anti-tumor immune response in vivo, MC-38 solid tumors grown subcutaneously at the right hindlimbs of C57BL/6 mice were treated in an experimental HIFU system. Three different treatment strategies that produce thermal, mechanical, or thermal combined with mechanical damage to the tumor tissue were evaluated. To detect anti-tumor immune response, a tumor challenge was performed on the left hindlimbs of the mice one day following the HIFU treatment, and subsequently, cytotoxic T lymphocyte (CTL) response was evaluated on day 14. All three HIFU treatment strategies were found to cause significant regression of the primary tumor, with the best suppressive effect produced by the thermal HIFU. In contrast, the most significant regression of the challenged tumor with concomitantly elevated CTL response were detected in mice treated by the mechanical HIFU, followed by the thermal combined with mechanical HIFU, but not in mice treated by the thermal HIFU alone. These findings suggest that alternative treatment strategies that promote mechanical lysis of the tumor cells (in contrast to purely thermal ablation) may enhance HIFU-induced anti-tumor immune response.

  15. Plasmodium berghei: immunosuppression of the cell-mediated immune response induced by nonviable antigenic preparations

    SciTech Connect

    Gross, A.; Frankenburg, S.

    1989-01-01

    In this work, plasmodial antigens were examined for their ability to suppress the cellular immune response during lethal Plasmodium berghei infection. Splenic enlargement and the number and function of white spleen cells were assessed after injection of normal mice with irradiated parasitized erythrocytes (IPE) or with parasitized erythrocytes (PE) membranes. Both IPE and PE membranes caused splenomegaly and an increase in the number of splenic white cells with concurrent alteration of the relative proportions of T cells and macrophages. The percentage of T lymphocytes was fractionally diminished, but there was a marked increase in Lyt 2.2 positive (suppressor and cytotoxic) T subsets and in the number of splenic macrophage precursors. The pathological enlargement of the spleen was induced by various plasma membrane-derived antigens containing both proteins and carbohydrates. Splenocytes of mice injected with liposomes containing deoxycholate-treated PE or PE fractions showed both diminished interleukin 2 production and a decreased response to mitogen. It appears that some of the changes in the cellular immune response during P. berghei infection are a consequence of the massive provision of a wide spectrum of antigens, capable of suppressing the immune response. Thus, it may be appropriate to evaluate the possible negative effect of parasite epitopes that are candidates for vaccine.

  16. Female Sterilization (Tubal Ligation)

    MedlinePlus

    ... when you want to have it done. Some women are sterilized right after they have a baby or an abortion, ... videos on Youtube © 1998-2016 | Center for Young Women's Health, Boston Children's Hospital. All rights reserved.

  17. Sterilization of space hardware.

    NASA Technical Reports Server (NTRS)

    Pflug, I. J.

    1971-01-01

    Discussion of various techniques of sterilization of space flight hardware using either destructive heating or the action of chemicals. Factors considered in the dry-heat destruction of microorganisms include the effects of microbial water content, temperature, the physicochemical properties of the microorganism and adjacent support, and nature of the surrounding gas atmosphere. Dry-heat destruction rates of microorganisms on the surface, between mated surface areas, or buried in the solid material of space vehicle hardware are reviewed, along with alternative dry-heat sterilization cycles, thermodynamic considerations, and considerations of final sterilization-process design. Discussed sterilization chemicals include ethylene oxide, formaldehyde, methyl bromide, dimethyl sulfoxide, peracetic acid, and beta-propiolactone.

  18. Sand fly salivary proteins induce strong cellular immunity in a natural reservoir of visceral leishmaniasis with adverse consequences for Leishmania.

    PubMed

    Collin, Nicolas; Gomes, Regis; Teixeira, Clarissa; Cheng, Lily; Laughinghouse, Andre; Ward, Jerrold M; Elnaiem, Dia-Eldin; Fischer, Laurent; Valenzuela, Jesus G; Kamhawi, Shaden

    2009-05-01

    Immunity to a sand fly salivary protein protects against visceral leishmaniasis (VL) in hamsters. This protection was associated with the development of cellular immunity in the form of a delayed-type hypersensitivity response and the presence of IFN-gamma at the site of sand fly bites. To date, there are no data available regarding the cellular immune response to sand fly saliva in dogs, the main reservoirs of VL in Latin America, and its role in protection from this fatal disease. Two of 35 salivary proteins from the vector sand fly Lutzomyia longipalpis, identified using a novel approach termed reverse antigen screening, elicited strong cellular immunity in dogs. Immunization with either molecule induced high IgG(2) antibody levels and significant IFN-gamma production following in vitro stimulation of PBMC with salivary gland homogenate (SGH). Upon challenge with uninfected or infected flies, immunized dogs developed a cellular response at the bite site characterized by lymphocytic infiltration and IFN-gamma and IL-12 expression. Additionally, SGH-stimulated lymphocytes from immunized dogs efficiently killed Leishmania infantum chagasi within autologous macrophages. Certain sand fly salivary proteins are potent immunogens obligatorily co-deposited with Leishmania parasites during transmission. Their inclusion in an anti-Leishmania vaccine would exploit anti-saliva immunity following an infective sand fly bite and set the stage for a protective anti-Leishmania immune response. PMID:19461875

  19. Sterilization: A Review and Update.

    PubMed

    Moss, Chailee; Isley, Michelle M

    2015-12-01

    Sterilization is a frequently used method of contraception. Female sterilization is performed 3 times more frequently than male sterilization, and it can be performed immediately postpartum or as an interval procedure. Methods include mechanical occlusion, coagulation, or tubal excision. Female sterilization can be performed using an abdominal approach, or via laparoscopy or hysteroscopy. When an abdominal approach or laparoscopy is used, sterilization occurs immediately. When hysteroscopy is used, tubal occlusion occurs over time, and additional testing is needed to confirm tubal occlusion. Comprehensive counseling about sterilization should include discussion about male sterilization (vasectomy) and long-acting reversible contraceptive methods. PMID:26598311

  20. Auditing radiation sterilization facilities

    NASA Astrophysics Data System (ADS)

    Beck, Jeffrey A.

    The diversity of radiation sterilization systems available today places renewed emphasis on the need for thorough Quality Assurance audits of these facilities. Evaluating compliance with Good Manufacturing Practices is an obvious requirement, but an effective audit must also evaluate installation and performance qualification programs (validation_, and process control and monitoring procedures in detail. The present paper describes general standards that radiation sterilization operations should meet in each of these key areas, and provides basic guidance for conducting QA audits of these facilities.

  1. Investigating the Role for IL-21 in Rabies Virus Vaccine-induced Immunity

    PubMed Central

    Dorfmeier, Corin L.; Tzvetkov, Evgeni P.; Gatt, Anthony; McGettigan, James P.

    2013-01-01

    Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R−/−) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R−/− mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R−/− mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R−/− mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of

  2. Investigating the role for IL-21 in rabies virus vaccine-induced immunity.

    PubMed

    Dorfmeier, Corin L; Tzvetkov, Evgeni P; Gatt, Anthony; McGettigan, James P

    2013-01-01

    Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R-/-) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R-/- mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R-/- mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R-/- mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of optimal vaccine-induced

  3. Degradation of chitosan-based materials after different sterilization treatments

    NASA Astrophysics Data System (ADS)

    San Juan, A.; Montembault, A.; Gillet, D.; Say, J. P.; Rouif, S.; Bouet, T.; Royaud, I.; David, L.

    2012-02-01

    Biopolymers have received in recent years an increasing interest for their potential applications in the field of biomedical engineering. Among the natural polymers that have been experimented, chitosan is probably the most promising in view of its exceptional biological properties. Several techniques may be employed to sterilize chitosan-based materials. The aim of our study was to compare the effect of common sterilization treatments on the degradation of chitosan-based materials in various physical states: solutions, hydrogels and solid flakes. Four sterilization methods were compared: gamma irradiation, beta irradiation, exposure to ethylene oxide and saturated water steam sterilization (autoclaving). Exposure to gamma or beta irradiation was shown to induce an important degradation of chitosan, regardless of its physical state. The chemical structure of chitosan flakes was preserved after ethylene oxide sterilization, but this technique has a limited use for materials in the dry state. Saturated water steam sterilization of chitosan solutions led to an important depolymerization. Nevertheless, steam sterilization of chitosan flakes bagged or dispersed in water was found to preserve better the molecular weight of the polymer. Hence, the sterilization of chitosan flakes dispersed in water would represent an alternative step for the preparation of sterilized chitosan solutions. Alternatively, autoclaving chitosan physical hydrogels did not significantly modify the macromolecular structure of the polymer. Thus, this method is one of the most convenient procedures for the sterilization of physical chitosan hydrogels after their preparation.

  4. Cross-stage immunity for malaria vaccine development.

    PubMed

    Nahrendorf, Wiebke; Scholzen, Anja; Sauerwein, Robert W; Langhorne, Jean

    2015-12-22

    A vaccine against malaria is urgently needed for control and eventual eradication. Different approaches are pursued to induce either sterile immunity directed against pre-erythrocytic parasites or to mimic naturally acquired immunity by controlling blood-stage parasite densities and disease severity. Pre-erythrocytic and blood-stage malaria vaccines are often seen as opposing tactics, but it is likely that they have to be combined into a multi-stage malaria vaccine to be optimally safe and effective. Since many antigenic targets are shared between liver- and blood-stage parasites, malaria vaccines have the potential to elicit cross-stage protection with immune mechanisms against both stages complementing and enhancing each other. Here we discuss evidence from pre-erythrocytic and blood-stage subunit and whole parasite vaccination approaches that show that protection against malaria is not necessarily stage-specific. Parasites arresting at late liver-stages especially, can induce powerful blood-stage immunity, and similarly exposure to blood-stage parasites can afford pre-erythrocytic immunity. The incorporation of a blood-stage component into a multi-stage malaria vaccine would hence not only combat breakthrough infections in the blood should the pre-erythrocytic component fail to induce sterile protection, but would also actively enhance the pre-erythrocytic potency of this vaccine. We therefore advocate that future studies should concentrate on the identification of cross-stage protective malaria antigens, which can empower multi-stage malaria vaccine development. PMID:26469724

  5. Mechanism study of tumor-specific immune responses induced by laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

  6. DC targeting DNA vaccines induce protective and therapeutic antitumor immunity in mice

    PubMed Central

    Wang, Qun; Cao, Wei; Yang, Zhi-Gang; Zhao, Guang-Fa

    2015-01-01

    Background: Anti-CD11c antibodies target to the CD11c receptor that mediates antigen presentation to T cells by dendritic cells (DCs). To exploit these properties for immunization purposes, we obtained DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from N418 (scFvN418), a monoclonal antibody binding the mouse DC-restricted surface molecule CD11c, and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models. Methods: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in transplantable HER2/neu-expressing murine tumor models and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas. Results: Upon injection of the breast tumor cell line D2F2/E2 (stably expressing human wild-type HER2), scFvN418-HER2 immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted D2F2/E2 cells by injection of scFvN418-HER2 conjugates into tumor bearing hosts. The existing tumors were eradicated by treatment with scFvN418-HER2 combined with low-dose cyclophosphamide (CTX), which can make a temporary regulatory T cells (Treg) depletion. What’s more, in combination with the low-dose CTX, vaccination with scFvN418-neu significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice. Conclusion: Our results show that DNA vaccine which targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity. PMID:26770347

  7. Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells

    PubMed Central

    Aldhamen, Yasser A.; Pepelyayeva, Yuliya; Rastall, David P.W.; Seregin, Sergey S.; Zervoudi, Efthalia; Koumantou, Despoina; Aylsworth, Charles F.; Quiroga, Dionisia; Godbehere, Sarah; Georgiadis, Dimitris; Stratikos, Efstratios; Amalfitano, Andrea

    2015-01-01

    ERAP1 gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we have demonstrated that ERAP1 regulates key aspects of the innate immune response. Moreover, previous studies show ERAP1 to be ER-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating innate immune responses of human PBMCs using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 inflammasome. Importantly, these responses varied if autoimmune-disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases. PMID:25591727

  8. Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.

    PubMed

    Aldhamen, Yasser A; Pepelyayeva, Yuliya; Rastall, David P W; Seregin, Sergey S; Zervoudi, Efthalia; Koumantou, Despoina; Aylsworth, Charles F; Quiroga, Dionisia; Godbehere, Sarah; Georgiadis, Dimitris; Stratikos, Efstratios; Amalfitano, Andrea

    2015-01-01

    Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad5 vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 (NOD-like receptor, pyrin domain-containing 3) inflammasome. Importantly, these responses varied if autoimmune disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases. PMID:25591727

  9. Hysteroscopic Tubal Sterilization

    PubMed Central

    McMartin, K

    2013-01-01

    Background Hysteroscopic tubal sterilization is a minimally invasive alternative to laparoscopic tubal ligation for women who want permanent contraception. The procedures involves non-surgical placement of permanent microinserts into both fallopian tubes. Patients must use alternative contraception for at least 3 months postprocedure until tubal occlusion is confirmed. Compared to tubal ligation, potential advantages of the hysteroscopic procedure are that it can be performed in 10 minutes in an office setting without the use of general or even local anesthesia. Objective The objective of this analysis was to determine the effectiveness and safety of hysteroscopic tubal sterilization compared with tubal ligation for permanent female sterilization. Data Sources A standard systematic literature search was conducted for studies published from January 1, 2008, until December 11, 2012. Review Methods Observational studies, randomized controlled trials (RCTs), systematic reviews and meta-analyses with 1 month or more of follow-up were examined. Outcomes included failure/pregnancy rates, adverse events, and patient satisfaction. Results No RCTs were identified. Two systematic reviews covered 22 observational studies of hysteroscopic sterilization. Only 1 (N = 93) of these 22 studies compared hysteroscopic sterilization to laparoscopic tubal ligation. Two other noncomparative case series not included in the systematic reviews were also identified. In the absence of comparative studies, data on tubal ligation were derived for this analysis from the CREST study, a large, multicentre, prospective, noncomparative observational study in the United States (GRADE low). Overall, hysteroscopic sterilization is associated with lower pregnancy rates and lower complication rates compared to tubal ligation. No deaths have been reported for hysteroscopic sterilization. Limitations A lack of long-term follow-up for hysteroscopic sterilization and a paucity of studies that directly

  10. Imperfect vaccine-induced immunity and whooping cough transmission to infants

    PubMed Central

    Broutin, Hélène; Harvill, Eric T.; Bjørnstad, Ottar N.

    2010-01-01

    Whooping cough, caused by B. pertussis and B. parapertussis, has increased in incidence throughout much of the developed world since the 1980s despite high vaccine coverage, causing an increased risk of infection in infants who have substantial disease-induced mortality. Duration of immunity and epidemically significant routes of transmission across age groups remain unclear and deserve further investigation to inform vaccination strategies to better control pertussis burden. The authors analyze age- and species-specific whooping cough tests and vaccine histories in Massachusetts from 1990–2008. On average, the disease-free duration is 10.5 years. However, it has been decreasing over time, possibly due to a rising force of infection through increased circulation. Despite the importance of teenage cases during epidemics, wavelet analyses suggest that they are not the most important source of transmission to infants. In addition, the data indicate that the B. pertussis vaccine is not protective against disease induced by B. parapertussis. PMID:21034823

  11. Imperfect vaccine-induced immunity and whooping cough transmission to infants.

    PubMed

    Lavine, Jennie; Broutin, Hélène; Harvill, Eric T; Bjørnstad, Ottar N

    2010-12-10

    Whooping cough, caused by B. pertussis and B. parapertussis, has increased in incidence throughout much of the developed world since the 1980s despite high vaccine coverage, causing an increased risk of infection in infants who have substantial disease-induced mortality. Duration of immunity and epidemically significant routes of transmission across age groups remain unclear and deserve further investigation to inform vaccination strategies to better control pertussis burden. The authors analyze age- and species-specific whooping cough tests and vaccine histories in Massachusetts from 1990 to 2008. On average, the disease-free duration is 10.5 years. However, it has been decreasing over time, possibly due to a rising force of infection through increased circulation. Despite the importance of teenage cases during epidemics, wavelet analyses suggest that they are not the most important source of transmission to infants. In addition, the data indicate that the B. pertussis vaccine is not protective against disease induced by B. parapertussis. PMID:21034823

  12. Immunization of mice with Trypanosoma rhodesiense exposed to ultraviolet irradiation

    SciTech Connect

    Charoenvit, Y.; Campbell, G.H.

    1981-11-01

    Exposure time of Trypanosoma rhodesiense as short as 1 minute to ultraviolet (uv) light prevents the organisms from causing infection. Live trypanosome challenge of mice immunized with uv-irradiated trypanosomes results in sterile immunity. This allows a method for the induction of protective immunity to experimental trypanosomiasis which can be performed in most laboratories using uv germicidal lamps found in sterile hoods.

  13. Multi-therapeutic potential of autoantibodies induced by immune complexes trapped on follicular dendritic cells

    PubMed Central

    El Shikh, Mohey Eldin; Kmieciak, Maciej; Manjili, Masoud H; Szakal, Andras K; Pitzalis, Costantino; Tew, John G

    2013-01-01

    Induction of autoantibodies (autoAbs) targeting disease drivers / mediators is emerging as a potential immunotherapeutic strategy. Auto-immune complex (IC)-retaining follicular dendritic cells (FDCs) critically regulate pathogenic autoAb production in autoreactive germinal centers (GCs); however, their ability to induce potentially therapeutic autoAbs has not been explored. We hypothesized that deliberate display of clinically targeted antigens (Ags) in the form of ICs on FDC membranes induces target-specific autoreactive GCs and autoAbs that may be exploited therapeutically. To test our hypothesis, three therapeutically relevant Ags: TNF-α, HER2/neu and IgE, were investigated. Our results indicated that TNF-α-, HER2/neu- and IgE-specific autoAbs associated with strong GC reactions were induced by TNF-α-, HER2/neu- and IgE-IC retention on FDCs. Moreover, the induced anti-TNF-α autoAbs neutralized mouse and human TNF-α with half maximal Inhibitory Concentration (IC50) of 7.1 and 1.6 nM respectively. In addition, we demonstrated that FDC-induced Ab production could be non-specifically inhibited by the IgG-specific Endo-S that accessed the light zones of GCs and interfered with FDC-IC retention. In conclusion, the ability of FDCs to productively present autoAgs raises the potential for a novel immunotherapeutic platform targeting mediators of autoimmune disorders, allergic diseases, and Ab responsive cancers. PMID:23836278

  14. Immune/Inflammatory Response and Hypocontractility of Rabbit Colonic Smooth Muscle After TNBS-Induced Colitis

    PubMed Central

    Zhang, Yonggang; Li, Fang; Wang, Hong; Yin, Chaoran; Huang, JieAn; Mahavadi, Sunila; Murthy, Karnam S.

    2016-01-01

    Background The contractility of colonic smooth muscle is dysregulated due to immune/inflammatory responses in inflammatory bowel diseases. Inflammation in vitro induces up-regulation of regulator of G-protein signaling 4 (RGS4) expression in colonic smooth muscle cells. Aims To characterize the immune/inflammatory responses and RGS4 expression pattern in colonic smooth muscle after induction of colitis. Methods Colitis was induced in rabbits by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Innate/adaptive immune response RT-qPCR array was performed using colonic circular muscle strips. At 1–9 weeks after colonic intramuscular microinjection of lentivirus, the distal and proximal colons were collected, and muscle strips and dispersed muscle cells were prepared from circular muscle layer. Expression levels of RGS4 and NFκB signaling components were determined by Western blot analysis. The biological consequences of RGS4 knockdown were assessed by measurement of muscle contraction and phospholipase C (PLC)-β activity in response to acetylcholine (ACh). Results Contraction in response to ACh was significantly inhibited in the inflamed colonic circular smooth muscle cells. RGS4, IL-1, IL-6, IL-8, CCL3, CD1D, and ITGB2 were significantly up-regulated, while IL-18, CXCR4, CD86, and C3 were significantly down-regulated in the inflamed muscle strips. RGS4 protein expression in the inflamed smooth muscles was dramatically increased. RGS4 stable knockdown in vivo augmented ACh-stimulated PLC-β activity and contraction in colonic smooth muscle cells. Conclusion Inflamed smooth muscle exhibits up-regulation of IL-1-related signaling components, Th1 cytokines and RGS4, and inhibition of contraction. Stable knockdown of endogenous RGS4 in colonic smooth muscle increases PLC-β activity and contractile responses. PMID:26879904

  15. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    SciTech Connect

    Miyata, Ryohei; Eeden, Stephan F. van

    2011-12-15

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}m or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  16. Atomic description of the immune complex involved in heparin-induced thrombocytopenia

    DOE PAGESBeta

    Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang; Rauova, Lubica; Hayes, Vincent; Lebedeva, Tatiana; Liu, Qun; Poncz, Mortimer; Arepally, Gowthami; Cines, Douglas B.; et al

    2015-09-22

    Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed’ end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open’ end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize’ the ternary pathogenic immune complex. Bindingmore » of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.« less

  17. Atomic description of the immune complex involved in heparin-induced thrombocytopenia

    PubMed Central

    Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang; Rauova, Lubica; Hayes, Vincent; Lebedeva, Tatiana; Liu, Qun; Poncz, Mortimer; Arepally, Gowthami; Cines, Douglas B.; Greene, Mark I.

    2015-01-01

    Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open' end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT. PMID:26391892

  18. Adenovirus vector-induced immune responses in nonhuman primates: responses to prime boost regimens1

    PubMed Central

    Tatsis, Nia; Lasaro, Marcio O.; Lin, Shih-Wen; Xiang, Zhi Q.; Zhou, Dongming; DiMenna, Lauren; Li, Hua; Bian, Ang; Abdulla, Sarah; Li, Yan; Giles-Davis, Wynetta; Engram, Jessica; Ratcliffe, Sarah J.; Silvestri, Guido; Ertl, Hildegund C.; Betts, Michael R.

    2009-01-01

    In the phase IIb STEP trial an HIV-1 vaccine based on adenovirus (Ad) vectors of the human serotype 5 (AdHu5) not only failed to induce protection but also increased susceptibility to HIV-1 infection in individuals with pre-existing neutralizing antibodies against AdHu5. The mechanisms underlying the increased HIV-1 acquisition rates have not yet been elucidated. Furthermore, it remains unclear if the lack of the vaccine's efficacy reflects a failure of the concept of T cell-mediated protection against HIV-1 or a product failure of the vaccine. Here we compared two vaccine regimens based on sequential use of AdHu5 vectors or two different chimpanzee derived Ad (AdC) vectors in rhesus macaques that were AdHu5 seropositive or seronegative at the onset of vaccination. Our results show that heterologous booster immunizations with the AdC vectors induced higher T and B cell responses than repeated immunizations with the AdHu5 vector especially in AdHu5-pre-exposed macaques. PMID:19414814

  19. Adenovirus vector-induced immune responses in nonhuman primates: responses to prime boost regimens.

    PubMed

    Tatsis, Nia; Lasaro, Marcio O; Lin, Shih-Wen; Haut, Larissa H; Xiang, Zhi Q; Zhou, Dongming; Dimenna, Lauren; Li, Hua; Bian, Ang; Abdulla, Sarah; Li, Yan; Giles-Davis, Wynetta; Engram, Jessica; Ratcliffe, Sarah J; Silvestri, Guido; Ertl, Hildegund C; Betts, Michael R

    2009-05-15

    In the phase IIb STEP trial an HIV-1 vaccine based on adenovirus (Ad) vectors of the human serotype 5 (AdHu5) not only failed to induce protection but also increased susceptibility to HIV-1 infection in individuals with preexisting neutralizing Abs against AdHu5. The mechanisms underlying the increased HIV-1 acquisition rates have not yet been elucidated. Furthermore, it remains unclear if the lack of the vaccine's efficacy reflects a failure of the concept of T cell-mediated protection against HIV-1 or a product failure of the vaccine. Here, we compared two vaccine regimens based on sequential use of AdHu5 vectors or two different chimpanzee-derived Ad vectors in rhesus macaques that were AdHu5 seropositive or seronegative at the onset of vaccination. Our results show that heterologous booster immunizations with the chimpanzee-derived Ad vectors induced higher T and B cell responses than did repeated immunizations with the AdHu5 vector, especially in AdHu5-preexposed macaques. PMID:19414814

  20. Toxoplasma gondii-induced immune suppression by human peripheral blood monocytes: role of gamma interferon.

    PubMed Central

    Channon, J Y; Kasper, L H

    1996-01-01

    The ability of Toxoplasma gondii to evade the host immune response during primary infection in humans is poorly understood. In murine toxoplasmosis, infected spleen macrophages release soluble factors that mediate a transient immunosuppression, which may allow the parasite to become established. When an enriched population of human monocytes from seronegative individuals was incubated with toxoplasmas in vitro, soluble factors that mediated market suppression of mitogen-induced lymphocyte DNA synthesis were released. Irradiated tachyzoites that do not undergo replication were sufficient stimuli for near-maximal soluble factor release. Up to 50% of the soluble factor-mediated suppression is attributable to a gamma interferon (IFN-gamma)-dependent pathway, and the mediator of the remaining inhibition is neither interleukin-10, transforming growth factor beta, prostaglandin E2, lipoxygenase products, nitric oxide, nor tumor necrosis factor alpha-induced mitochondrial cell-derived reactive oxygen intermediates. IFN-gamma also mediates the up-regulation of an antigen-presenting cell phenotype by both infected and uninfected macrophages. However, IFN-gamma does not activate macrophages to become toxoplasmacidal; instead, intracellular toxoplasmas replicate and reinfect, eventually lysing the macrophage population. These results suggest that T. gondii is able to evade the naive host immune response by induction of soluble immunosuppressive factors that allow the parasite to become established during an acute infection. PMID:8606076

  1. Adjuvants and immunization strategies to induce influenza virus hemagglutinin stalk antibodies.

    PubMed

    Goff, Peter H; Eggink, Dirk; Seibert, Christopher W; Hai, Rong; Martínez-Gil, Luis; Krammer, Florian; Palese, Peter

    2013-01-01

    The global population remains vulnerable in the face of the next pandemic influenza virus outbreak, and reformulated vaccinations are administered annually to manage seasonal epidemics. Therefore, development of a new generation of vaccines is needed to generate broad and persistent immunity to influenza viruses. Here, we describe three adjuvants that enhance the induction of stalk-directed antibodies against heterologous and heterosubtypic influenza viruses when administered with chimeric HA proteins. Addavax, an MF59-like nanoemulsion, poly(I:C), and an RNA hairpin derived from Sendai virus (SeV) Cantell were efficacious intramuscularly. The SeV RNA and poly(I:C) also proved to be effective respiratory mucosal adjuvants. Although the quantity and quality of antibodies induced by the adjuvants varied, immunized mice demonstrated comparable levels of protection against challenge with influenza A viruses on the basis of HA stalk reactivity. Finally, we present that intranasally, but not intramuscularly, administered chimeric HA proteins induce mucosal IgA antibodies directed at the HA stalk. PMID:24223176

  2. Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses.

    PubMed

    Demenesku, Jelena; Popov Aleksandrov, Aleksandra; Mirkov, Ivana; Ninkov, Marina; Zolotarevski, Lidija; Kataranovski, Dragan; Brceski, Ilija; Kataranovski, Milena

    2016-08-10

    The impact of genetic background on effects of acute i.p. cadmium administration (0.5mg/kg and 1mg/kg) on basic immune activity of spleen and lungs was examined in two rat strains, Albino Oxford (AO) and Dark Agouti (DA), known to react differently to chemicals. More pronounced inhibition of Concanavalin A (ConA)-induced and Interleukin (IL)-2 stimulated spleen cell proliferation as well as higher levels of nitric oxide (known to decrease cell's proliferative ability) in DA rats at 1mg/kg, along with greater inhibition of ConA-induced Interferon (IFN-γ)-production by total and mononuclear (MNC) spleen cells and IL-17 production by spleen MNC in DA vs. AO rats at this dose show greater susceptibility of this strain to Cd effects on spleen cells response. More pronounced infiltration of neutrophils/CD11b(+) cells to lungs of DA rats treated with 1mg/kg of Cd and decreased IL-17 lung cell responses noted solely in DA rats speaks in favor of their higher susceptibility to this metal. However, lack of strain disparity in lung cells IFN-γ responses show that there are regional differences as well. Novel data from this study depict complexity of the influence of genetic background on the effects of cadmium on host immune reactivity. PMID:27234498

  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. Effect of domperidone-induced hyperprolactinemia on selected immune parameters in healthy women.

    PubMed

    Rovenský, J; Buc, M; Lojda, Z; Ruzicková, M; Blazícková, S; Rauová, L; Mistina, T; Vigas, M; Lackovic, V

    1995-01-01

    Domperidone, anti-emetic drug, given to healthy female volunteers, induced an elevation of plasma prolactin (PRL) concentration with the peak in 1-4 h. The release of prolactin had a transient stimulating effect on theophylline sensitive T lymphocytes and on concanavalin A induced mitogenic activity, suggesting an enhanced activity of T suppressor lymphocytes. The relative number of CD4+ lymphocytes decreased markedly one hour after domperidone administration and returned to normal values within 2 h (that means 3 h after taking the drug). The number of lymphocytes positive for dipeptidyl peptidase IV exhibited similar transient increase and normalization of activity. No change was observed in the number of CD8+ lymphocytes. The production of interferon by leukocytes treated with Newcastle disease virus was found to be significantly increased 2 h after domperidone administration. The results suggest that prolactin can selectively stimulate some functions of cellular immunity as well as the release of cytokines (IFN). The present study may contribute to the understanding of the role of the immune system in endogenous hyperprolactinemia. PMID:8744700

  5. A novel elicitor protein from Phytophthora parasitica induces plant basal immunity and systemic acquired resistance.

    PubMed

    Chang, Yi-Hsuan; Yan, Hao-Zhi; Liou, Ruey-Fen

    2015-02-01

    The interaction between Phytophthora pathogens and host plants involves the exchange of complex molecular signals from both sides. Recent studies of Phytophthora have led to the identification of various apoplastic elicitors known to trigger plant immunity. Here, we provide evidence that the protein encoded by OPEL of Phytophthora parasitica is a novel elicitor. Homologues of OPEL were identified only in oomycetes, but not in fungi and other organisms. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that OPEL is expressed throughout the development of P. parasitica and is especially highly induced after plant infection. Infiltration of OPEL recombinant protein from Escherichia coli into leaves of Nicotiana tabacum (cv. Samsun NN) resulted in cell death, callose deposition, the production of reactive oxygen species and induced expression of pathogen-associated molecular pattern (PAMP)-triggered immunity markers and salicylic acid-responsive defence genes. Moreover, the infiltration conferred systemic resistance against a broad spectrum of pathogens, including Tobacco mosaic virus, the bacteria wilt pathogen Ralstonia solanacearum and P. parasitica. In addition to the signal peptide, OPEL contains three conserved domains: a thaumatin-like domain, a glycine-rich protein domain and a glycosyl hydrolase (GH) domain. Intriguingly, mutation of a putative laminarinase active site motif in the predicted GH domain abolished its elicitor activity, which suggests enzymatic activity of OPEL in triggering the defence response. PMID:24965864

  6. Atomic description of the immune complex involved in heparin-induced thrombocytopenia

    SciTech Connect

    Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang; Rauova, Lubica; Hayes, Vincent; Lebedeva, Tatiana; Liu, Qun; Poncz, Mortimer; Arepally, Gowthami; Cines, Douglas B.; Greene, Mark I.

    2015-09-22

    Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed’ end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open’ end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize’ the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.

  7. Atomic description of the immune complex involved in heparin-induced thrombocytopenia.

    PubMed

    Cai, Zheng; Yarovoi, Serge V; Zhu, Zhiqiang; Rauova, Lubica; Hayes, Vincent; Lebedeva, Tatiana; Liu, Qun; Poncz, Mortimer; Arepally, Gowthami; Cines, Douglas B; Greene, Mark I

    2015-01-01

    Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the 'open' end of the tetramer. Fondaparinux and KKO thereby collaborate to 'stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT. PMID:26391892

  8. Allopurinol induces innate immune responses through mitogen-activated protein kinase signaling pathways in HL-60 cells.

    PubMed

    Nakajima, Akira; Oda, Shingo; Yokoi, Tsuyoshi

    2016-09-01

    Allopurinol, an inhibitor of xanthine oxidase, is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we examined whether allopurinol has the ability to induce innate immune responses in vitro using human dendritic cell (DC)-like cell lines, including HL-60, THP-1 and K562, and a human keratinocyte cell line, HaCaT. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA expression levels of interleukin-8, monocyte chemotactic protein-1 and tumor necrosis factor α in a time- and concentration-dependent manner. Furthermore, allopurinol induced the phosphorylation of mitogen-activated protein kinases (MAPK), such as c-Jun N-terminal kinase and extracellular signal-regulated kinase, which regulate cytokine production in DC. In addition, allopurinol-induced increases in cytokine expression were inhibited by co-treatment with the MAPK inhibitors. Collectively, these results suggest that allopurinol has the ability to induce innate immune responses in a DC-like cell line through activation of the MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26641773

  9. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

    PubMed Central

    Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

    2015-01-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  10. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant.

    PubMed

    Monaris, D; Sbrogio-Almeida, M E; Dib, C C; Canhamero, T A; Souza, G O; Vasconcellos, S A; Ferreira, L C S; Abreu, P A E

    2015-08-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigA(C)) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigA(C), either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigA(C) or LigA(C) coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  11. EPICUTANEOUS IMMUNIZATION WITH TNP-Ig AND ZYMOSAN INDUCES TCRαβ+ CD4+ CONTRASUPPRESSOR CELLS THAT REVERSE SKIN-INDUCED SUPPRESSION VIA IL-17A

    PubMed Central

    Majewska-Szczepanik, Monika; Strzepa, Anna; Marcińska, Katarzyna; Wen, Li; Szczepanik, Marian

    2014-01-01

    Background Our previous work showed that epicutaneous (EC) immunization with protein antigen e.g. TNP-conjugated mouse immunoglobulin (TNP-Ig) in the form of a patch prior to hapten sensitization inhibits Th1-mediated contact hypersensitivity (CHS) in mice. We also found that suppression of CHS was mediated by TCRαβ+ CD4+ CD8+ T suppressor (Ts) cells producing TGF-β. The aim of the current study was to investigate the role of innate immunity in suppression of CHS. Methods Mice were immunized by applying gauze patches containing protein antigen alone or in the presence of zymosan and then tested for CHS response. Adoptive cell transfer experiments were used to study mechanisms involved in reversal of skin-induced suppression. Influence of EC immunization on cytokine production by lymph node cells was measured by ELISA. Results We found that EC immunization with TNP-Ig and zymosan before TNP-Cl sensitization reverses skin-induced suppression as demonstrated in vivo and in vitro. The reversal of skin-induced suppression was transferable by antigen-specific TCRαβ+ CD4+ T contrasuppressor (Tcs) cells. Furthermore, we showed that the contrasuppression was IL-17A dependent and TLR2 and MyD88 independent. Conclusions Our work strongly suggests that EC immunization with protein antigen and zymosan reverses skin-induced suppression and that this approach may be a potential tool to increase immunogenicity of weekly immunogenic antigens. PMID:24993442

  12. Construction of recombinant Lactobacillus casei efficiently surface displayed and secreted porcine parvovirus VP2 protein and comparison of the immune responses induced by oral immunization

    PubMed Central

    Yigang, X U; Yijing, L I

    2008-01-01

    Lactobacillus casei ATCC 393 was selected as a bacterial carrier for the development of mucosal vaccine against porcine parvovirus (PPV) infection. The PPV major structural polypeptide VP2 was used as the model parvovirus antigen. Two inducible expression systems, namely pPG611.1 of the cell-surface expression system and pPG612.1 of the secretion expression system based on the xylose operon promoter were used to express the VP2 protein. The immunogenicity of recombinant strains producing VP2 protein in two cellular locations, cell-surface exposed and secreted, was compared to each other by immunizing mice through the intragastric administration. The two types of constructs were able to induce strong specific immune responses against VP2 via intragastric administration and maximum titres of IgA and IgG were attained on days 46 post oral immunization, while the highest antibody levels were obtained with the strain producing the VP2 protein in extracellular milieu. The induced antibodies demonstrated neutralizing effects on PPV infection. PMID:18034821

  13. Sterile Neutrinos in Cold Climates

    SciTech Connect

    Jones, Benjamin J.P.

    2015-09-01

    Measurements of neutrino oscillations at short baselines contain an intriguing set of experimental anomalies that may be suggestive of new physics such as the existence of sterile neutrinos. This three-part thesis presents research directed towards understanding these anomalies and searching for sterile neutrino oscillations. Part I contains a theoretical discussion of neutrino coherence properties. The open-quantum-system picture of neutrino beams, which allows a rigorous prediction of coherence distances for accelerator neutrinos, is presented. Validity of the standard treatment of active and sterile neutrino oscillations at short baselines is verified, and non-standard coherence loss effects at longer baselines are predicted. Part II concerns liquid argon detector development for the MicroBooNE experiment, which will search for short-baseline oscillations in the Booster Neutrino Beam at Fermilab. Topics include characterization and installation of the MicroBooNE optical system; test-stand measurements of liquid argon optical properties with dissolved impurities; optimization of wavelength-shifting coatings for liquid argon scintillation light detection; testing and deployment of high-voltage surge arrestors to protect TPC field cages; and software development for optical and TPC simulation and reconstruction. Part III presents a search for sterile neutrinos using the IceCube neutrino telescope, which has collected a large sample of atmospheric-neutrino-induced events in the 1-10 TeV energy range. Sterile neutrinos would modify the detected neutrino flux shape via MSW-resonant oscillations. Following a careful treatment of systematic uncertainties in the sample, no evidence for MSW-resonant oscillations is observed, and exclusion limits on 3+1 model parameter space are derived. Under the mixing assumptions made, the 90% confidence level exclusion limit extends to sin224 ≤ 0.02 at m2 ~ 0.3 eV2, and the LSND and Mini

  14. Intervention of Grape Seed Proanthocyanidin Extract on the Subchronic Immune Injury in Mice Induced by Aflatoxin B1

    PubMed Central

    Long, Miao; Zhang, Yi; Li, Peng; Yang, Shu-Hua; Zhang, Wen-Kui; Han, Jian-Xin; Wang, Yuan; He, Jian-Bin

    2016-01-01

    The aim was to investigate the prevention of grape seed proanthocyanidin extract (GSPE) on the subchronic immune injury induced by aflatoxin B1 (AFB1) and the possible ameliorating effect of GSPE in mice. The subchronic AFB1-induced immune injury mice model was set up with the continuous administration of 100 μg/kg body weight (BW) AFB1 for six weeks by intragastric administration. Then, intervention with different doses (50 and 100 mg/kg BW) of GSPE was conducted on mice to analyze the changes of body weight, immune organ index, antioxidant capability of spleen, serum immunoglobulin content, and the expression levels of inflammatory cytokines. The prevention of GSPE on the immune injury induced by AFB1 was studied. The GSPE could relieve the AFB1-induced reduction of body weight gain and the atrophy of the immune organ. The malondialdehyde (MDA) level of the spleen in the AFB1 model group significantly increased, but levels of catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) significantly decreased. The GSPE could significantly inhibit the oxidative stress injury of the spleen induced by AFB1. AFB1 exposure could not significantly change the contents of IgA, IgG, or IgM. AFB1 significantly improved the expression of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Additionally, GSPE could decrease the expression of these four proinflammatory factors to different degrees and inhibit the inflammatory reaction of mice. The results suggest that GSPE alleviates AFB1-induced oxidative stress and significantly improves the immune injury of mice induced by AFB1. PMID:27070584

  15. Immunosuppression in Early Postnatal Days Induces Persistent and Allergen-Specific Immune Tolerance to Asthma in Adult Mice

    PubMed Central

    Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

    2015-01-01

    Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma. PMID:25860995

  16. Immunosuppression in early postnatal days induces persistent and allergen-specific immune tolerance to asthma in adult mice.

    PubMed

    Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

    2015-01-01

    Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma. PMID:25860995

  17. Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

    PubMed Central

    Wang, Ze-Yu; Xing, Yun; Liu, Bin; Lu, Lei; Huang, Xiao; Ge, Chi-Yu; Yao, Wen-Jun; Xu, Mao-Lei; Gao, Zhen-Qiu; Cao, Rong-Yue; Wu, Jie; Li, Tai-Ming

    2012-01-01

    Cancer cell vaccine-based immunotherapy has received increasing interest in many clinical trials involving patients with breast cancer. Combining with appropriate adjuvants can enhance the weak immunogenic properties of tumor cell lysates (TCL). In this study, diphtheria toxin (DT) and two tandem repeats of mycobacterial heat shock protein 70 (mHSP70) fragment 407-426 (M2) were conjugated to TCL with glutaraldehyde, and the constructed cancer cell vaccine was named DT-TCL-M2. Subcutaneous injection of DT-TCL-M2 in mice effectively elicited tumor-specific polyclonal immune responses, including humoral and cellular immune responses. High levels of antibodies against TCL were detected in the serum of immunized mice with ELISA and verified with Western blot analyses. The splenocytes from immunized mice showed potent cytotoxicity on Ehrlich ascites carcinoma cells. Moreover, the protective antitumor immunity induced by DT-TCL-M2 inhibited tumor growth in a mouse breast tumor model. DT-TCL-M2 also attenuated tumor-induced angiogenesis and slowed tumor growth in a mouse intradermal tumor model. These findings demonstrate that TCL conjugated with appropriate adjuvants induced effective antitumor immunity in vivo. Improvements in potency could further make cancer cell vaccines a useful and safe method for preventing cancer recurrence after resection. PMID:22464650

  18. The immunization-induced antibody response to the Anaplasma marginale major surface protein 2 and its association with protective immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many vector-borne pathogens evade clearance via rapid variation in immunogenic surface expressed proteins. In the case of A. marginale, the generation of major surface protein 2 (Msp2) variants allows for immune escape and long-term pathogen persistence. In the experiments reported here, we pose t...

  19. CD226 as a genetic adjuvant to enhance immune efficacy induced by Ag85A DNA vaccination.

    PubMed

    Li, Yan; Yang, Fangli; Zhu, Junfeng; Sang, Lixuan; Han, Xue; Wang, Danan; Shan, Fengping; Li, Shengjun; Sun, Xun; Lu, Changlong

    2015-03-01

    Antigen-85A (Ag85A) is one of the major proteins secreted by Mycobacterium tuberculosis. Many studies on animal models have shown that vaccination with the recombinant Ag85A-DNA or Ag85A protein induces powerful immune response. However, these vaccines cannot generate sufficient protective immunity in the systemic compartment. CD226, a member of the immunoglobulin superfamily, is expressed in the majority of NK cells, T cells, monocytes, and platelets, and can be served as a co-stimulator that contributes to multiple innate and adaptive responses. However, there has been no study where either CD226 protein or DNA has been used as an adjuvant for vaccine development. The aim of this study was to develop a novel Ag85A DNA vaccine with CD226 as the genetic adjuvant to increase the immune efficacy induced by Ag85A. Oral vaccination with pcDNA3.1-Ag85A-CD226 DNA induced potent immune responses in mice. CD226 was an effective genetic adjuvant that improved the immune efficacy induced by Ag85A and enhanced the activity of cytotoxic T lymphocytes (CTL) and NK cells in mice. Th1 dominant cytokines (i.e. IL-2, IFN-γ and TNF-α), cellular immunity (i.e. CD4(+)IFN-γ(+)T cells and CD8(+)IFN-γ(+)T cells in splenocytes) and MLNs were also significantly elevated by pcDNA3.1-Ag85A-CD226 DNA vaccination. Our results suggest that CD226 is an effective adjuvant to enhance the immune efficacy induced by Ag85A. Our findings provide a new strategy for the development of a DNA vaccine co-expressing Ag85A and CD226. PMID:25582686

  20. STAT3, a Key Parameter of Cytokine-Driven Tissue Protection during Sterile Inflammation – the Case of Experimental Acetaminophen (Paracetamol)-Induced Liver Damage

    PubMed Central

    Mühl, Heiko

    2016-01-01

    Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions. PMID:27199988

  1. Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.

    PubMed

    Kumagai, Kazuyoshi; Lewandowski, Ryan; Jackson-Humbles, Daven N; Li, Ning; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

    2016-06-01

    Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure. PMID:26559808

  2. Escherichia coli-induced immune paralysis is not exacerbated during chronic filarial infection

    PubMed Central

    Buerfent, Benedikt C; Gondorf, Fabian; Wohlleber, Dirk; Schumak, Beatrix; Hoerauf, Achim; Hübner, Marc P

    2015-01-01

    Sepsis initially starts with a systemic inflammatory response (SIRS phase) and is followed by a compensatory anti-inflammatory response syndrome (CARS) that causes impaired adaptive T-cell immunity, immune paralysis and an increased susceptibility to secondary infections. In contrast, parasitic filariae release thousands of microfilariae into the peripheral blood without triggering inflammation, as they induce regulatory, anti-inflammatory host responses. Hence, we investigated the impact of chronic filarial infection on adaptive T-cell responses during the SIRS and CARS phases of a systemic bacterial infection and analysed the development of T-cell paralysis following a subsequent adenovirus challenge in BALB/c mice. Chronic filarial infection impaired adenovirus-specific CD8+ T-cell cytotoxicity and interferon-γ responses in the absence of a bacterial challenge and led to higher numbers of splenic CTLA-4+ CD4+ T cells, whereas splenic T-cell expression of CD69 and CD62 ligand, serum cytokine levels and regulatory T-cell frequencies were comparable to naive controls. Irrespective of filarial infection, the SIRS phase dominated 6–24 hr after intravenous Escherichia coli challenge with increased T-cell activation and pro-inflammatory cytokine production, whereas the CARS phase occurred 6 days post E. coli challenge and correlated with high levels of transforming growth factor-β and increased CD62 ligand T-cell expression. Escherichia coli-induced impairment of adenovirus-specific CD8+ T-cell cytotoxicity and interferon-γ production was not additionally impaired by chronic filarial infection. This suggests that filarial immunoregulation does not exacerbate E. coli-induced T-cell paralysis. PMID:25521437

  3. Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape.

    PubMed

    Bandyopadhyay, Sanmay; Quinn, Thomas J; Scandiuzzi, Lisa; Basu, Indranil; Partanen, Ari; Tomé, Wolfgang A; Macian, Fernando; Guha, Chandan

    2016-02-15

    Immune responses against cancer cells are often hindered by immunosuppressive mechanisms that are developed in the tumor microenvironment. Induction of a hyporesponsive state in tumor Ag-specific T cells is one of the major events responsible for the inability of the adaptive immune system to mount an efficient antitumor response and frequently contributes to lessen the efficacy of immunotherapeutic approaches. Treatment of localized tumors by focused ultrasound (FUS) is a minimally invasive therapy that uses a range of input energy for in situ tumor ablation through the generation of thermal and cavitation effect. Using a murine B16 melanoma tumor model, we show that a variant of FUS that delivers a reduced level of energy at the focal point and generates mild mechanical and thermal stress in target cells has the ability to increase immunogenic presentation of tumor Ags, which results in reversal of tumor-induced T cell tolerance. Furthermore, we show that the combination of nonablative low-energy FUS with an ablative hypofractionated radiation therapy results in synergistic control of primary tumors and leads to a dramatic reduction in spontaneous pulmonary metastases while prolonging recurrence-free survival only in immunocompetent mice. PMID:26755821

  4. The emergence of load-oriented sterilization.

    PubMed

    Kolstad, R A

    1994-01-01

    Achieving maximum equipment sterilization is critical. Factors that contribute to sterilization efficiency are covered, including sterilization accuracy level, chamber loading and biological indicators. PMID:8031354

  5. Inducing Herd Immunity against Seasonal Influenza in Long-Term Care Facilities through Employee Vaccination Coverage: A Transmission Dynamics Model

    PubMed Central

    Wendelboe, Aaron M.; Grafe, Carl; McCumber, Micah; Anderson, Michael P.

    2015-01-01

    Introduction. Vaccinating healthcare workers (HCWs) in long-term care facilities (LTCFs) may effectively induce herd immunity and protect residents against influenza-related morbidity and mortality. We used influenza surveillance data from all LTCFs in New Mexico to validate a transmission dynamics model developed to investigate herd immunity induction. Material and Methods. We adjusted a previously published transmission dynamics model and used surveillance data from an active system among 76 LTCFs in New Mexico during 2006-2007 for model validation. We used a deterministic compartmental model with a stochastic component for transmission between residents and HCWs in each facility in order to simulate the random variation expected in such populations. Results. When outbreaks were defined as a dichotomous variable, our model predicted that herd immunity could be induced. When defined as an attack rate, the model demonstrated a curvilinear trend, but insufficiently strong to induce herd immunity. The model was sensitive to changes in the contact parameter β but was robust to changes in the visitor contact probability. Conclusions. These results further elucidate previous studies' findings that herd immunity may not be induced by vaccinating HCWs in LTCFs; however, increased influenza vaccination coverage among HCWs reduces the probability of influenza infection among residents. PMID:26101542

  6. Lactobacillus paracasei Lp6 favors immune modulation induced by allergoid treatment in ragweed sensitized mice.

    PubMed

    Petrarca, C; Lazzarin, F; Lanuti, P; Marchisio, M; Miscia, S; Rossi, C; Braga, M; Mistrello, G; Di Gioacchino, M

    2011-01-01

    It has been hypothesized that lactic acid bacteria (LAB) could be used as adjuvant for specific immunotherapy (SIT), as various studies conducted on humans and animals converge to define LAB as anti-Th2 modulators and Treg inducers. In the present study we evaluated the effects of LAB, in particular Lactobacillus paracasei Lp6 (Lp6), in a mouse model of ragweed (RW) allergy. Groups of Balb/c mice, experimentally sensitized towards ragweed, were treated by viable Lp6 or by RWallergoid with or without co-administration of Lp6. A control group was sham-sensitized with PBS and sham-treated with water and a group was sensitized with RW and treated with water. Serum IgE, RW-induced release of IFN-gamma, IL-4 and IL-10 from splenocytes and the frequency of CD4CD25 regulatory T cells (Tregs) expressing Foxp3 or IL-10 were evaluated in various groups. RW-allergoid treatment induced a reduction of serum IgE, with a decrease in RW-induced release of IL-4, and an increase in IL-10 and IFN-gamma, along with a significant change in the frequency of Tregs, both CD25+ and -. The joint RWallergoid+ Lp6 treatment induced the highest degree of suppression of allergen-driven IL-4, the greatest reduction of IL-4/IFN-gamma and IL-4/IL-10 ratios and the most significant increase of Foxp3 and IL-10 expressing Tregs. The study shows that Lp6 strengthens the immune modulation induced by allergoid-SIT in RW-sensitized mice, essentially characterized by a differential induction of Tregs associated to a reduction of IL-4; data converge to define a role of SIT adjuvant for Lp6. PMID:22230395

  7. Modified Vaccinia Virus Ankara Encoding Influenza Virus Hemagglutinin Induces Heterosubtypic Immunity in Macaques

    PubMed Central

    Florek, Nicholas W.; Weinfurter, Jason T.; Jegaskanda, Sinthujan; Brewoo, Joseph N.; Powell, Tim D.; Young, Ginger R.; Das, Subash C.; Hatta, Masato; Broman, Karl W.; Hungnes, Olav; Dudman, Susanne G.; Kawaoka, Yoshihiro; Kent, Stephen J.; Stinchcomb, Dan T.

    2014-01-01

    ABSTRACT Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA-based vaccines 4 weeks apart and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza virus HA and/or NP had high frequencies of virus-specific CD4+ and CD8+ T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC plays a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective. IMPORTANCE Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging

  8. Karlson ozone sterilizer. Final report

    SciTech Connect

    Karlson, E.

    1984-05-07

    The authors have a functional sterilization system employing ozone as a sterilization agent. This final report covers the work that led to the first medical sterilizer using ozone as the sterilizing agent. The specifications and the final design were set by hospital operating room personnel and public safety standards. Work on kill tests using bacteria, viruses and fungi determined the necessary time and concentration of ozone necessary for sterilization. These data were used in the Karlson Ozone Sterilizer to determine the length of the steps of the operating cycle and the concentration of ozone to be used. 27 references.

  9. Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans

    PubMed Central

    Kelly, Christabel; Swadling, Leo; Capone, Stefania; Brown, Anthony; Richardson, Rachel; Halliday, John; von Delft, Annette; Oo, Ye; Mutimer, David; Kurioka, Ayako; Hartnell, Felicity; Collier, Jane; Ammendola, Virginia; Sorbo, Mariarosaria Del; Grazioli, Fabiana; Esposito, Maria Luisa; Marco, Stefania Di; Siani, Loredana; Traboni, Cinzia; Hill, Adrian V.S.; Colloca, Stefano; Nicosia, Alfredo; Cortese, Riccardo; Folgori, Antonella; Klenerman, Paul

    2016-01-01

    Adenoviral vectors encoding hepatitis C virus (HCV) nonstructural (NS) proteins induce multispecific, high‐magnitude, durable CD4+ and CD8+ T‐cell responses in healthy volunteers. We assessed the capacity of these vaccines to induce functional HCV‐specific immune responses and determine T‐cell cross‐reactivity to endogenous virus in patients with chronic HCV infection. HCV genotype 1‐infected patients were vaccinated using heterologous adenoviral vectors (ChAd3‐NSmut and Ad6‐NSmut) encoding HCV NS proteins in a dose escalation, prime‐boost regimen, with and without concomitant pegylated interferon‐α/ribavirin therapy. Analysis of immune responses ex vivo used human leukocyte antigen class I pentamers, intracellular cytokine staining, and fine mapping in interferon‐γ enzyme‐linked immunospot assays. Cross‐reactivity of T cells with population and endogenous viral variants was determined following viral sequence analysis. Compared to healthy volunteers, the magnitude of HCV‐specific T‐cell responses following vaccination was markedly reduced. CD8+ HCV‐specific T‐cell responses were detected in 15/24 patients at the highest dose, whereas CD4+ T‐cell responses were rarely detectable. Analysis of the host circulating viral sequence showed that T‐cell responses were rarely elicited when there was sequence homology between vaccine immunogen and endogenous virus. In contrast, T cells were induced in the context of genetic mismatch between vaccine immunogen and endogenous virus; however, these commonly failed to recognize circulating epitope variants and had a distinct partially functional phenotype. Vaccination was well tolerated but had no significant effect on HCV viral load. Conclusion: Vaccination with potent HCV adenoviral vectored vaccines fails to restore T‐cell immunity except where there is genetic mismatch between vaccine immunogen and endogenous virus; this highlights the major challenge of overcoming T‐cell exhaustion

  10. Mucosal and systemic cellular immune responses induced by Toxoplasma gondii antigens in cyst orally infected mice.

    PubMed Central

    Chardès, T; Velge-Roussel, F; Mevelec, P; Mevelec, M N; Buzoni-Gatel, D; Bout, D

    1993-01-01

    This study was performed to determine the T-cellular immune responses following Toxoplasma gondii oral infection and to assess further toxoplasma antigens on their ability to stimulate in vitro mucosal and systemic T-cell immunity. Parasite-specific cellular immune responses in Peyer's patches (PP), in mesenteric lymph nodes (MLN) and in spleen (SPL) were investigated using a lymphoblastic transformation test following oral infection of mice with strain 76K cysts of T. gondii. An early toxoplasma sonicate-induced mucosal T-cell proliferation occurred in MLN and PP with a peak responsiveness on day 6 post-infection (PI) and rapidly reached background levels on day 7 PI in PP and on day 8 PI in mesenteric lymph nodes. A later splenic cellular blastogenesis was observed from day 28 PI and persisted throughout the experiment (day 91). At the time of T-cell proliferation, FACS analyses revealed a decrease in the relative percentages of CD4+ and CD8+ T cells with a predominance of CD8+ lymphocytes which leads to an inversion of the CD4/CD8 ratios. We found that CBA/J is a high responder mouse strain in the induction of mesenteric and splenic T-lymphocyte blastogenesis compared to the intermediate responder BALB/c and low responder C57BL/6. Toxoplasma gondii antigens SAG1 (30,000 MW) and GRA4 (40,000-41,000 MW), which are known to induce locally IgA antibodies, are shown to stimulate primed mucosal T lymphocytes from CBA/J and BALB/c mice whereas no proliferation was demonstrated with C57BL/6 T cells. 229-242 peptide, derived from the deduced amino acid sequence of GRA4, only induces detectable proliferation of primed-CBA/J T lymphocytes. Following oral experimental infection, the in vitro mesenteric response to a toxoplasma sonicate is dominated by a Th2-type cytokine pattern whereas a predominant Th1 cytokine response is observed in the spleen. Finally, in vitro stimulation of mesenteric T cells with the three defined toxoplasma antigens resulted in secretion of

  11. Eimeria maxima microneme protein 2 delivered as DNA vaccine and recombinant protein induces immunity against experimental homogenous challenge.

    PubMed

    Huang, Jingwei; Zhang, Zhenchao; Li, Menghui; Song, Xiaokai; Yan, Ruofeng; Xu, Lixin; Li, Xiangrui

    2015-10-01

    E. maxima is one of the seven species of Eimeria that infects chicken. Until now, only a few antigenic genes of E. maxima have been reported. In the present study, the immune protective effects against E. maxima challenge of recombinant protein and DNA vaccine encoding EmMIC2 were evaluated. Two-week-old chickens were randomly divided into five groups. The experimental group of chickens was immunized with 100 μg DNA vaccine pVAX1-MIC2 or 200 μg rEmMIC2 protein while the control group of chickens was injected with pVAX1 plasmid or sterile PBS. The results showed that the anti-EmMIC2 antibody titers of both rEmMIC2 protein and pVAX1-MIC2 groups were significantly higher as compared to PBS and pVAX1 control (P<0.05). The splenocytes from both vaccinated groups of chickens displayed significantly greater proliferation compared with the controls (P<0.05). Serum from chickens immunized with pVAX1-MIC2 and rEmMIC2 protein displayed significantly high levels of IL-2, IFN-γ, IL-10, IL-17, TGF-β and IL-4 (P<0.05) compared to those of negative controls. The challenge experiment results showed that both the recombinant protein and the DNA vaccine could obviously alleviate jejunum lesions, body weight loss, increase oocyst, decrease ratio and provide ACIs of more than 165. All the above results suggested that immunization with EmMIC2 was effective in imparting partial protection against E. maxima challenge and it could be an effective antigen candidate for the development of new vaccines against E. maxima. PMID:26072304

  12. Sterilization of Cotton Fabrics Using Plasma Treatment

    NASA Astrophysics Data System (ADS)

    Shahidi, S.; Ghoranneviss, M.

    2013-10-01

    Microbial contamination induces surface deformations and strength degradation of cotton fabrics by invading deeply into the fibers. In this study, the sterilization effects of low pressure plasmas on bacteria-inoculated cotton fabrics were investigated. Oxygen plasma treatment completely sterilized the cotton fabrics inoculated with various concentrations of staphylococcus aureus. Also, the influence of plasma treatment on physical properties of fabrics was examined. It was found that the plasma treatment did not affect ultimate tensile strength and surface morphology of the fabrics because it took advantage of relatively low plasma temperature.

  13. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages

    PubMed Central

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto

    2016-01-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5. Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. PMID:27183578

  14. Biodegradable polylactide microspheres enhance specific immune response induced by Hepatitis B surface antigen

    PubMed Central

    Qiu, Shaohui; Wei, Qiang; Liang, Zhenglun; Ma, Guanghui; Wang, Lianyan; An, Wenqi; Ma, Xiaowei; Fang, Xin; He, Peng; Li, Hemin; Hu, Zhongyu

    2014-01-01

    Hepatitis B (HB) infection caused by Hepatitis B virus (HBV) is the most common liver disease in the world. HB vaccine, when administered in conjunction with alum adjuvants, induces Th2 immunity that confers protection against HBV. However, currently available vaccine formulations and adjuvants do not elicit adequate Th1 and CTL responses that are important for prevention of maternal transmission of the virus. Microspheres synthesized from poly (D, L-lactide-co-glycolide) (PLGA) or poly (D, L-lactide) (PLA) polymers have been considered as promising tools for in vivo delivery of antigens and drugs. Here we describe PLA microspheres synthesized by premix membrane emulsification method and their application in formulating a new microsphere based HB vaccine. To evaluate the immunogenicity of this microsphere vaccine, BALB/c mice were immunized with microsphere vaccine and a series of immunological assays were conducted. Results of Enzyme-linked ImmunoSpot (ELISPOT) assays revealed that the number of interferon-gamma (IFN-γ)-producing splenocytes and CD8+ T cells increased significantly in the microsphere vaccine group. Microsphere vaccine group showed enhanced specific cell lysis when compared with HB surface antigen (HBsAg) only group in 51Cr cytotoxicity assays. Moreover, microsphere vaccine elicited a comparable level of antibody production as that of HB vaccine administered with alum adjuvant. We show that phagocytosis of HBsAg by dendritic cells is more pronounced in microsphere vaccine group when compared with other control groups. These results clearly demonstrate the potential of using PLA microspheres as effective HB vaccine adjuvants for an enhanced Th1 immune response. PMID:25424942

  15. Biodegradable polylactide microspheres enhance specific immune response induced by Hepatitis B surface antigen.

    PubMed

    Qiu, Shaohui; Wei, Qiang; Liang, Zhenglun; Ma, Guanghui; Wang, Lianyan; An, Wenqi; Ma, Xiaowei; Fang, Xin; He, Peng; Li, Hemin; Hu, Zhongyu

    2014-01-01

    Hepatitis B (HB) infection caused by Hepatitis B virus (HBV) is the most common liver disease in the world. HB vaccine, when administered in conjunction with alum adjuvants, induces Th2 immunity that confers protection against HBV. However, currently available vaccine formulations and adjuvants do not elicit adequate Th1 and CTL responses that are important for prevention of maternal transmission of the virus. Microspheres synthesized from poly (D, L-lactide-co-glycolide) (PLGA) or poly (D, L-lactide) (PLA) polymers have been considered as promising tools for in vivo delivery of antigens and drugs. Here we describe PLA microspheres synthesized by premix membrane emulsification method and their application in formulating a new microsphere based HB vaccine. To evaluate the immunogenicity of this microsphere vaccine, BALB/c mice were immunized with microsphere vaccine and a series of immunological assays were conducted. Results of Enzyme-linked ImmunoSpot (ELISPOT) assays revealed that the number of interferon-gamma (IFN-γ)-producing splenocytes and CD8(+) T cells increased significantly in the microsphere vaccine group. Microsphere vaccine group showed enhanced specific cell lysis when compared with HB surface antigen (HBsAg) only group in (51)Cr cytotoxicity assays. Moreover, microsphere vaccine elicited a comparable level of antibody production as that of HB vaccine administered with alum adjuvant. We show that phagocytosis of HBsAg by dendritic cells is more pronounced in microsphere vaccine group when compared with other control groups. These results clearly demonstrate the potential of using PLA microspheres as effective HB vaccine adjuvants for an enhanced Th1 immune response. PMID:25424942

  16. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages.

    PubMed

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto; Becker, María Inés

    2016-06-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5 Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. PMID:27183578

  17. Photodynamic therapy can induce non-specific protective immunity against a bacterial infection

    NASA Astrophysics Data System (ADS)

    Tanaka, Masamitsu; Mroz, Pawel; Dai, Tianhong; Kinoshita, Manabu; Morimoto, Yuji; Hamblin, Michael R.

    2012-03-01

    Photodynamic therapy (PDT) for cancer is known to induce an immune response against the tumor, in addition to its well-known direct cell-killing and vascular destructive effects. PDT is becoming increasingly used as a therapy for localized infections. However there has not to date been a convincing report of an immune response being generated against a microbial pathogen after PDT in an animal model. We have studied PDT as a therapy for bacterial arthritis caused by Staphylococcus aureus infection in the mouse knee. We had previously found that PDT of an infection caused by injection of MRSA (5X107 CFU) into the mouse knee followed 3 days later by 1 μg of Photofrin and 635- nm diode laser illumination with a range of fluences within 5 minutes, gave a biphasic dose response. The greatest reduction of MRSA CFU was seen with a fluence of 20 J/cm2, whereas lower antibacterial efficacy was observed with fluences that were either lower or higher. We then tested the hypothesis that the host immune response mediated by neutrophils was responsible for most of the beneficial antibacterial effect. We used bioluminescence imaging of luciferase expressing bacteria to follow the progress of the infection in real time. We found similar results using intra-articular methylene blue and red light, and more importantly, that carrying out PDT of the noninfected joint and subsequently injecting bacteria after PDT led to a significant protection from infection. Taken together with substantial data from studies using blocking antibodies we believe that the pre-conditioning PDT regimen recruits and stimulates neutrophils into the infected joint which can then destroy bacteria that are subsequently injected and prevent infection.

  18. Anisakis simplex: from Obscure Infectious Worm to Inducer of Immune Hypersensitivity

    PubMed Central

    Audicana, M. Teresa; Kennedy, Malcolm W.

    2008-01-01

    Summary: Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites (“gastroallergic anisakiasis”), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive. PMID:18400801

  19. Light sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Gariazzo, S.; Giunti, C.; Laveder, M.; Li, Y. F.; Zavanin, E. M.

    2016-03-01

    The theory and phenomenology of light sterile neutrinos at the eV mass scale is reviewed. The reactor, gallium and Liquid Scintillator Neutrino Detector anomalies are briefly described and interpreted as indications of the existence of short-baseline oscillations which require the existence of light sterile neutrinos. The global fits of short-baseline oscillation data in 3 + 1 and 3 + 2 schemes are discussed, together with the implications for β-decay and neutrinoless double-β decay. The cosmological effects of light sterile neutrinos are briefly reviewed and the implications of existing cosmological data are discussed. The review concludes with a summary of future perspectives. This review is dedicated to the memory of Hai-Wei Long, our dear friend and collaborator, who passed away on 29 May 2015. He was an exceptionally kind person and an enthusiastic physicist. We deeply miss him.

  20. Light sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Gariazzo, S.; Giunti, C.; Laveder, M.; Li, Y. F.; Zavanin, E. M.

    2015-03-01

    The theory and phenomenology of light sterile neutrinos at the eV mass scale is reviewed. The reactor, gallium and Liquid Scintillator Neutrino Detector anomalies are briefly described and interpreted as indications of the existence of short-baseline oscillations which require the existence of light sterile neutrinos. The global fits of short-baseline oscillation data in 3 + 1 and 3 + 2 schemes are discussed, together with the implications for β-decay and neutrinoless double-β decay. The cosmological effects of light sterile neutrinos are briefly reviewed and the implications of existing cosmological data are discussed. The review concludes with a summary of future perspectives. This review is dedicated to the memory of Hai-Wei Long, our dear friend and collaborator, who passed away on 29 May 2015. He was an exceptionally kind person and an enthusiastic physicist. We deeply miss him.

  1. Recent findings on vertebrate developmental immunity using the zebrafish model.

    PubMed

    Galindo-Villegas, Jorge

    2016-01-01

    To grant survival against sterile or microbe induced inflammation, all animals rely on correct immune system functioning. The development of immunity occurs in vertebrates during embryogenesis in a process called hematopoiesis, which is characterized by the formation of blood cellular components such as embryonic erythrocytes and primitive macrophages. These cells are formed in a sterile environment from a rare subset of pluripotent hematopoietic stem cells (HSC) during a brief period of the primitive hematopoietic wave. Diverse signals, like Notch, are indispensable in HSC emergence and differentiation. However, to successfully replicate the process in vitro using pluripotent precursors, the full set of required signals is still a matter of debate. Among the latest findings, proinflammatory signals produced by transient primitive myelocites in zebrafish have been seen to act as essential mediators in establishing the HSC program of the adult vertebrate hematopoietic system. In this regard, the zebrafish immune model has emerged as a feasible live vertebrate model for examining developmental immunity and related host-microbe interactions, both at the molecular and cellular level. Thus, using the zebrafish embryo, this review summarizes recent findings, on the signals required for immune development and further maturation of the system, in a context where no adaptive immune response has yet been developed. PMID:26589453

  2. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

    PubMed

    Khosravi, Ali Reza; Erle, David J

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  3. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

    PubMed Central

    Erle, David J.

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  4. Prevailing Sydney like Norovirus GII.4 VLPs induce systemic and mucosal immune responses in mice.

    PubMed

    Huo, Yuqi; Wan, Xin; Ling, Tong; Wu, Jie; Wang, Zejun; Meng, Shengli; Shen, Shuo

    2015-12-01

    The newly emerged Norovirus (NoV) Sydney 2012 strain has been sweeping all over the world, causing acute non-bacterial gastroenteritis in adults and children. Due to a lack of cell culture system, virus like particles (VLPs) has been assembled and used as vaccine candidates in preclinical and clinical studies. Expression of the major capsid protein of NoVs using recombinant baculovirus expression system in Sf9 cells leads to formation of VLPs that are morphologically and antigenically similar to true virions. In this study, VLPs were successfully produced using the VP1 of Sydney-2012-like strain and its immunogenicity was evaluated by different routes and its capability in inducing mucosal immune responses in the presence and absence of adjuvants in BALB/c mice. Administration of NoV VLPs in the presence of Al(OH)3 or monophosphoryl lipid A (MPL-A) led to high titers of VLP-specific IgG antibodies. Administration of VLPs orally in the presence of cholera toxin subunit B (CTB) didn't enhance mucosal immune response as less fecal IgA positive mice were observed when compared with those given VLPs only. Our study represents the first immunogenicity study of VLPs derived from current pandemic Sydney 2012 strain and which might have implications in the development of NoVs vaccine in china. PMID:26375574

  5. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia

    PubMed Central

    ARNOLD, D. M.; KUKASWADIA, S.; NAZI, I.; ESMAIL, A.; DEWAR, L.; SMITH, J. W.; WARKENTIN, T. E.; KELTON, J. G.

    2016-01-01

    Summary Background Drug-induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drug-dependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. Objective To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. Patients/Methods We developed a grading system to evaluate the quality of DITP laboratory testing. The ‘DITP criteria’ were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. Results Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin. Conclusions We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient. PMID:23121994

  6. [Zinc- and tin-induced apoptotic mechanisms in immune system and cranial nerve system].

    PubMed

    Tomiyama, Kenichi; Arakawa, Yasuaki

    2016-07-01

    This review explains the mechanisms of apoptosis related to the impacts of zinc deficiency and organotin exposure on the immune and central nervous systems. In the immune systems, both zinc deficiency and trialkyltin exposure lead to severe thymic atrophy and affect T-lymphocyte development through apoptosis of double positive stage pre-T-cells(CD4+/CD8+) in the cortex region. Their apoptosis are caused mainly through decrease in Bcl-2 expression, activation of ROS production/release, oxidative stress, mitochondrial cytochrome c release and activation of caspase cascade, with increases in glucocorticoids in zinc deficiency, without the involvement of glucocorticoid in organotin exposure In the central nervous system, both zinc deficiency and trialkyltin exposure reduce learning, memory and sensory functions through neuronal apoptosis caused by activation of ROS production/release, release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor(AIF), with Fe excessive accumulation leading to ROS production and with depletion of hippocampus Zn (mossy fiber Zn) causing various Ca2+ channel disorder of synapse in the hippocampus, and with excessive accumulation of Ca through cAMP-dependent Ca(2+)-channel disorder by excessive PTH and cAMP excessive production in the olfactory systems such as olfactory epithelium and olfactory bulb. PMID:27455799

  7. Probiotic cheese attenuates exercise-induced immune suppression in Wistar rats.

    PubMed

    Lollo, P C B; Cruz, A G; Morato, P N; Moura, C S; Carvalho-Silva, L B; Oliveira, C A F; Faria, J A F; Amaya-Farfan, J

    2012-07-01

    Intense physical activity results in a substantial volume of stress and hence a significant probability of immunosuppression in athletes, with milk proteins being, perhaps, the most recommended protein supplements. Consumption of a probiotic cheese can attenuate immune suppression induced by exhausting exercise in rats. A popular Brazilian fresh cheese (Minas Frescal cheese) containing Lactobacillus acidophilus LA14 and Bifidobacterium longum BL05 was fed for 2wk to adult Wistar rats, which then were brought to exhaustion on the treadmill. Two hours after exhaustion, the rats were killed and material was collected for the determination of serum uric acid, total and high-density lipoprotein cholesterol fraction, total protein, triacylglycerols, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and blood cell (monocyte, lymphocyte, neutrophil, and leukocyte) counts. Exercise was efficient in reducing lymphocyte counts, irrespective of the type of ingested cheese, but the decrease in the group fed the probiotic cheese was 22% compared with 48% in the animals fed regular cheese. Monocyte counts were unaltered in the rats fed probiotic cheese compared with a significant decrease in the rats fed the regular cheese. Most importantly, ingestion of the probiotic cheese resulted in a >100% increase in serum high-density lipoprotein cholesterol and a 50% decrease in triacylglycerols. We conclude that probiotic Minas Frescal cheese may be a viable alternative to enhance the immune system and could be used to prevent infections, particularly those related to the physical overexertion of athletes. PMID:22720913

  8. Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity.

    PubMed

    Wevers, Brigitte A; Kaptein, Tanja M; Zijlstra-Willems, Esther M; Theelen, Bart; Boekhout, Teun; Geijtenbeek, Teunis B H; Gringhuis, Sonja I

    2014-04-01

    Recognition of fungal pathogens by C-type lectin receptor (CLR) dectin-1 on human dendritic cells is essential for triggering protective antifungal TH1 and TH17 immune responses. We show that Fonsecaea monophora, a causative agent of chromoblastomycosis, a chronic fungal skin infection, evades these antifungal responses by engaging CLR mincle and suppressing IL-12, which drives TH1 differentiation. Dectin-1 triggering by F. monophora activates transcription factor IRF1, which is crucial for IL12A transcription via nucleosome remodeling. However, simultaneous F. monophora binding to mincle induces an E3 ubiquitin ligase Mdm2-dependent degradation pathway, via Syk-CARD9-mediated PKB signaling, that leads to loss of nuclear IRF1 activity, hence blocking IL12A transcription. The absence of IL-12 leads to impaired TH1 responses and promotes TH2 polarization. Notably, mincle is similarly exploited by other chromoblastomycosis-associated fungi to redirect TH responses. Thus, mincle is a fungal receptor that can suppress antifungal immunity and, as such, is a potential therapeutic target. PMID:24721577

  9. Non-thermal Nanoelectroablation of UV-induced Murine Melanomas Stimulates an Immune Response

    PubMed Central

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

    2013-01-01

    Summary 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. PMID:22686288

  10. Photodynamic Therapy Can Induce a Protective Innate Immune Response against Murine Bacterial Arthritis via Neutrophil Accumulation

    PubMed Central

    Tanaka, Masamitsu; Mroz, Pawel; Dai, Tianhong; Huang, Liyi; Morimoto, Yuji; Kinoshita, Manabu; Yoshihara, Yasuo; Nemoto, Koichi; Shinomiya, Nariyoshi; Seki, Suhji; Hamblin, Michael R.

    2012-01-01

    Background Local microbial infections induced by multiple-drug-resistant bacteria in the orthopedic field can be intractable, therefore development of new therapeutic modalities is needed. Photodynamic therapy (PDT) is a promising alternative modality to antibiotics for intractable microbial infections, and we recently reported that PDT has the potential to accumulate neutrophils into the infected site which leads to resolution of the infection. PDT for cancer has long been known to be able to stimulate the innate and adaptive arms of the immune system. Methodology/Principal Findings In the present study, a murine methicillin-resistant Staphylococcus aureus (MRSA) arthritis model using bioluminescent MRSA and polystyrene microparticles was established, and both the therapeutic (Th-PDT) and preventive (Pre-PDT) effects of PDT using methylene blue as photosensitizer were examined. Although Th-PDT could not demonstrate direct bacterial killing, neutrophils were accumulated into the infectious joint space after PDT and MRSA arthritis was reduced. With the preconditioning Pre-PDT regimen, neutrophils were quickly accumulated into the joint immediately after bacterial inoculation and bacterial growth was suppressed and the establishment of infection was inhibited. Conclusions/Significance This is the first demonstration of a protective innate immune response against a bacterial pathogen produced by PDT. PMID:22761911

  11. Activation-induced Cytidine Deaminase in B Cell Immunity and Cancers

    PubMed Central

    2012-01-01

    Activation-induced cytidine deaminase (AID) is an enzyme that is predominantly expressed in germinal center B cells and plays a pivotal role in immunoglobulin class switch recombination and somatic hypermutation for antibody (Ab) maturation. These two genetic processes endow Abs with protective functions against a multitude of antigens (pathogens) during humoral immune responses. In B cells, AID expression is regulated at the level of either transcriptional activation on AID gene loci or post-transcriptional suppression of AID mRNA. Furthermore, AID stabilization and targeting are determined by post-translational modifications and interactions with other cellular/nuclear factors. On the other hand, aberrant expression of AID causes B cell leukemias and lymphomas, including Burkitt's lymphoma caused by c-myc/IgH translocation. AID is also ectopically expressed in T cells and non-immune cells, and triggers point mutations in relevant DNA loci, resulting in tumorigenesis. Here, I review the recent literatures on the function of AID, regulation of AID expression, stability and targeting in B cells, and AID-related tumor formation. PMID:23396757

  12. Mechanistic studies of systemic immune responses induced by laser-nanotechnology

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Zhou, Feifan; Henderson, Brock; Vasquez, Bailey; Liu, Hong; Hode, Tomas; Nordquist, Robert E.

    2014-02-01

    With the help of the specific absorption spectrum of carbon nanotubes, we achieved selective photothermal tumor cell destruction, particularly using a near-infrared laser to reduce potential damage to untargeted tissues. Combined with immunological stimulation, using a novel adjuvant, we also observed the anti-tumor immune responses when treating animal tumors using the laser-nano treatment. In fact, the local application of laser-nano-immunotherapy appeared to result in a systemic curative effect. In our mechanistic study, we found that the laser-nano-immuno treatment can activate antigen-presenting cells, such as dendritic cells (DCs). More importantly, the uptake and presentation of antigens by these antigen presenting cells were significantly enhanced, as shown by the strong binding of tumor cells and DCs as well as the proliferation of T cells caused by the DCs after the DCs had been incubated with laser-nano-immuno treated tumors. These cellular observations provide evidence that a systemic anti-tumor immune response was induced by the combination of laser and nanotechnology.

  13. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study.

    PubMed

    Garbe, Edeltraut; Andersohn, Frank; Bronder, Elisabeth; Klimpel, Andreas; Thomae, Michael; Schrezenmeier, Hubert; Hildebrandt, Martin; Späth-Schwalbe, Ernst; Grüneisen, Andreas; Mayer, Beate; Salama, Abdulgabar; Kurtal, Hanife

    2011-09-01

    Drug-induced immune haemolytic anaemia is a rare but serious condition. This study investigated the possibility of drug aetiology of immune haemolytic anaemia (IHA) in 134 patients with new onset of IHA who were identified in the Berlin Case-Control Surveillance Study between 2000 and 2009. Single drugs related to IHA in three or more patients and assessed more than once as a certain or probable cause of IHA in a standardized causality assessment included diclofenac, fludarabine, oxaliplatin, ceftriaxone and piperacillin. In a case-control study including all 124 IHA cases developed in outpatient care and 731 controls, significantly increased odds ratios (OR) were observed for beta-lactam antibiotics (OR=8·8; 95% confidence interval [CI] 3·2-25·2), cotrimoxazole (OR=6·5; CI 1·1-37·9), ciprofloxacin (OR=6·9, CI 1·3-38·5), fludarabine (OR=22·2; CI: 2·8-454·5) and lorazepam (OR=5·3; CI: 1·2-21·2). Excluding new onset cases with a chronic IHA disease course, an increased risk became also apparent for diclofenac with an OR of 3·1 (CI 1·3-7·0). This is the first case-control study investigating drugs as risk factors for IHA. It corroborates an increased risk for several drugs that have been implicated as a cause of IHA in the standardized causality assessment of individual cases. PMID:21749359

  14. Cigarette Smoke Induces Immune Responses to Vimentin in both, Arthritis-Susceptible and -Resistant Humanized Mice.

    PubMed

    Bidkar, Mitali; Vassallo, Robert; Luckey, David; Smart, Michele; Mouapi, Kelly; Taneja, Veena

    2016-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease marked by chronic synovial inflammation and both, genetic and environmental factors are involved in its pathogenesis. Human leukocyte antigen (HLA) DRB1*0401 is associated with susceptibility to develop RA, while cigarette smoke (CS) exposure promotes seropositive disease with increased severity in DRB1*0401+ individuals. Smokers have higher levels of antibodies against citrullinated peptides. In this study, we determined whether the response to a known autoantigen, Vimentin (Vim) is shared epitope specific and how CS influences this response using transgenic-mice carrying RA-susceptible,*0401, and -resistant, *0402, genes. Following relatively brief exposure to CS, peptidyl arginine deiminase (PAD) enzyme expression was increased in murine lungs. Cigarette smoking led to production of Interferon (IFN)-γ with reduced levels of Interleukin (IL)-10 by splenocytes of *0401 mice. In contrast, CS augmented Th2 cytokines along with T-regulatory cells in *0402 mice. An increase in levels of antibodies to native and citrullinated Vim was observed in naïve mice of both strains following CS exposure. Our data showed that both arthritis-susceptible and -resistant mice can generate cellular and humoral immunity to Vim; however CS-induced modulation of host immunity is dependent on the interaction with the host HLA genes. PMID:27602574

  15. A recombinant varicella vaccine harboring a respiratory syncytial virus gene induces humoral immunity.

    PubMed

    Murakami, Kouki; Matsuura, Masaaki; Ota, Megumi; Gomi, Yasuyuki; Yamanishi, Koichi; Mori, Yasuko

    2015-11-01

    The varicella-zoster virus (VZV) Oka vaccine strain (vOka) is highly efficient and causes few adverse events; therefore, it is used worldwide. We previously constructed recombinant vOka (rvOka) harboring the mumps virus gene. Immunizing guinea pigs with rvOka induced the production of neutralizing antibodies against the mumps virus and VZV. Here, we constructed recombinant vOka viruses containing either the respiratory syncytial virus (RSV) subgroup A fusion glycoprotein (RSV A-F) gene or RSV subgroup B fusion glycoprotein (RSV B-F) gene (rvOka-RSV A-F or rvOka-RSV B-F). Indirect immunofluorescence and Western blot analyses confirmed the expression of each recombinant RSV protein in virus-infected cells. Immunizing guinea pigs with rvOka-RSV A-F or rvOka-RSV B-F led to the induction of antibodies against RSV proteins. These results suggest that the current varicella vaccine genome can be used to generate custom-made vaccine vectors to develop the next generation of live vaccines. PMID:26116253

  16. Regulatory effects of interleukin-6 in immunoglobulin G immune-complex-induced lung injury.

    PubMed Central

    Shanley, T. P.; Foreback, J. L.; Remick, D. G.; Ulich, T. R.; Kunkel, S. L.; Ward, P. A.

    1997-01-01

    Interleukin-6 (IL-6) is a cytokine produced in response to a variety of inflammatory stimuli. Although IL-6 is often observed in increased amounts in acute respiratory distress syndrome, its role in the development of lung injury is unclear. The role of IL-6 was studied in the rat model of lung injury induced by the intra-alveolar deposition of IgG immune complexes. IL-6 induction, as determined by Northern blot analysis and bioactivity, was found as a function of time during the course of development of injury. Recombinant IL-6 instilled intratracheally at commencement of injury led to substantial reductions in lung vascular permeability, neutrophil accumulation, and levels of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluids. Conversely, blocking of intrinsic IL-6 by a neutralizing antibody resulted in increases in lung vascular permeability, neutrophil content, and TNF-alpha levels in bronchoalveolar lavage fluids. Rat alveolar macrophages stimulated in vitro with lipopolysaccharide in the presence of IL-6 showed a significant reduction in TNF-alpha expression. Together, these findings suggest that IL-6 acts as an intrinsic regulator of lung inflammatory injury after deposition of IgG immune complexes and that the protective effects of exogenously administered IL-6 may be in part linked to suppressed TNF-alpha production. Images Figure 1 Figure 4 PMID:9212745

  17. Innate immune response in experimentally induced bovine intramammary infection with Staphylococcus simulans and S. epidermidis

    PubMed Central

    2011-01-01

    Coagulase-negative staphylococci (CNS) are in several countries the most common bacteria isolated in subclinical mastitis. To investigate the innate immune response of cows to infections with two common mastitis-causing CNS species, Staphylococcus epidermidis and Staphylococcus simulans, experimental intramammary infection was induced in eight cows using a crossover design. The milk somatic cell count (SCC), N-acetyl-β-D-glucosaminidase (NAGase) activity, milk amyloid A (MAA), serum amyloid A (SAA) and proinflammatory cytokines interleukin (IL)-1β, IL-8, and tumor necrosis factor α (TNF-α) were determined at several time points before and after challenge. All cows became infected and showed mild to moderate clinical signs of mastitis. The spontaneous elimination rate of the 16 infections was 31.3%, with no difference between species. Infections triggered a local cytokine response in the experimental udder quarters, but cytokines were not detected in the uninfected control quarters or in systemic circulation. The innate local immune response for S. simulans was slightly stronger, with significantly higher concentrations of IL-1β and IL-8. The IL-8 response could be divided into early, delayed, or combined types of response. The CNS species or persistency of infection was not associated with the type of IL-8 response. No significant differences were seen between spontaneously eliminated or persistent infections. PMID:21414189

  18. Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

    PubMed Central

    Erkes, Dan A.; Selvan, Senthamil R.

    2014-01-01

    Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD) using animal contact hypersensitivity (CHS) models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD) to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1) ex vivo haptenation, (2) in situ haptenation, (3) epifocal hapten application, and (4) antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field. PMID:24949488

  19. Regulation of antiviral innate immune signaling by stress-induced RNA granules

    PubMed Central

    Yoneyama, Mitsutoshi; Jogi, Michihiko; Onomoto, Koji

    2016-01-01

    Activation of antiviral innate immunity is triggered by cellular pattern recognition receptors. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) detect viral non-self RNA in cytoplasm of virus-infected cells and play a critical role in the clearance of the invaded viruses through production of antiviral cytokines. Among the three known RLRs, RIG-I and melanoma differentiation-associated gene 5 recognize distinct non-self signatures of viral RNA and activate antiviral signaling. Recent reports have clearly described the molecular machinery underlying the activation of RLRs and interactions with the downstream adaptor, mitochondrial antiviral signaling protein (MAVS). RLRs and MAVS are thought to form large multimeric filaments around cytoplasmic organelles depending on the presence of Lys63-linked ubiquitin chains. Furthermore, RLRs have been shown to localize to stress-induced ribonucleoprotein aggregate known as stress granules and utilize them as a platform for recognition/activation of signaling. In this review, we will focus on the current understanding of RLR-mediated signal activation and the interactions with stress-induced RNA granules. PMID:26748340

  20. Regulation of antiviral innate immune signaling by stress-induced RNA granules.

    PubMed

    Yoneyama, Mitsutoshi; Jogi, Michihiko; Onomoto, Koji

    2016-03-01

    Activation of antiviral innate immunity is triggered by cellular pattern recognition receptors. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) detect viral non-self RNA in cytoplasm of virus-infected cells and play a critical role in the clearance of the invaded viruses through production of antiviral cytokines. Among the three known RLRs, RIG-I and melanoma differentiation-associated gene 5 recognize distinct non-self signatures of viral RNA and activate antiviral signaling. Recent reports have clearly described the molecular machinery underlying the activation of RLRs and interactions with the downstream adaptor, mitochondrial antiviral signaling protein (MAVS). RLRs and MAVS are thought to form large multimeric filaments around cytoplasmic organelles depending on the presence of Lys63-linked ubiquitin chains. Furthermore, RLRs have been shown to localize to stress-induced ribonucleoprotein aggregate known as stress granules and utilize them as a platform for recognition/activation of signaling. In this review, we will focus on the current understanding of RLR-mediated signal activation and the interactions with stress-induced RNA granules. PMID:26748340

  1. Porphyromonas gingivalis Peptidoglycans Induce Excessive Activation of the Innate Immune System in Silkworm Larvae*

    PubMed Central

    Ishii, Kenichi; Hamamoto, Hiroshi; Imamura, Katsutoshi; Adachi, Tatsuo; Shoji, Mikio; Nakayama, Koji; Sekimizu, Kazuhisa

    2010-01-01

    Porphyromonas gingivalis, a pathogen that causes inflammation in human periodontal tissue, killed silkworm (Bombyx mori, Lepidoptera) larvae when injected into the blood (hemolymph). Silkworm lethality was not rescued by antibiotic treatment, and heat-killed bacteria were also lethal. Heat-killed bacteria of mutant P. gingivalis strains lacking virulence factors also killed silkworms. Silkworms died after injection of peptidoglycans purified from P. gingivalis (pPG), and pPG toxicity was blocked by treatment with mutanolysin, a peptidoglycan-degrading enzyme. pPG induced silkworm hemolymph melanization at the same dose as that required to kill the animal. pPG injection increased caspase activity in silkworm tissues. pPG-induced silkworm death was delayed by injecting melanization-inhibiting reagents (a serine protease inhibitor and 1-phenyl-2-thiourea), antioxidants (N-acetyl-l-cysteine, glutathione, and catalase), and a caspase inhibitor (Ac-DEVD-CHO). Thus, pPG induces excessive activation of the innate immune response, which leads to the generation of reactive oxygen species and apoptotic cell death in the host tissue. PMID:20702417

  2. Porphyromonas gingivalis peptidoglycans induce excessive activation of the innate immune system in silkworm larvae.

    PubMed

    Ishii, Kenichi; Hamamoto, Hiroshi; Imamura, Katsutoshi; Adachi, Tatsuo; Shoji, Mikio; Nakayama, Koji; Sekimizu, Kazuhisa

    2010-10-22

    Porphyromonas gingivalis, a pathogen that causes inflammation in human periodontal tissue, killed silkworm (Bombyx mori, Lepidoptera) larvae when injected into the blood (hemolymph). Silkworm lethality was not rescued by antibiotic treatment, and heat-killed bacteria were also lethal. Heat-killed bacteria of mutant P. gingivalis strains lacking virulence factors also killed silkworms. Silkworms died after injection of peptidoglycans purified from P. gingivalis (pPG), and pPG toxicity was blocked by treatment with mutanolysin, a peptidoglycan-degrading enzyme. pPG induced silkworm hemolymph melanization at the same dose as that required to kill the animal. pPG injection increased caspase activity in silkworm tissues. pPG-induced silkworm death was delayed by injecting melanization-inhibiting reagents (a serine protease inhibitor and 1-phenyl-2-thiourea), antioxidants (N-acetyl-l-cysteine, glutathione, and catalase), and a caspase inhibitor (Ac-DEVD-CHO). Thus, pPG induces excessive activation of the innate immune response, which leads to the generation of reactive oxygen species and apoptotic cell death in the host tissue. PMID:20702417

  3. Neonatal immune challenge exacerbates seizure-induced hippocampus-dependent memory impairment in adult rats.

    PubMed

    Yin, Ping; Li, Zhen; Wang, Ying-Yan; Qiao, Na-Na; Huang, Shan-Ying; Sun, Ruo-Peng; Wang, Ji-Wen

    2013-04-01

    Our aim was to examine whether neonatal lipopolysaccharide (LPS) exposure is associated with changes in microglia and whether these alternations could influence later seizure-induced neurobehavioral outcomes. Male pups were first injected intraperitoneally with either LPS or saline on postnatal day 3 (P3) and postnatal day 5 (P5). Immunohistochemical analysis showed that LPS-treated animals exhibited increased microglia activation that persisted into adolescence. At P45, seizures were induced in rats by intraperitoneal injection of kainic acid (KA). Rats treated with LPS neonatally showed significantly greater proinflammatory responses and performed significantly worse in the Y-maze, Morris water maze, and inhibitory avoidance tasks after KA insult. Treatment with minocycline at the time of neonatal LPS exposure to block LPS-induced microglia alternation attenuated the exaggerated neuroinflammatory responses and alleviated memory impairment associated with the KA insult. Our findings suggest that neonatal immune activation can predispose the brain to exacerbated behavioral deficits following seizures in adulthood, possibly by priming microglia. PMID:23353000

  4. Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism.

    PubMed

    Federico, Alessandro; Aitella, Ernesto; Sgambato, Dolores; Savoia, Alfonso; De Bartolomeis, Fabio; Dallio, Marcello; Ruocco, Eleonora; Pezone, Luciano; Abbondanza, Ciro; Loguercio, Carmela; Astarita, Corrado

    2015-01-01

    The HCV protease inhibitor telaprevir associated with peginterferon-alpha and ribavirin, was widely used in the recent past as standard treatment in HCV genotype-1 infected patients. Telaprevir improves the sustained virology response rates, but at the same time increases the frequency of adverse cutaneous reactions. However, mechanisms through which telaprevir induces cutaneous lesions are not yet defined. A 50-year-old woman, affected by HCV genotype 1b, was admitted to our Department for a telaprevir-related severe cutaneous eruptions, eight weeks after starting a triple therapy (telaprevir associated with Peginterferon-alpha and ribavirin). Mechanisms of cutaneous reactions were investigated by skin tests with non-irritating concentrations of telaprevir and by activating in vitro T lymphocyte with different concentrations. Immediate and delayed responses to skin testing were negative, but the drug-induced lymphocytes activation was significantly higher as compared to patient's baseline values and to parallel results obtained in three healthy subjects (p < 0.05). In conclusion, adverse cutaneous reactions of our patient were caused by a telaprevir-induced T-cell dependent immune mechanism. PMID:25864225

  5. Attenuation of Cocaine-Induced Locomotor Activity in Male and Female Mice by Active Immunization

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; Kinsey, Berma M.; Kosten, Thomas R.; Orson, Frank M.

    2014-01-01

    Background and objectives Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Methods Male and female BALB/c mice were vaccinated (n=44) or served as non-vaccinated controls (n=34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7-wk and plasma obtained at 8-wk to assess antibody levels. Results High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. Discussion and conclusions The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Scientific significance Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. PMID:25251469

  6. Bacillus amyloliquefaciens SQR9 induces dendritic cell maturation and enhances the immune response against inactivated avian influenza virus

    PubMed Central

    Huang, Lulu; Qin, Tao; Yin, YinYan; Gao, Xue; Lin, Jian; Yang, Qian; Yu, Qinghua

    2016-01-01

    The objective of this study was to evaluate the stimulatory effects of Bacillus amyloliquefaciens SQR9 on dendritic cells (DCs) and to verify its ability to enhance the immune response by modulating DC maturation. The results demonstrated that B. amyloliquefaciens SQR9 can adhere to the nasal epithelium and be taken up by DCs in the nasal mucosa, thereby inducing DC maturation and resulting in increased CD80, CD86, CD40 and MHCII expression and cytokine secretion. The frequencies of CD4+ and CD8+ T cells and CD69+ memory T cells were increased in spleens after nasal immunization with virus plus B. amyloliquefaciens SQR9 compared to immunization with inactivated H9N2 AIV alone. Moreover, the levels of sIgA in the nasal cavity, the trachea, and the lung and the levels of IgG, IgG1, and IgG2a in serum were significantly increased in mice administered WIV plus SQR9 compared to mice administered H9N2 WIV alone. The results of this study demonstrated that B. amyloliquefaciens SQR9 can stimulate DC maturation to effectively induce an immune response. In conclusion, an effective immune response may result from the uptake of H9N2 by DCs in the nasal mucosa, thereby stimulating DC maturation and migration to cervical lymph nodes to initiate immune response. PMID:26892720

  7. Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells

    PubMed Central

    Bangi, Erdem; Pitsouli, Chrysoula; Rahme, Laurence G; Cagan, Ross; Apidianakis, Yiorgos

    2012-01-01

    Although pathogenic bacteria are suspected contributors to colorectal cancer progression, cancer-promoting bacteria and their mode of action remain largely unknown. Here we report that sustained infection with the human intestinal colonizer Pseudomonas aeruginosa synergizes with the Ras1V12 oncogene to induce basal invasion and dissemination of hindgut cells to distant sites. Cross-talk between infection and dissemination requires sustained activation by the bacteria of the Imd–dTab2–dTak1 innate immune pathway, which converges with Ras1V12 signalling on JNK pathway activation, culminating in extracellular matrix degradation. Hindgut, but not midgut, cells are amenable to this cooperative dissemination, which is progressive and genetically and pharmacologically inhibitable. Thus, Drosophila hindgut provides a valuable system for the study of intestinal malignancies. PMID:22498775

  8. Bacterial lysates and ribosomes as inducers of specific immune responses: a comparative study.

    PubMed

    Béné, M C; Kahl, L; Perruchet, A M; Hermes, H; Mösges, M; Normier, G; Binz, H; Faure, G C

    1993-11-01

    A bacterial lysate (OM-85 BV), a preparation of purified bacterial ribosomes (D53) and a placebo were tested for ability to induce the local appearance of specific antibody-containing cells. The three compounds were given orally to 90 children who required tonsillectomy. Surgery was carried out after 1 month of therapy. Frozen-cut sections of each tonsil were tested in indirect immunofluorescence. Cells containing antibodies directed to Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae or Klebsiella pneumoniae were enumerated. Lowest values were noted in the placebo group. Slightly higher numbers were observed after treatment with OM-85 BV, but significant increases were noted only for the elevated numbers of specific antibody-containing cells observed after D53 therapy. Bacterial ribosomal preparations thus contribute efficient induction of specific local immune responses in man. PMID:8235452

  9. Animal-induced injuries and disease, neonatal jaundice, immunizations, and viral infections.

    PubMed

    Gerson, W T

    1996-08-01

    Highlights from the past years' literature on the topics of animal-induced injuries and diseases, neonatal jaundice, immunizations, and viral infections are discussed from the perspective of the general pediatrician. An effort is made to place recent advances in care or understanding of clinical problems into the context of the pediatric office practice. The current reality of health care-be it managed care, care for the underserved, or the recent pressures on academic and hospital-based medicine-does not alter the importance of the delivery of quality care at the office level. Although it is now popular to define quality of health care in cute advertising copy, as if we are selling durable goods, excellence in pediatric office-based practice continues to require broad strokes of medical knowledge coupled with a unswerving commitment to and advocacy for the needs and well-being of infants, children, and young adults. PMID:8954278

  10. Cellular immune mechanisms in Coxsackievirus group B, type 3 induced myocarditis in Balb/C mice

    SciTech Connect

    Huber, S.A.; Job, L.P.

    1983-01-01

    Coxsackie B viruses are a common cause of viral myocarditis in humans. A murine model of the human disease has been developed using Coxsackievirus group B, type 3 and inbred Balb/c mice. Infection of T lymphocyte deficient mice does not result in significant myocarditis indicating the importance of T cells in this disease. The virus can be isolated from the hearts of T cell deficient and normal mice in equal concentrations. Virus elimination presumably is mediated by virus specific neutralizing antibody induced in both groups. T lymphocytes, natural killer cells and macrophage obtained from normal virus infected mice are all capable of lysing myofibers in vitro. Maximum lysis is obtained with the cytolytic T cells. When these cell populations or Coxsackievirus immune antibody were adoptively transferred into T lymphocyte deficient animals infected with the virus, only animals given T cells developed significant myocarditis.

  11. Inhibitory effect of BMAP-28 on Leptospiral Lipopolysaccharide-Induced TLR2-Dependent Immune Response in Bovine Cells

    PubMed Central

    GUO, Yijie; Ding, Cuiping; Zhang, Bo; XU, Jun; XUN, Meng; XU, Jiru

    2016-01-01

    Background Bovine leptospirosis is a widespread zoonotic disease, leading to serious economic losses in animal production and causing potential hazards to human health. Leptospiral lipopolysaccharide (L-LPS) plays an important role in leptospirosis pathogenicity. Objectives With respect to L-LPS endotoxin-like activity, we examined bovine immune response to L-LPS and the inhibitory ability of bovine myeloid antimicrobial peptide-28 (BMAP-28) against L-LPS-induced immune activation in bovine cells. Materials and Methods In this study, L-LPS-induced proinflammatory cytokine production in bovine cells was quantitatively measured with real-time PCR and ELISA, and we determined which cell membrane receptors (toll-like receptor [TLR]2 and TLR4) played a major role. In addition, the ability of BMAP-28 to inhibit L-LPS-induced endotoxin-like immune activation in bovine cells was determined by the decrease in cytokine secretion. Results L-LPS showed the ability to induce cytokine production in bovine cells, and its induction was TLR2-dependent. BMAP-28 was used to inhibit L-LPS-induced endotoxin-like activity. The function of BMAP-28 was to inhibit LPS-induced TLR2 expression and cytokine production. Conclusions In this study, the L-LPS immune response of bovine cells was significant, indicating that TLR2 is the predominant receptor for L-LPS. Due to L-LPS endotoxin-like activity, we found a strategy through using BMAP-28 to prevent L-LPS-induced TLR2-dependent immune activation in bovine cells.

  12. Induced hyperketonemia affects the mammary immune response during lipopolysaccharide challenge in dairy cows.

    PubMed

    Zarrin, M; Wellnitz, O; van Dorland, H A; Bruckmaier, R M

    2014-01-01

    Metabolic adaptations during negative energy and nutrient balance in dairy cows are thought to cause impaired immune function and hence increased risk of infectious diseases, including mastitis. Characteristic adaptations mostly occurring in early lactation are an elevation of plasma ketone bodies and free fatty acids (nonesterified fatty acids, NEFA) and diminished glucose concentration. The aim of this study was to investigate effects of elevated plasma β-hydroxybutyrate (BHBA) at simultaneously even or positive energy balance and thus normal plasma NEFA and glucose on factors related to the immune system in liver and mammary gland of dairy cows. In addition, we investigated the effect of elevated plasma BHBA and intramammary lipopolysaccharide (LPS) challenge on the mammary immune response. Thirteen dairy cows were infused either with BHBA (HyperB, n=5) to induce hyperketonemia (1.7 mmol/L) or with a 0.9% saline solution (NaCl, n=8) for 56 h. Two udder quarters were injected with 200 μg of LPS after 48 h of infusion. Rectal temperature (RT) and somatic cell counts (SCC) were measured before, at 48 h after the start of infusions, and hourly during the LPS challenge. The mRNA abundance of factors related to the immune system was measured in hepatic and mammary tissue biopsies 1 wk before and 48 h after the start of the infusion, and additionally in mammary tissue at 56 h of infusion (8h after LPS administration). At 48 h of infusion in HyperB, the mRNA abundance of serum amyloid A (SAA) in the mammary gland was increased and that of haptoglobin (Hp) tended to be increased. Rectal temperature, SCC, and mRNA abundance of candidate genes in the liver were not affected by the BHBA infusion until 48 h. During the following LPS challenge, RT and SCC increased in both groups. However, SCC increased less in HyperB than in NaCl. Quarters infused with LPS showed a more pronounced increase of mRNA abundance of IL-8 and IL-10 in HyperB than in NaCl. The results demonstrate

  13. Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1+ Acute Myeloid Leukemia

    PubMed Central

    Sundarasetty, Bala Sai; Singh, Vijay Kumar; Salguero, Gustavo; Geffers, Robert; Rickmann, Mareike; Macke, Laura; Borchers, Sylvia; Figueiredo, Constanca; Schambach, Axel; Gullberg, Urban; Provasi, Elena; Bonini, Chiara; Ganser, Arnold; Woelfel, Thomas

    2013-01-01

    Abstract Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable “SmartDC/tWT1” (GM-CSF+, IL-4+, tWT1+, IL-6+, IL-8+, TNF-α+, MCP-1+, HLA-DR+, CD86+, CCR2+, CCR5+) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD+ AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8+ T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1+ leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1−/−.IL2rγc−/− mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1+ tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1

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

    PubMed Central

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

    2016-01-01

    DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor– bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID:27453950

  15. IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

    PubMed Central

    Bahri, Rajia; Pateras, Ioannis S; D’Orlando, Orietta; Goyeneche-Patino, Diego A; Campbell, Michelle; Polansky, Julia K; Sandig, Hilary; Papaioannou, Marilena; Evangelou, Kostas; Foukas, Periklis G; Gorgoulis, Vassilis G; Bulfone-Paus, Silvia

    2015-01-01

    IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15−/− and Il15rα−/− mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15−/− but not Il15rα−/− mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15−/− mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFNγ, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu. PMID:26405589

  16. Protective effect of hydrogen-rich saline against radiation-induced immune dysfunction

    PubMed Central

    Zhao, Sanhu; Yang, Yanyong; Liu, Wen; Xuan, Zhiqiang; Wu, Shouming; Yu, Shunfei; Mei, Ke; Huang, Yijuan; Zhang, Pei; Cai, Jianming; Ni, Jin; Zhao, Yaoxian

    2014-01-01

    Recent studies showed that hydrogen can be used as an effective radioprotective agent through scavenging free radicals. This study was undertaken to evaluate the radioprotective effects of hydrogen on immune system in mice. H2 was dissolved in physiological saline using an apparatus produced by our department. Spleen index and histological analysis were used to evaluate the splenic structural damage. Spleen superoxide dismutase, GSH, MDA were measured to appraise the antioxidant capacity and a DCF assay for the measurement of radical oxygen species. Cell apoptosis was evaluated by an Annexin V-FITC and propidium iodide staining method as well as the apoptotic proteins such as Bcl-2, Bax, caspase-3 and c-caspase-3. CD4+ and CD8+ T cells subtypes were detected by flow cytometry with FITC-labelled antimouse CD4 and PE antimouse CD8 staining. Real-time PCR was utilized to determine the CD4+ T cell subtypes and related cytokines. Our study demonstrated that pre-treatment with H2 could increase the spleen index and attenuate the radiation damage on splenic structure. Radical oxygen species level was also reduced by H2 treatment. H2 also inhibited radiation-induced apoptosis in splenocytes and down-regulated pro-apoptotic proteins in living mice. Radiation-induced imbalance of T cells was attenuated by H2. Finally, we found that H2 could regulate the polarization of CD4+ T cells and the level of related cytokines. This study suggests H2 as an effective radioprotective agent on immune system by scavenging reactive oxygen species. PMID:24618260

  17. Treatment of Collagen-Induced Arthritis Using Immune Modulatory Properties of Human Mesenchymal Stem Cells.

    PubMed

    Park, Kyu-Hyung; Mun, Chin Hee; Kang, Mi-Il; Lee, Sang-Won; Lee, Soo-Kon; Park, Yong-Beom

    2016-01-01

    Mesenchymal stem cells (MSCs) have immune modulatory properties. We investigated the potential therapeutic effects of human bone marrow (BM)-, adipose tissue (AD)-, and cord blood (CB)-derived MSCs in an experimental animal model of rheumatoid arthritis (RA) and explored the mechanism underlying immune modulation by MSCs. We evaluated the therapeutic effect of clinically available human BM-, AD-, and CB-derived MSCs in DBA/1 mice with collagen-induced arthritis (CIA). CIA mice were injected intraperitoneally with three types of MSCs. Treatment control animals were injected with 35 mg/kg methotrexate (MTX) twice weekly. Clinical activity in CIA mice, degree of inflammation, cytokine expression in the joint, serum cytokine levels, and regulatory T cells (Tregs) were evaluated. Mice treated with human BM-, AD-, and CB-MSCs showed significant improvement in clinical joint score, comparable to MTX-treated mice. Histologic examination showed greatly reduced joint inflammation and damage in MSC-treated mice compared with untreated mice. Microcomputed tomography also showed little joint damage in the MSC-treated group. MSCs significantly decreased serum interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon-γ and increased IL-10 and transforming growth factor-β levels. Tregs were increased in mice treated with MSCs compared to untreated or MTX-treated mice. Human BM-, AD-, and CB-MSCs significantly suppressed joint inflammation in CIA mice. The cells decreased proinflammatory cytokines and upregulated anti-inflammatory cytokines and induced Tregs. Therefore, our study suggests that the use of human BM-, AD-, and CB-MSCs could be an effective therapeutic approach for RA. PMID:25853338

  18. Bifidobacterium longum CECT 7347 Modulates Immune Responses in a Gliadin-Induced Enteropathy Animal Model

    PubMed Central

    Laparra, José Moisés; Olivares, Marta; Gallina, Onofrio; Sanz, Yolanda

    2012-01-01

    Coeliac disease (CD) is an autoimmune disorder triggered by gluten proteins (gliadin) that involves innate and adaptive immunity. In this study, we hypothesise that the administration of Bifidobacterium longum CECT 7347, previously selected for reducing gliadin immunotoxic effects in vitro, could exert protective effects in an animal model of gliadin-induced enteropathy. The effects of this bacterium were evaluated in newborn rats fed gliadin alone or sensitised with interferon (IFN)-γ and fed gliadin. Jejunal tissue sections were collected for histological, NFκB mRNA expression and cytokine production analyses. Leukocyte populations and T-cell subsets were analysed in peripheral blood samples. The possible translocation of the bacterium to different organs was determined by plate counting and the composition of the colonic microbiota was quantified by real-time PCR. Feeding gliadin alone reduced enterocyte height and peripheral CD4+ cells, but increased CD4+/Foxp3+ T and CD8+ cells, while the simultaneous administration of B. longum CECT 7347 exerted opposite effects. Animals sensitised with IFN-γ and fed gliadin showed high cellular infiltration, reduced villi width and enterocyte height. Sensitised animals also exhibited increased NFκB mRNA expression and TNF-α production in tissue sections. B. longum CECT 7347 administration increased NFκB expression and IL-10, but reduced TNF-α, production in the enteropathy model. In sensitised gliadin-fed animals, CD4+, CD4+/Foxp3+ and CD8+ T cells increased, whereas the administration of B. longum CECT 7347 reduced CD4+ and CD4+/Foxp3+ cell populations and increased CD8+ T cell populations. The bifidobacterial strain administered represented between 75–95% of the total bifidobacteria isolated from all treated groups, and translocation to organs was not detected. These findings indicate that B. longum attenuates the production of inflammatory cytokines and the CD4+ T-cell mediated immune response in an animal model

  19. Heat killed multi-serotype Shigella immunogens induced humoral immunity and protection against heterologous challenge in rabbit model.

    PubMed

    Nag, Dhrubajyoti; Sinha, Ritam; Mitra, Soma; Barman, Soumik; Takeda, Yoshifumi; Shinoda, Sumio; Chakrabarti, M K; Koley, Hemanta

    2015-11-01

    Recently we have shown the homologous protective efficacy of heat killed multi-serotype Shigella (HKMS) immunogens in a guinea pig colitis model. In our present study, we have advanced our research by immunizing rabbits with a reduced number of oral doses and evaluating the host's adaptive immune responses. The duration of immunogenicity and subsequently protective efficacy was determined against wild type heterologous Shigella strains in a rabbit luminal model. After three successive oral immunizations with HKMS immunogens, serum and lymphocyte supernatant antibody titer against the heterologous shigellae were reciprocally increased and remained at an elevated level up to 180 days. Serogroup and serotype specific O-antigen of lipopolysaccharide and immunogenic proteins of heterologous challenge strains were detected by immunoblot assay. Up-regulation of IL-12p35, IFN-γ and IL-10 mRNA expression was detected in immunized rabbit peripheral blood mononuclear cells (PBMC) after stimulation with HKMS in vitro. HKMS-specific plasma cell response was confirmed by production of a relatively higher level of HKMS-specific IgG in immunized PBMC supernatant compared to control group. Furthermore, the immunized groups of rabbits exhibited complete protection against wild type heterologous shigellae challenge. Thus HKMS immunogens induced humoral and Th1-mediated adaptive immunity and provided complete protection in a rabbit model. These immunogens could be a broad spectrum non-living vaccine candidate for human use in the near future. PMID:26210044

  20. Schistosoma mansoni: is acquired immunity induced by highly x-irradiated cercariae dependent on the size of the challenging dose

    SciTech Connect

    Hsue, S.Y.; Hsue, H.F.; Osborne, J.W.; Johnson, S.C.

    1982-04-01

    A high degree of immunity, as shown by a 91% reduction of the number of worms recovered was found in five groups of mice that were immunized five times with highly X-irradiated cercariae and then challenged with 10, 20, 50, 100, or 500 normal Schistosoma mansoni cercariae. The results indicated that there were no significant differences in worm reduction in immunized mice challenged with different numbers of cercariae; consequently the immunity induced by this immunization method did not appear to be challenge-dose-dependent. However, the results also showed that when immunized mice were challenged with 500, 100, 50, 20, and 10 cercariae, 0, 13, 26, 56, and 68%, respectively, of the experimental animals were free of worms. Thus, the percentage of worm-negative cases increased as the number of challenge cercariae decreased. When viewed in this manner, the acquired immunity may be considered challenge-dose-dependent as well. If this method of vaccination is used for schistosomiasis control, we may anticipate that in both hypo- and hyperendemic areas, the intensity of infection and the severity of the disease will be reduced owing to a reduction in worms burdens, and in hypoendemic areas, there will be a number of worm-free cases.

  1. The Use of a Dexamethasone-inducible System to Synchronize Xa21 Expression to Study Rice Immunity

    PubMed Central

    Caddell, Daniel F.; Wei, Tong; Park, Chang-Jin; Ronald, Pamela C.

    2016-01-01

    Inducible gene expression systems offer researchers the opportunity to synchronize target gene expression at particular developmental stages and in particular tissues. The glucocorticoid receptor (GR), a vertebrate steroid receptor, has been well adopted for this purpose in plants. To generate steroid-inducible plants, a construct of GAL4-binding domain-VP16 activation domain-GR fusion (GVG) with the target gene under the control of upstream activation sequence (UAS) has been developed and extensively used in plant research. Immune receptors perceive conserved molecular patterns secreted by pathogens and initiate robust immune responses. The rice immune receptor, XA21, recognizes a molecular pattern highly conserved in all sequenced genomes of Xanthomonas, and confers robust resistance to X. oryzae pv. oryzae (Xoo). However, identifying genes downstream of XA21 has been hindered because of the restrained lesion and thus limited defense response region in the plants expressing Xa21. Inducible expression allows for a synchronized immune response across a large amount of rice tissue, well suited for studying XA21-mediated immunity by genome-wide approaches such as transcriptomics and proteomics. In this protocol, we describe the use of this GVG system to synchronize Xa21 expression.

  2. Irradiation of Anastrepha ludens (Diptera: Tephritidae) revisited: optimizing sterility induction.

    PubMed

    Rull, Juan; Diaz-Fleischer, Francisco; Arredondo, Jose

    2007-08-01

    Irradiation doses currently applied to sterilize Mexican fruit flies, Anastrepha ludens (Loew) (Diptera: Tephritidae), for release under the sterile insect technique eradication campaign in Mexico, were reviewed in an effort to increase sterile male performance in the field. A dose maximizing sterility induction into wild populations was sought by balancing somatic fitness with genetic sterility. Doses of 40, 60, and 80 Gy induced 95% or more sterility in all males, which in turn induced similar degrees of sterility into a cohort of wild flies in the laboratory. However, a low dose of 40 Gy was sufficient to completely suppress egg production in females. Similarly, a mild carryover of genetic damage might have been transferred to the F1 progeny of males irradiated at 40 Gy crossed with fertile wild females. Our results suggest that the 80-Gy dose currently applied in Mexico can be lowered substantially without jeopardizing program goals. This view could be strengthened by comparing performance of males irradiated at different doses under more natural settings. In general, we discuss the value of determining irradiation doses for pest species where females are more radiosensitive than males, by selecting the dose that causes 100% sterility in females. PMID:17849864

  3. Continuous sterilization of plumbing systems

    NASA Technical Reports Server (NTRS)

    Bryan, C. J.; Moyers, C. V.; Wright, E. E., Jr.

    1979-01-01

    Continuous sterilization of plumbing, such as in hospitals, clinics, and biological testing laboratories is possible with ethylene oxide/Freon 12 (ETO/F-12) humidifier developed for sterilization of potable water systems.

  4. Sterilization surgery - making a decision

    MedlinePlus

    ... have sterilization surgery. However, some may regret the decision later. Men or women who are younger at ... the options available to you before making the decision to have a sterilization procedure.

  5. Intranasal Immunization with a Colloid-Formulated Bacterial Extract Induces an Acute Inflammatory Response in the Lungs and Elicits Specific Immune Responses