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  1. Article ; Online: Oral tolerance to systemic vaccination remains intact without RORγt expression in regulatory T cells.

    Potchen, Nicole B / Johnson, Andrew M F / Hager, Kevin / Graham, Jessica / Van, Phuong / Lyn-Kew, Katelyn H / Warrier, Lakshmi / Talavera, Irene Cruz / Lund, Jennifer M / Kublin, James G

    iScience

    2023  Volume 26, Issue 12, Page(s) 108504

    Abstract: Many promising vaccine candidates and licensed vaccines lead to variable immune responses within humans. Studies suggest that environmental exposures in the gastrointestinal tract could contribute to a reduction in vaccine efficacy via immune tolerance ... ...

    Abstract Many promising vaccine candidates and licensed vaccines lead to variable immune responses within humans. Studies suggest that environmental exposures in the gastrointestinal tract could contribute to a reduction in vaccine efficacy via immune tolerance at this site; this is partly achieved by a high abundance of regulatory T cells (Tregs). It is unclear if Treg subsets regulate systemic vaccine responses following oral antigen pre-exposure. Here, we implemented a conditional knock-out mouse model of RORγt+ Tregs to examine the role of these cells in mediating this process. Following oral exposure to the model antigen ovalbumin (OVA) prior to immunization, we found similar induction of vaccine-induced antibody responses in mice lacking RORγt expression in Tregs compared to sufficient controls. Use of various adjuvants led to distinct findings. Our data suggest that expression of RORγt+ within Tregs is not required to regulate tolerance to systemic vaccination following oral antigen exposure.
    Language English
    Publishing date 2023-11-22
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.108504
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.

    Johnson, Andrew M F / Hager, Kevin / Alameh, Mohamad-Gabriel / Van, Phuong / Potchen, Nicole / Mayer-Blackwell, Koshlan / Fiore-Gartland, Andrew / Minot, Samuel / Lin, Paulo J C / Tam, Ying K / Weissman, Drew / Kublin, James G

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine ... ...

    Abstract Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific-pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. While the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle (LNP) immunization, the microbiome suppresses immunoglobulin and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA-LNP vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for their continued therapeutic development and deployment.
    Language English
    Publishing date 2023-02-19
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.18.529093
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The Regulation of Nucleic Acid Vaccine Responses by the Microbiome.

    Johnson, Andrew M F / Hager, Kevin / Alameh, Mohamad-Gabriel / Van, Phuong / Potchen, Nicole / Mayer-Blackwell, Koshlan / Fiore-Gartland, Andrew / Minot, Samuel / Lin, Paulo J C / Tam, Ying K / Weissman, Drew / Kublin, James G

    Journal of immunology (Baltimore, Md. : 1950)

    2023  Volume 211, Issue 11, Page(s) 1680–1692

    Abstract: Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine ... ...

    Abstract Nucleic acid vaccines, including both RNA and DNA platforms, are key technologies that have considerable promise in combating both infectious disease and cancer. However, little is known about the extrinsic factors that regulate nucleic acid vaccine responses and which may determine their effectiveness. The microbiome is recognized as a significant regulator of immune development and response, whose role in regulating some traditional vaccine platforms has recently been discovered. Using germ-free and specific pathogen-free mouse models in combination with different protein, DNA, and mRNA vaccine regimens, we demonstrate that the microbiome is a significant regulator of nucleic acid vaccine immunogenicity. Although the presence of the microbiome enhances CD8+ T cell responses to mRNA lipid nanoparticle immunization, the microbiome suppresses Ig and CD4+ T cell responses to DNA-prime, DNA-protein-boost immunization, indicating contrasting roles for the microbiome in the regulation of these different nucleic acid vaccine platforms. In the case of mRNA lipid nanoparticle vaccination, germ-free mice display reduced dendritic cell/macrophage activation that may underlie the deficient vaccine response. Our study identifies the microbiome as a relevant determinant of nucleic acid vaccine response with implications for continued therapeutic development and deployment of these vaccines.
    MeSH term(s) Mice ; Animals ; Nucleic Acid-Based Vaccines ; CD8-Positive T-Lymphocytes ; Vaccines, DNA ; DNA ; Microbiota ; RNA, Messenger ; Immunization, Secondary
    Chemical Substances Nucleic Acid-Based Vaccines ; Vaccines, DNA ; DNA (9007-49-2) ; RNA, Messenger
    Language English
    Publishing date 2023-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2300196
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Multi-trial analysis of HIV-1 envelope gp41-reactive antibodies among global recipients of candidate HIV-1 vaccines.

    Mayer-Blackwell, Koshlan / Johnson, Andrew M / Potchen, Nicole / Minot, Simon S / Heptinstall, Jack / Seaton, Kelly / Sawant, Sheetal / Shen, Xiaoying / Tomaras, Georgia D / Fiore-Gartland, Andrew / Kublin, James G

    Frontiers in immunology

    2022  Volume 13, Page(s) 983313

    Abstract: Many participants in HIV-1 vaccine trials, who have not previously been exposed to or vaccinated against HIV-1, display serum immunoglobulin antibodies that bind the gp41 region of HIV-1 envelope prior to vaccination. Previous studies have hypothesized ... ...

    Abstract Many participants in HIV-1 vaccine trials, who have not previously been exposed to or vaccinated against HIV-1, display serum immunoglobulin antibodies that bind the gp41 region of HIV-1 envelope prior to vaccination. Previous studies have hypothesized that these pre-existing antibodies may be cross-reactive and may skew future vaccine responses. In 12 large studies conducted by the HIV Vaccine Trial Network (HVTN) (n=1470 individuals), we find wide variation among participants in the pre-vaccine levels of gp41-reactive antibodies as measured by the binding antibody multiplex assay (BAMA). In the absence of exposure to the gp41 immunogen, anti-gp41 IgG levels were temporally stable over 26-52 weeks in repeated measures of placebo recipients. The analysis revealed that the geometric mean of pre-vaccine anti-gp41 IgG response was greater among participants in South Africa compared with participants in the United States. With gene-level metagenomic sequencing of pre-vaccination fecal samples collected from participants in one trial (HVTN 106), we detected positive associations between pre-vaccine anti-gp41 IgG and abundance of genes from multiple taxa in the
    MeSH term(s) Humans ; HIV-1 ; HIV Antibodies ; AIDS Vaccines ; HIV Infections/prevention & control ; HIV Seropositivity ; Immunoglobulin G
    Chemical Substances HIV Antibodies ; AIDS Vaccines ; Immunoglobulin G
    Language English
    Publishing date 2022-10-12
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.983313
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Guide RNA selection for CRISPR-Cas9 transfections in Plasmodium falciparum.

    Ribeiro, Jose M / Garriga, Meera / Potchen, Nicole / Crater, Anna K / Gupta, Ankit / Ito, Daisuke / Desai, Sanjay A

    International journal for parasitology

    2018  Volume 48, Issue 11, Page(s) 825–832

    Abstract: CRISPR-Cas9 mediated genome editing is addressing key limitations in the transfection of malaria parasites. While this method has already simplified the needed molecular cloning and reduced the time required to generate mutants in the human pathogen ... ...

    Abstract CRISPR-Cas9 mediated genome editing is addressing key limitations in the transfection of malaria parasites. While this method has already simplified the needed molecular cloning and reduced the time required to generate mutants in the human pathogen Plasmodium falciparum, optimal selection of required guide RNAs and guidelines for successful transfections have not been well characterised, leading workers to use time-consuming trial and error approaches. We used a genome-wide computational approach to create a comprehensive and publicly accessible database of possible guide RNA sequences in the P. falciparum genome. For each guide, we report on-target efficiency and specificity scores as well as information about the genomic site relevant to optimal design of CRISPR-Cas9 transfections to modify, disrupt, or conditionally knockdown any gene. As many antimalarial drug and vaccine targets are encoded by multigene families, we also developed a new paralog specificity score that should facilitate modification of either a single family member of interest or multiple paralogs that serve overlapping roles. Finally, we tabulated features of successful transfections in our laboratory, providing broadly useful guidelines for parasite transfections. Molecular studies aimed at understanding parasite biology or characterising drug and vaccine targets in P. falciparum should be facilitated by this comprehensive database.
    MeSH term(s) CRISPR-Cas Systems/genetics ; Computer Simulation ; Gene Editing ; Genetic Markers ; Genetic Vectors ; Genome, Protozoan ; Genome-Wide Association Study ; Models, Genetic ; Plasmodium falciparum/genetics ; RNA, Guide, CRISPR-Cas Systems/genetics ; Transfection
    Chemical Substances Genetic Markers ; RNA, Guide, CRISPR-Cas Systems
    Language English
    Publishing date 2018-06-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 120518-3
    ISSN 1879-0135 ; 0020-7519
    ISSN (online) 1879-0135
    ISSN 0020-7519
    DOI 10.1016/j.ijpara.2018.03.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Cervicovaginal Tissue Residence Confers a Distinct Differentiation Program upon Memory CD8 T Cells.

    Davé, Veronica A / Cardozo-Ojeda, E Fabian / Mair, Florian / Erickson, Jami / Woodward-Davis, Amanda S / Koehne, Amanda / Soerens, Andrew / Czartoski, Julie / Teague, Candice / Potchen, Nicole / Oberle, Susanne / Zehn, Dietmar / Schiffer, Joshua T / Lund, Jennifer M / Prlic, Martin

    Journal of immunology (Baltimore, Md. : 1950)

    2021  Volume 206, Issue 12, Page(s) 2937–2948

    Abstract: Tissue-resident memory CD8 T cells (CD8 ... ...

    Abstract Tissue-resident memory CD8 T cells (CD8 T
    MeSH term(s) Adult ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation/drug effects ; Cell Differentiation/immunology ; Cervix Uteri/drug effects ; Cervix Uteri/immunology ; Cervix Uteri/virology ; Female ; Herpes Simplex/drug therapy ; Herpes Simplex/immunology ; Herpes Simplex/virology ; Herpesvirus 2, Human/drug effects ; Herpesvirus 2, Human/immunology ; Humans ; Injections, Subcutaneous ; Medroxyprogesterone Acetate/administration & dosage ; Medroxyprogesterone Acetate/pharmacology ; Mice ; Mice, Inbred C57BL ; Vagina/drug effects ; Vagina/immunology ; Vagina/virology ; Young Adult
    Chemical Substances Medroxyprogesterone Acetate (C2QI4IOI2G)
    Language English
    Publishing date 2021-06-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100166
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization.

    Eastman, Alison J / Xu, Jintao / Bermik, Jennifer / Potchen, Nicole / den Dekker, Aaron / Neal, Lori M / Zhao, Guolei / Malachowski, Antoni / Schaller, Matt / Kunkel, Steven / Osterholzer, John J / Kryczek, Ilona / Olszewski, Michal A

    Science advances

    2019  Volume 5, Issue 12, Page(s) eaaw9051

    Abstract: Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of ... ...

    Abstract Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of adaptive immunity remains unknown. We report that DCs matured with IFNγ and TNFα or matured in the lungs during invasive fungal infection with endogenous TNFα acquired a stable TNFα-dependent DC1 program, rendering them resistant to both antigen- and cytokine-induced alternative activation. TNFα-programmed DC1 had increased association of H3K4me3 with DC1 gene promoter regions. Furthermore, MLL1 inhibition blocked TNFα-mediated DC1 phenotype stabilization. During IFI, TNFα-programmed DC1s were required for the development of sustained T
    MeSH term(s) Animals ; Cell Polarity/drug effects ; Cellular Reprogramming/drug effects ; Cryptococcus/drug effects ; Cryptococcus/physiology ; Cytoprotection/drug effects ; Dendritic Cells/drug effects ; Dendritic Cells/metabolism ; Epigenesis, Genetic/drug effects ; Female ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Immunomodulation/drug effects ; Lysine/metabolism ; Methylation ; Mice, Inbred CBA ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Phenotype ; Promoter Regions, Genetic/genetics ; Suppression, Genetic/drug effects ; T-Lymphocytes/cytology ; T-Lymphocytes/drug effects ; Th1 Cells/drug effects ; Th1 Cells/immunology ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/pharmacology
    Chemical Substances Histones ; Tumor Necrosis Factor-alpha ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Kmt2a protein, mouse (EC 2.1.1.43) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2019-12-04
    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, Non-P.H.S.
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.aaw9051
    Database MEDical Literature Analysis and Retrieval System OnLINE

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