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Article: The OM-85 bacterial lysate: a new tool against SARS-CoV-2?

Pivniouk, Vadim / Vercelli, Donata

2023 Volume 18, Page(s) 906

Abstract: The emergence of SARS-CoV-2, a novel coronavirus, caused the global Coronavirus disease of 2019 (COVID-19) pandemic. Because SARS-CoV-2 mutates rapidly, vaccines that induce immune responses against viral components critical for target cell infection ... ...

Abstract	The emergence of SARS-CoV-2, a novel coronavirus, caused the global Coronavirus disease of 2019 (COVID-19) pandemic. Because SARS-CoV-2 mutates rapidly, vaccines that induce immune responses against viral components critical for target cell infection strongly mitigate but do not abrogate viral spread, and disease rates remain high worldwide. Complementary treatments are therefore needed to reduce the frequency and/or severity of SARS-CoV-2 infections. OM-85, a standardized lysate of 21 bacterial strains often found in the human airways, has immuno-modulatory properties and is widely used empirically in Europe, South America and Asia for the prophylaxis of recurrent upper airway infections in adults and children, with excellent safety profiles.
Language	English
Publishing date	2023-01-26
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2677839-7
ISSN	2049-6958 ; 1828-695X
ISSN (online)	2049-6958
ISSN	1828-695X
DOI	10.4081/mrm.2023.906
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Article ; Online: Administration of a Bacterial Lysate to the Airway Compartment Is Sufficient to Inhibit Allergen-Induced Lung Eosinophilia in Germ-free Mice.

Michael, Ashley N / Pivniouk, Oksana / Ezeh, Peace C / Banskar, Sunil / Hahn, Seongmin / DeVries, Avery / O'Connell, Kathryn / Pivniouk, Vadim / Vercelli, Donata

Journal of leukocyte biology

2024

Abstract: The nexus between eosinophils and microbes is attracting increasing attention. We previously showed that airway administration of sterile microbial products contained in dust collected from traditional dairy farms virtually abrogated broncho-alveolar ... ...

Abstract	The nexus between eosinophils and microbes is attracting increasing attention. We previously showed that airway administration of sterile microbial products contained in dust collected from traditional dairy farms virtually abrogated broncho-alveolar lavage (BAL) eosinophilia and other cardinal asthma phenotypes in allergen-sensitized specific pathogen-free (SPF) mice. Interestingly, comparable inhibition of allergen-induced BAL eosinophilia and promotion of airway barrier integrity were found upon administration of a sterile, pharmacological grade bacterial lysate, OM-85, to the airway compartment of allergen-sensitized SPF mice. Here we asked whether intrinsic properties of airway-delivered microbial products were sufficient to inhibit allergic lung inflammation or whether these effects were mediated by reprogramming of the host microbiota. We compared germ-free (GF) mice and offspring of GF mice associated with healthy mouse gut microbiota and maintained under SPF conditions for multiple generations (Ex-GF mice). These mice were treated intra-nasally with OM-85 and evaluated in the OVA and Alternaria models of allergic asthma focusing primarily on BAL eosinophilia. Levels of allergen-induced BAL eosinophilia were comparable in GF and conventionalized Ex-GF mice. Airway administration of the OM-85 bacterial lysate was sufficient to inhibit allergen-induced lung eosinophilia in both Ex-GF and GF mice, suggesting that host microbiota are not required for the protective effects of bacterial products in these models and local airway exposure to microbial products is an effective source of protection. OM-85-dependent inhibition of BAL eosinophilia in GF mice was accompanied by suppression of lung type-2 cytokines and eosinophil-attracting chemokines, suggesting that OM-85 may work at least by decreasing eosinophil lung recruitment.
Language	English
Publishing date	2024-03-12
Publishing country	England
Document type	Journal Article
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1093/jleuko/qiae047
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Zs.A 603: Show issues

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Article ; Online: Immune modulation by rural exposures and allergy protection.

Xing, Yuhan / Tsang, Miranda Sin-Man / Yang, Zhaowei / Wang, Maggie Haitian / Pivniouk, Vadim / Leung, Agnes Sze-Yin / Leung, Ting-Fan / Roponen, Marjut / Schaub, Bianca / Vercelli, Donata / Wong, Chun-Kwok / Li, Jing / Wong, Gary Wing-Kin

Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

2024 Volume 35, Issue 2, Page(s) e14086

Abstract: Background: Growing up on traditional farms protects children from the development of asthma and allergies. However, we have identified distinct asthma-protective factors, such as poultry exposure. This study aims to examine the biological effect of ... ...

Abstract	Background: Growing up on traditional farms protects children from the development of asthma and allergies. However, we have identified distinct asthma-protective factors, such as poultry exposure. This study aims to examine the biological effect of rural exposure in China. Methods: We recruited 67 rural children (7.4 ± 0.9 years) and 79 urban children (6.8 ± 0.6 years). Depending on the personal history of exposure to domestic poultry (DP), rural children were further divided into those with DP exposure (DP Results: There was a stepwise increase in the percentage of eosinophils (%) from rural DP Conclusions: Immune responses of rural children were dampened compared to urban children and those exposed to DP had further downregulated immune responsiveness. DP dust extracts ameliorated Th2-driven allergic airway inflammation in mice. Determining active protective components in the rural environment may provide directions for the development of primary prevention of asthma.
MeSH term(s)	Child ; Humans ; Animals ; Mice ; Lipopolysaccharides/adverse effects ; Hypersensitivity ; Asthma ; Allergens ; Cytokines/metabolism ; Dust ; Inflammation ; Disease Models, Animal ; Immunity ; Mice, Inbred BALB C ; Ovalbumin/adverse effects
Chemical Substances	Lipopolysaccharides ; Allergens ; Cytokines ; Dust ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2024-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	1057059-7
ISSN	1399-3038 ; 0905-6157 ; 0906-5784
ISSN (online)	1399-3038
ISSN	0905-6157 ; 0906-5784
DOI	10.1111/pai.14086
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Zs.A 3096: Show issues

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Article ; Online: The role of innate immunity in asthma development and protection: Lessons from the environment.

Pivniouk, Vadim / Gimenes Junior, Joao Antonio / Honeker, Linnea K / Vercelli, Donata

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

2020 Volume 50, Issue 3, Page(s) 282–290

Abstract: Asthma, a complex, chronic disease characterized by airway inflammation, hyperresponsiveness and remodelling, affects over 300 million people worldwide. While the disease is typically associated with exaggerated allergen-induced type 2 immune responses, ... ...

Abstract	Asthma, a complex, chronic disease characterized by airway inflammation, hyperresponsiveness and remodelling, affects over 300 million people worldwide. While the disease is typically associated with exaggerated allergen-induced type 2 immune responses, these responses are strongly influenced by environmental exposures that stimulate innate immune pathways capable of promoting or protecting from asthma. The dual role played by innate immunity in asthma pathogenesis offers multiple opportunities for both research and clinical interventions and is the subject of this review.
MeSH term(s)	Allergens/immunology ; Asthma/immunology ; Environmental Exposure/adverse effects ; Humans ; Immunity, Innate ; Th2 Cells/immunology
Chemical Substances	Allergens
Language	English
Publishing date	2020-06-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	645204-8
ISSN	1365-2222 ; 0954-7894 ; 0960-2178
ISSN (online)	1365-2222
ISSN	0954-7894 ; 0960-2178
DOI	10.1111/cea.13508
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Zs.A 767: Show issues

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Article ; Online: Asthma-protective agents in dust from traditional farm environments.

Marques Dos Santos, Mauricius / Pivniouk, Vadim / Rankl, Bettina / Walker, Alesia / Pagani, Giulia / Hertkorn, Norbert / Schmitt-Kopplin, Philippe / Müller, Christoph / Bracher, Franz / Merl-Pham, Juliane / Hauck, Stefanie M / Schloter, Michael / Michael, Ashley N / Anderson, Dayna / Honeker, Linnea / Gozdz, Justyna / Pivniouk, Oksana / Ober, Carole / Holbreich, Mark /

Martinez, Fernando D / Snyder, Shane A / von Mutius, Erika / Vercelli, Donata

The Journal of allergy and clinical immunology

2023 Volume 152, Issue 3, Page(s) 610–621

Abstract: Background: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma ... ...

Abstract	Background: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice. Objectives: This study sought to begin identifying farm-derived asthma-protective agents. Methods: Our work unfolded along 2 unbiased and independent but complementary discovery paths. Dust extracts (DEs) from protective and nonprotective farms (European and Amish cowsheds vs European sheep sheds) were analyzed by comparative nuclear magnetic resonance profiling and differential proteomics. Bioactivity-guided size fractionation focused on protective Amish cowshed DEs. Multiple in vitro and in vivo functional assays were used in both paths. Some of the proteins thus identified were characterized by in-solution and in-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzymatic digestion/peptide mapping followed by liquid chromatography/mass spectrometry. The cargo carried by these proteins was analyzed by untargeted liquid chromatography-high-resolution mass spectrometry. Results: Twelve carrier proteins of animal and plant origin, including the bovine lipocalins Bos d 2 and odorant binding protein, were enriched in DEs from protective European cowsheds. A potent asthma-protective fraction of Amish cowshed DEs (≈0.5% of the total carbon content of unfractionated extracts) contained 7 animal and plant proteins, including Bos d 2 and odorant binding protein loaded with fatty acid metabolites from plants, bacteria, and fungi. Conclusions: Animals and plants from traditional farms produce proteins that transport hydrophobic microbial and plant metabolites. When delivered to mucosal surfaces, these agents might regulate airway responses.
MeSH term(s)	Female ; Animals ; Cattle ; Mice ; Sheep ; Farms ; Dust/analysis ; Asthma/prevention & control ; Allergens ; Respiratory System
Chemical Substances	Dust ; Allergens
Language	English
Publishing date	2023-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.05.013
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Article ; Online: The OM-85 bacterial lysate inhibits SARS-CoV-2 infection of epithelial cells by downregulating SARS-CoV-2 receptor expression.

Pivniouk, Vadim / Pivniouk, Oksana / DeVries, Avery / Uhrlaub, Jennifer L / Michael, Ashley / Pivniouk, Denis / VanLinden, Sydney R / Conway, Michelle Y / Hahn, Seongmin / Malone, Sean P / Ezeh, Peace / Churko, Jared M / Anderson, Dayna / Kraft, Monica / Nikolich-Zugich, Janko / Vercelli, Donata

The Journal of allergy and clinical immunology

2021 Volume 149, Issue 3, Page(s) 923–933.e6

Abstract: Background: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with ... ...

Abstract	Background: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) on host cells. Multiple cells and organs are targeted, particularly airway epithelial cells. OM-85, a standardized lysate of human airway bacteria with strong immunomodulating properties and an impeccable safety profile, is widely used to prevent recurrent respiratory infections. We found that airway OM-85 administration inhibits Ace2 and Tmprss2 transcription in the mouse lung, suggesting that OM-85 might hinder SARS-CoV-2/host cell interactions. Objectives: We sought to investigate whether and how OM-85 treatment protects nonhuman primate and human epithelial cells against SARS-CoV-2. Methods: ACE2 and TMPRSS2 mRNA and protein expression, cell binding of SARS-CoV-2 S1 protein, cell entry of SARS-CoV-2 S protein-pseudotyped lentiviral particles, and SARS-CoV-2 cell infection were measured in kidney, lung, and intestinal epithelial cell lines, primary human bronchial epithelial cells, and ACE2-transfected HEK293T cells treated with OM-85 in vitro. Results: OM-85 significantly downregulated ACE2 and TMPRSS2 transcription and surface ACE2 protein expression in epithelial cell lines and primary bronchial epithelial cells. OM-85 also strongly inhibited SARS-CoV-2 S1 protein binding to, SARS-CoV-2 S protein-pseudotyped lentivirus entry into, and SARS-CoV-2 infection of epithelial cells. These effects of OM-85 appeared to depend on SARS-CoV-2 receptor downregulation. Conclusions: OM-85 inhibits SARS-CoV-2 epithelial cell infection in vitro by downregulating SARS-CoV-2 receptor expression. Further studies are warranted to assess whether OM-85 may prevent and/or reduce the severity of coronavirus disease 2019.
MeSH term(s)	Adjuvants, Immunologic/administration & dosage ; Angiotensin-Converting Enzyme 2/antagonists & inhibitors ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/immunology ; Animals ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19/virology ; Caco-2 Cells ; Cell Extracts/administration & dosage ; Cell Extracts/immunology ; Cells, Cultured ; Chlorocebus aethiops ; Down-Regulation/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/immunology ; Epithelial Cells/virology ; HEK293 Cells ; Host Microbial Interactions/drug effects ; Host Microbial Interactions/immunology ; Humans ; In Vitro Techniques ; Lung/drug effects ; Lung/immunology ; Lung/virology ; Mice ; Mice, Inbred BALB C ; Receptors, Virus/antagonists & inhibitors ; Receptors, Virus/immunology ; SARS-CoV-2/immunology ; Serine Endopeptidases/drug effects ; Serine Endopeptidases/genetics ; Serine Endopeptidases/immunology ; Transcription, Genetic/drug effects ; Transcription, Genetic/immunology ; Vero Cells
Chemical Substances	Adjuvants, Immunologic ; Broncho-Vaxom ; Cell Extracts ; Receptors, Virus ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, mouse (EC 3.4.21.-)
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2021.11.019
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Article ; Online: Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis.

Pivniouk, Vadim / Gimenes-Junior, Joao A / Ezeh, Peace / Michael, Ashley / Pivniouk, Oksana / Hahn, Seongmin / VanLinden, Sydney R / Malone, Sean P / Abidov, Amir / Anderson, Dayna / Gozdz, Justyna / DeVries, Avery / Martinez, Fernando D / Pasquali, Christian / Vercelli, Donata

The Journal of allergy and clinical immunology

2021 Volume 149, Issue 3, Page(s) 943–956

Abstract: Background: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is ... ...

Abstract	Background: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma. Objectives: We sought to investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma; and to identify protective cellular and molecular mechanisms activated through this natural route. Methods: Different strains of mice sensitized and challenged with ovalbumin or Alternaria received OM-85 intranasally, and cardinal cellular and molecular asthma phenotypes were measured. Airway transfer experiments assessed whether OM-85-treated dendritic cells protect allergen-sensitized, OM-85-naive mice against asthma. Results: Airway OM-85 administration suppressed allergic asthma in all models acting on multiple innate and adaptive immune targets: the airway epithelium/IL-33/ILC2 axis, lung allergen-induced type 2 responses, and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming was sufficient to transfer OM-85-induced asthma protection. Conclusions: We provide the first demonstration that administering a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways. Because protection required a cumulative dose 27- to 46-fold lower than the one reportedly active through the oral route, the efficacy of intranasal OM-85 administration may reflect its direct access to the airway mucosal networks controlling the initiation and development of allergic asthma.
MeSH term(s)	Allergens ; Animals ; Asthma ; Cell Extracts ; Dendritic Cells ; Disease Models, Animal ; Epithelium ; Humans ; Immunity, Innate ; Interleukin-33 ; Lung ; Lymphocytes ; Mice ; Mice, Inbred BALB C ; Ovalbumin
Chemical Substances	Allergens ; Broncho-Vaxom ; Cell Extracts ; Interleukin-33 ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2021-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2021.09.013
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Article ; Online: In utero and postnatal exposure to arsenic alters pulmonary structure and function.

Lantz, R Clark / Chau, Binh / Sarihan, Priyanka / Witten, Mark L / Pivniouk, Vadim I / Chen, Guan Jie

Toxicology and applied pharmacology

2008 Volume 235, Issue 1, Page(s) 105–113

Abstract: In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures ... ...

Abstract	In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 microm in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.
MeSH term(s)	Aging ; Animals ; Animals, Newborn ; Arsenic/toxicity ; Collagen/metabolism ; Dose-Response Relationship, Drug ; Elastin/metabolism ; Female ; Gene Expression Regulation, Developmental/drug effects ; Lung/drug effects ; Lung/growth & development ; Lung/physiology ; Lung Diseases/chemically induced ; Lung Diseases/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth/drug effects ; Muscle, Smooth/pathology ; Muscle, Smooth/physiology ; Pregnancy ; Prenatal Exposure Delayed Effects
Chemical Substances	Collagen (9007-34-5) ; Elastin (9007-58-3) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2008-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2008.11.012
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Article ; Online: Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children.

The New England journal of medicine

2016 Volume 375, Issue 5, Page(s) 411–421

Abstract: Background: The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter ... ...

Abstract	Background: The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities. Methods: We studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma. Results: Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling. Conclusions: The results of our studies in humans and mice indicate that the Amish environment provides protection against asthma by engaging and shaping the innate immune response. (Funded by the National Institutes of Health and others.).
MeSH term(s)	Adaptor Proteins, Vesicular Transport/deficiency ; Adolescent ; Agriculture ; Animals ; Asthma/epidemiology ; Asthma/immunology ; Child ; Christianity ; Cross-Sectional Studies ; Cytokines/blood ; Disease Models, Animal ; Dust/immunology ; Environmental Exposure ; Female ; Gene Expression ; Humans ; Immunity, Innate/genetics ; Immunity, Innate/immunology ; Immunoglobulin E/blood ; Leukocyte Count ; Leukocytes/physiology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Animal ; Myeloid Differentiation Factor 88/deficiency ; Prevalence
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Cytokines ; Dust ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; TICAM-1 protein, mouse ; Immunoglobulin E (37341-29-0)
Language	English
Publishing date	2016-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMoa1508749
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Article: Differential role of SLP-76 domains in T cell development and function.

Kumar, Lalit / Pivniouk, Vadim / de la Fuente, Miguel A / Laouini, Dhafer / Geha, Raif S

Proceedings of the National Academy of Sciences of the United States of America

2002 Volume 99, Issue 2, Page(s) 884–889

Abstract: The adapter SLP-76 is essential for thymocyte development. SLP-76(-/-) mice were reconstituted with SLP-76 deletion mutant transgenes to examine the role of SLP-76 domains in T cell development and function. The N-terminal domain deletion mutant ... ...

Abstract	The adapter SLP-76 is essential for thymocyte development. SLP-76(-/-) mice were reconstituted with SLP-76 deletion mutant transgenes to examine the role of SLP-76 domains in T cell development and function. The N-terminal domain deletion mutant completely failed to restore thymocyte development. Mice reconstituted with Gads-binding site and SH2 domain deletion mutants had decreased thymic cellularity, impaired transition from double to single positive thymocytes, and decreased numbers of mature T cells in the spleen. Calcium mobilization and extracellular signal-regulated protein kinase activation were decreased in the Gads-binding site mutant but almost normal in the SH2 domain mutant. T cells from both mutants failed to proliferate following T cell antigen receptor ligation. Nevertheless, both mutants mounted partial cutaneous hypersensitivity responses and normal T cell dependent IgG1 antibody responses. These results indicate differential roles for SLP-76 domains in T cell development, proliferation and effector functions.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Binding Sites/genetics ; Calcium/metabolism ; Cell Differentiation ; Cell Division ; Isoenzymes/metabolism ; Lectins, C-Type ; Lymphocyte Activation ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/metabolism ; Mutation ; Ovalbumin/immunology ; Phospholipase C gamma ; Phosphoproteins/chemistry ; Phosphoproteins/genetics ; Phosphoproteins/immunology ; Protein Structure, Tertiary ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Receptors, Interleukin-2/metabolism ; Sequence Deletion ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Type C Phospholipases/metabolism ; src Homology Domains
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antigens, CD ; Antigens, Differentiation, T-Lymphocyte ; CD69 antigen ; Isoenzymes ; Lectins, C-Type ; Phosphoproteins ; Receptors, Antigen, T-Cell, alpha-beta ; Receptors, Interleukin-2 ; SLP-76 signal Transducing adaptor proteins ; Ovalbumin (9006-59-1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Type C Phospholipases (EC 3.1.4.-) ; Phospholipase C gamma (EC 3.1.4.3) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2002-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.022619199
Database	MEDical Literature Analysis and Retrieval System OnLINE

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