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Article ; Online: Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH.

Parsons, Andrea J / Ophir, Sabrina I / Duty, J Andrew / Kraus, Thomas A / Stein, Kathryn R / Moran, Thomas M / Tortorella, Domenico

Communications biology

2022 Volume 5, Issue 1, Page(s) 387

Abstract: Human cytomegalovirus (HCMV) is a β-herpesvirus that increases morbidity and mortality in immunocompromised individuals including transplant recipients and newborns. New anti-HCMV therapies are an urgent medical need for diverse patient populations. HCMV ...

Abstract	Human cytomegalovirus (HCMV) is a β-herpesvirus that increases morbidity and mortality in immunocompromised individuals including transplant recipients and newborns. New anti-HCMV therapies are an urgent medical need for diverse patient populations. HCMV infection of a broad range of host tissues is dependent on the gH/gL/gO trimer and gH/gL/UL28/UL130/UL131A pentamer complexes on the viral envelope. We sought to develop safe and effective therapeutics against HCMV by generating broadly-neutralizing, human monoclonal antibodies (mAbs) from VelocImmune® mice immunized with gH/gL cDNA. Following high-throughput binding and neutralization screening assays, 11 neutralizing antibodies were identified with unique CDR3 regions and a high-affinity (K
MeSH term(s)	Animals ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antigens, Viral ; Broadly Neutralizing Antibodies ; Cytomegalovirus/genetics ; Humans ; Infant, Newborn ; Mice ; Viral Envelope Proteins/genetics
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antigens, Viral ; Broadly Neutralizing Antibodies ; Viral Envelope Proteins
Language	English
Publishing date	2022-04-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03294-z
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Article ; Online: Immunoglobulin A antibody composition is sculpted to bind the self gut microbiome.

Yang, Chao / Chen-Liaw, Alice / Spindler, Matthew P / Tortorella, Domenico / Moran, Thomas M / Cerutti, Andrea / Faith, Jeremiah J

Science immunology

2022 Volume 7, Issue 73, Page(s) eabg3208

Abstract: Despite being the most abundantly secreted immunoglobulin isotype, the pattern of reactivity of immunoglobulin A (IgA) antibodies toward each individual's own gut commensal bacteria still remains elusive. By colonizing germ-free mice with defined ... ...

Abstract	Despite being the most abundantly secreted immunoglobulin isotype, the pattern of reactivity of immunoglobulin A (IgA) antibodies toward each individual's own gut commensal bacteria still remains elusive. By colonizing germ-free mice with defined commensal bacteria, we found that the binding specificity of bulk fecal and serum IgA toward resident gut bacteria resolves well at the species level and has modest strain-level specificity. IgA hybridomas generated from lamina propria B cells of gnotobiotic mice showed that most IgA clones recognized a single bacterial species, whereas a small portion displayed cross-reactivity. Orally administered hybridoma-produced IgAs still retained bacterial antigen binding capability, implying the potential for a new class of therapeutic antibodies. Species-specific IgAs had a range of strain specificities. Given the distinctive bacterial species and strain composition found in each individual's gut, our findings suggest the IgA antibody repertoire is shaped uniquely to bind "self" gut bacteria.
MeSH term(s)	Animals ; B-Lymphocytes ; Clone Cells ; Gastrointestinal Microbiome ; Hybridomas ; Immunoglobulin A ; Mice
Chemical Substances	Immunoglobulin A
Language	English
Publishing date	2022-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abg3208
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Article: Immune responses to viruses, bacteria, parasites and fungi in humans.

Moran, Thomas M

International reviews of immunology

2002 Volume 21, Issue 4-5, Page(s) i–vi

MeSH term(s)	Animals ; Antibody Formation ; Bacteria/immunology ; Fungi/immunology ; Humans ; Immunity, Cellular ; Parasites/immunology ; Viruses/immunology
Language	English
Publishing date	2002-07
Publishing country	England
Document type	Editorial
ZDB-ID	632825-8
ISSN	1545-5858 ; 0883-0185
ISSN (online)	1545-5858
ISSN	0883-0185
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Article ; Online: CD46 facilitates entry and dissemination of human cytomegalovirus.

Stein, Kathryn R / Gardner, Thomas J / Hernandez, Rosmel E / Kraus, Thomas A / Duty, James A / Ubarretxena-Belandia, Iban / Moran, Thomas M / Tortorella, Domenico

Nature communications

2019 Volume 10, Issue 1, Page(s) 2699

Abstract: Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature ... ...

Abstract	Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature of CMV pathogenesis and to develop targeted therapeutics. To that end, we establish a vaccination strategy utilizing membrane vesicles derived from epithelial cells to generate a library of monoclonal antibodies (mAbs) targeting cell surface proteins in their native conformation. A high-throughput inhibition assay is employed to screen these antibodies for their ability to limit infection, and mAbs targeting CD46 are identified. In addition, a significant reduction of viral proliferation in CD46-KO epithelial cells confirms a role for CD46 function in viral dissemination. Further, we demonstrate a CD46-dependent entry pathway of virus infection in trophoblasts, but not in fibroblasts, highlighting the complexity of CMV entry and identifying CD46 as an entry factor in congenital infection.
MeSH term(s)	Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/administration & dosage ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/administration & dosage ; Antibodies, Viral/immunology ; Cell Line ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/immunology ; Cytomegalovirus Infections/prevention & control ; Cytomegalovirus Infections/virology ; Epithelial Cells/immunology ; Epithelial Cells/virology ; Fibroblasts/immunology ; Fibroblasts/virology ; Gene Knockout Techniques ; Host-Pathogen Interactions/immunology ; Humans ; Membrane Cofactor Protein/genetics ; Membrane Cofactor Protein/immunology ; RNA, Small Interfering/metabolism ; Trophoblasts/immunology ; Trophoblasts/virology ; Viral Vaccines/administration & dosage ; Viral Vaccines/immunology ; Virus Internalization
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; CD46 protein, human ; Membrane Cofactor Protein ; RNA, Small Interfering ; Viral Vaccines
Language	English
Publishing date	2019-06-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10587-1
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Article ; Online: Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of γδ T cells.

Li, Wenjing / Moltedo, Bruno / Moran, Thomas M

Journal of virology

2012 Volume 86, Issue 22, Page(s) 12304–12312

Abstract: The majority of deaths following influenza virus infection result from secondary bacterial superinfection, most commonly caused by Streptococcus pneumoniae. Several models have been proposed to explain how primary respiratory viral infections exacerbate ... ...

Abstract	The majority of deaths following influenza virus infection result from secondary bacterial superinfection, most commonly caused by Streptococcus pneumoniae. Several models have been proposed to explain how primary respiratory viral infections exacerbate secondary bacterial disease, but the mechanistic explanations have been contradictory. In this study, mice were infected with S. pneumoniae at different days after primary influenza A (X31) virus infection. Our findings show that the induction of type I interferons (IFNs) during a primary nonlethal influenza virus infection is sufficient to promote a deadly S. pneumoniae secondary infection. Moreover, mice deficient in type I interferon receptor (IFNAR knockout [KO] mice) effectively cleared the secondary bacterial infection from their lungs, increased the recruitment of neutrophils, and demonstrated an enhanced innate expression of interleukin-17 (IL-17) relative to wild-type (WT) mice. Lung γδ T cells were responsible for almost all IL-17 production, and their function is compromised during secondary S. pneumoniae infection of WT but not IFNAR KO mice. Adoptive transfer of γδ T cells from IFNAR KO mice reduced the susceptibility to secondary S. pneumoniae infection in the lung of WT mice. Altogether, our study highlights the importance of type I interferon as a key master regulator that is exploited by opportunistic pathogens such as S. pneumoniae. Our findings may be utilized to design effective preventive and therapeutic strategies that may be beneficial for coinfected patients during influenza epidemics.
MeSH term(s)	Animals ; Female ; Flow Cytometry/methods ; Humans ; Influenza, Human/complications ; Influenza, Human/metabolism ; Interferon Type I/metabolism ; Interleukin-17/metabolism ; Lung/virology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/immunology ; Orthomyxoviridae/metabolism ; Pneumonia, Pneumococcal/etiology ; Pneumonia, Pneumococcal/virology ; Receptors, Antigen, T-Cell, gamma-delta/metabolism ; Signal Transduction ; Streptococcus pneumoniae/metabolism ; T-Lymphocytes/immunology
Chemical Substances	Interferon Type I ; Interleukin-17 ; Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2012-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01269-12
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Article ; Online: TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer.

Kang, Chifei / Rostoker, Ran / Ben-Shumel, Sarit / Rashed, Rola / Duty, James Andrew / Demircioglu, Deniz / Antoniou, Irini M / Isakov, Lika / Shen-Orr, Zila / Bravo-Cordero, Jose Javier / Kase, Nathan / Cuajungco, Math P / Moran, Thomas M / LeRoith, Derek / Gallagher, Emily Jane

Cells

2021 Volume 10, Issue 12

Abstract: TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene ... ...

Abstract	TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene expression, cell proliferation, and migration in vitro, as well as tumor growth in vivo. We generated breast cancer cell lines with overexpressed and silenced TMEM176B, and a therapeutic antibody targeting TMEM176B. Proliferation and migration assays were performed in vitro, and tumor growth was evaluated in vivo. We performed gene expression and Western blot analyses to identify the most differentially regulated genes and signaling pathways in cells with TMEM176B overexpression and silencing. Silencing TMEM176B or inhibiting it with a therapeutic antibody impaired cell proliferation, while overexpression increased proliferation in vitro. Syngeneic and xenograft tumor studies revealed the attenuated growth of tumors with TMEM176B gene silencing compared with controls. We found that the AKT/mTOR signaling pathway was activated or repressed in cells overexpressing or silenced for TMEM176B, respectively. Overall, our results suggest that TMEM176B expression in breast cancer cells regulates key signaling pathways and genes that contribute to cancer cell growth and progression, and is a potential target for therapeutic antibodies.
MeSH term(s)	Animals ; CD24 Antigen/genetics ; CD24 Antigen/immunology ; Carcinogenesis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Heterografts ; Humans ; Membrane Proteins/genetics ; Mice ; Oncogene Protein v-akt/genetics ; RNA-Seq ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/genetics ; Tamoxifen/pharmacology ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/immunology ; Triple Negative Breast Neoplasms/pathology
Chemical Substances	CD24 Antigen ; Membrane Proteins ; TMEM176B protein, human ; Tamoxifen (094ZI81Y45) ; Oncogene Protein v-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10123430
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Article ; Online: Broadly neutralizing anti-influenza virus antibodies: enhancement of neutralizing potency in polyclonal mixtures and IgA backbones.

He, Wenqian / Mullarkey, Caitlin E / Duty, J Andrew / Moran, Thomas M / Palese, Peter / Miller, Matthew S

Journal of virology

2015 Volume 89, Issue 7, Page(s) 3610–3618

Abstract: Unlabelled: Current influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and ... ...

Abstract	Unlabelled: Current influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of "universal" influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferior in vitro but was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during "universal" influenza virus vaccine design. Importance: Influenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a "universal" influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of "universal" influenza virus vaccines and therapeutics.
MeSH term(s)	Adult ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Female ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Humans ; Immunoglobulin A/immunology ; Influenza A virus/immunology ; Influenza Vaccines/immunology ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; Male ; Middle Aged ; Young Adult
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Hemagglutinin Glycoproteins, Influenza Virus ; Immunoglobulin A ; Influenza Vaccines
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.03099-14
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Article: Perfluoroalkyl substance serum concentrations and immune response to FluMist vaccination among healthy adults

Stein, Cheryl R / Ge, Yongchao / Wolff, Mary S / Ye, Xiaoyun / Calafat, Antonia M / Kraus, Thomas / Moran, Thomas M

Elsevier Inc. Environmental research. 2016 Aug., v. 149

2016

Abstract: Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination ...

Abstract	Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination with FluMist intranasal live attenuated influenza vaccine in relation to four PFAS (perfluorooctanoate, perfluorononanoate, perfluorooctane sulfonate, perfluorohexane sulfonate) serum concentrations among 78 healthy adults vaccinated during the 2010–2011 influenza season. We measured anti-A H1N1 antibody response and cytokine and chemokine concentrations in serum pre-vaccination, 3 days post-vaccination, and 30 days post-vaccination. We measured cytokine, chemokine, and mucosal IgA concentration in nasal secretions 3 days post-vaccination and 30 days post-vaccination. Adults with higher PFAS concentrations were more likely to seroconvert after FluMist vaccination as compared to adults with lower PFAS concentrations. The associations, however, were imprecise and few participants seroconverted as measured either by hemagglutination inhibition (9%) or immunohistochemical staining (25%). We observed no readily discernable or consistent pattern between PFAS concentration and baseline cytokine, chemokine, or mucosal IgA concentration, or between PFAS concentration and change in these immune markers between baseline and FluMist-response states. The results of this study do not support a reduced immune response to FluMist vaccination among healthy adults in relation to serum PFAS concentration. Given the study's many limitations, however, it does not rule out impaired vaccine response to other vaccines or vaccine components in either children or adults.
Keywords	adults ; antibodies ; blood serum ; chemokines ; children ; hemagglutination ; immunoglobulin A ; immunohistochemistry ; immunotoxicity ; influenza ; influenza vaccines ; laboratory animals ; nose ; perfluorocarbons ; perfluorooctane sulfonic acid ; perfluorooctanoic acid ; staining ; vaccination
Language	English
Dates of publication	2016-08
Size	p. 171-178.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205699-9
ISSN	1096-0953 ; 0013-9351
ISSN (online)	1096-0953
ISSN	0013-9351
DOI	10.1016/j.envres.2016.05.020
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Granulocyte colony-stimulating factor protects mice during respiratory virus infections.

Hermesh, Tamar / Moran, Thomas M / Jain, Deepika / López, Carolina B

PloS one

2012 Volume 7, Issue 5, Page(s) e37334

Abstract: A burst in the production of pro-inflammatory molecules characterizes the beginning of the host response to infection. Cytokines, chemokines, and growth factors work in concert to control pathogen replication and activate innate and adaptive immune ... ...

Abstract	A burst in the production of pro-inflammatory molecules characterizes the beginning of the host response to infection. Cytokines, chemokines, and growth factors work in concert to control pathogen replication and activate innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF) mobilizes and activates hematopoietic cells from the bone marrow, and it has been shown to mediate the generation of effective immunity against bacterial and fungal infections. G-CSF is produced at high levels in the lungs during infection with influenza and parainfluenza viruses, but its role during these infections is unknown. Here we show that during infection of mice with a non-lethal dose of influenza or Sendai virus, G-CSF promotes the accumulation of activated Ly6G+ granulocytes that control the extent of the lung pro-inflammatory response. Remarkably, these G-CSF-mediated effects facilitate viral clearance and sustain mouse survival.
MeSH term(s)	Adaptive Immunity ; Animals ; Granulocyte Colony-Stimulating Factor/biosynthesis ; Granulocyte Colony-Stimulating Factor/deficiency ; Granulocyte Colony-Stimulating Factor/immunology ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Granulocytes/immunology ; Influenza A virus ; Lung/immunology ; Lung/virology ; Mice ; Orthomyxoviridae Infections/drug therapy ; Orthomyxoviridae Infections/immunology ; Respiratory Tract Infections/drug therapy ; Respiratory Tract Infections/immunology ; Respirovirus Infections/drug therapy ; Respirovirus Infections/immunology ; Sendai virus ; Viral Load
Chemical Substances	Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2012-05-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0037334
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Article ; Online: The influence of pregnancy on systemic immunity.

Pazos, Michael / Sperling, Rhoda S / Moran, Thomas M / Kraus, Thomas A

Immunologic research

2012 Volume 54, Issue 1-3, Page(s) 254–261

Abstract: Adaptations in maternal systemic immunity are presumed to be responsible for observed alterations in disease susceptibility and severity as pregnancy progresses. Epidemiological evidence as well as animal studies have shown that influenza infections are ... ...

Abstract	Adaptations in maternal systemic immunity are presumed to be responsible for observed alterations in disease susceptibility and severity as pregnancy progresses. Epidemiological evidence as well as animal studies have shown that influenza infections are more severe during the second and third trimesters of pregnancy, resulting in greater morbidity and mortality, although the reason for this is still unclear. Our laboratory has taken advantage of 20 years of experience studying the murine immune response to respiratory viruses to address questions of altered immunity during pregnancy. With clinical studies and unique animal model systems, we are working to define the mechanisms responsible for altered immune responses to influenza infection during pregnancy and what roles hormones such as estrogen or progesterone play in these alterations.
MeSH term(s)	Animals ; Cytokines/immunology ; Disease Models, Animal ; Female ; Humans ; Influenza Vaccines ; Orthomyxoviridae ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/prevention & control ; Pregnancy ; Pregnancy Complications, Infectious/immunology ; Pregnancy Complications, Infectious/prevention & control
Chemical Substances	Cytokines ; Influenza Vaccines
Keywords	covid19
Language	English
Publishing date	2012-03-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632857-x
ISSN	1559-0755 ; 0257-277X
ISSN (online)	1559-0755
ISSN	0257-277X
DOI	10.1007/s12026-012-8303-9
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