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101. Modulation of RAS Pathways as a Biomarker of Protection against HIV and as a Means to Improve Vaccine Efficacy

Author

Fourati, Slim, primary, Vaccari, Monica, additional, Gordon, Shari N., additional, Schifanella, Luca, additional, Cameron, Mark, additional, Keele, Brandon F., additional, Shen, Xiaoying, additional, Tomoras, Georgia D., additional, Billings, Erik, additional, Rao, Mangala, additional, Chung, Amy W., additional, Dowell, Karen, additional, Bailey-Kellogg, Chris, additional, Brown, Eric, additional, Ackerman, Margaret E., additional, Liyanage, Namal P.M., additional, Vargas-Inchaistegui, Diego A., additional, Whitney, Stephen, additional, Doster, Melvin N., additional, Binello, Nicolo, additional, Pegu, Poonam, additional, Montefiori, David C., additional, Foulds, Kathryn, additional, Quinn, David S., additional, Donaldson, Mitzi, additional, Liang, Frank, additional, Loré, Karin, additional, Roederer, Mario, additional, Koup, Richard A, additional, McDermott, Adrian, additional, Ma, Zhong-Min, additional, Miller, Christopher J, additional, Phan, Tran B, additional, Forthal, Donald N., additional, Blackburn, Matthew, additional, Caccuri, Francesca, additional, Ferrari, Guido, additional, Thompson, Devon, additional, Robert-Guroff, Marjorie, additional, Ratto-Kim, Silvia, additional, Kim, Jerome H., additional, Michael, Nelson L., additional, Phogat, Sanjay, additional, Barnett, Susan W., additional, Tartaglia, James, additional, Venzon, David, additional, Stablein, Donald M., additional, Alter, Galit, additional, Sekaly, Rafick-Pierre, additional, and Franchini, Genoveffa, additional

Published
2014
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103. Coadministration of Polyinosinic:Polycytidylic Acid and Immunostimulatory Complexes Modifies Antigen Processing in Dendritic Cell Subsets and Enhances HIV Gag-Specific T Cell Immunity

Author

Quinn, Kylie M., primary, Yamamoto, Ayako, additional, Costa, Andreia, additional, Darrah, Patricia A., additional, Lindsay, Ross W. B., additional, Hegde, Sonia T., additional, Johnson, Teresa R., additional, Flynn, Barbara J., additional, Loré, Karin, additional, and Seder, Robert A., additional

Published
2013
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105. Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation

Author

Sandgren, Kerrie J., primary, Smed-Sörensen, Anna, additional, Forsell, Mattias N., additional, Soldemo, Martina, additional, Adams, William C., additional, Liang, Frank, additional, Perbeck, Leif, additional, Koup, Richard A., additional, Wyatt, Richard T., additional, Karlsson Hedestam, Gunilla B., additional, and Loré, Karin, additional

Published
2013
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107. Type I IFN Induced by Adenovirus Serotypes 28 and 35 Has Multiple Effects on T Cell Immunogenicity

Author

Johnson, Matthew J., primary, Petrovas, Constantinos, additional, Yamamoto, Takuya, additional, Lindsay, Ross W. B., additional, Loré, Karin, additional, Gall, Jason G. D., additional, Gostick, Emma, additional, Lefebvre, François, additional, Cameron, Mark J., additional, Price, David A., additional, Haddad, Elias, additional, Sekaly, Rafick-Pierre, additional, Seder, Robert A., additional, and Koup, Richard A., additional

Published
2012
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109. Plasmacytoid Dendritic Cells Infiltrate the Skin in Positive Tuberculin Skin Test Indurations

Author

Bond, Emily, primary, Liang, Frank, additional, Sandgren, Kerrie J., additional, Smed-Sörensen, Anna, additional, Bergman, Peter, additional, Brighenti, Susanna, additional, Adams, William C., additional, Betemariam, Senait A., additional, Rangaka, Molebogeng X., additional, Lange, Christoph, additional, Wilkinson, Robert J., additional, Andersson, Jan, additional, and Loré, Karin, additional

Published
2012
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110. Neutrophils acquire the capacity for antigen presentation to memory CD4+T cells in vitro and ex vivo

Author

Vono, Maria, Lin, Ang, Norrby-Teglund, Anna, Koup, Richard A., Liang, Frank, and Loré, Karin

Abstract

Neutrophils are critical cells of the innate immune system and rapidly respond to tissue injury and infection. Increasing evidence also indicates that neutrophils have versatile functions in contributing to adaptive immunity by internalizing and transporting antigen and influencing antigen-specific responses. Here, we demonstrate that freshly isolated human neutrophils can function as antigen-presenting cells (APCs) to memory CD4+T cells. Neutrophils pulsed with the cognate antigens cytomegalovirus pp65 or influenza hemagglutinin were able to present the antigens to autologous antigen-specific CD4+T cells in a major histocompatibility complex class II (MHC-II; HLA-DR)-dependent manner. Although myeloid dendritic cells and monocytes showed superior presenting ability, neutrophils consistently displayed antigen presentation capability. Upregulation of HLA-DR on neutrophils required the presence of the antigen-specific or activated T cells whereas exposure to innate stimuli such as Toll-like receptor ligands was not sufficient. Neutrophils sorted from vaccine-draining lymph nodes from rhesus macaques also showed expression of HLA-DR and were capable of presenting vaccine antigen to autologous antigen-specific memory CD4+T cells ex vivo. Altogether, the data demonstrate that neutrophils can adapt a function as APCs and, in combination with their abundance in the immune system, may have a significant role in regulating antigen-specific T-cell responses.

Published
2017
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115. Immunization with Wild-Type or CD4-Binding-Defective HIV-1 Env Trimers Reduces Viremia Equivalently following Heterologous Challenge with Simian-Human Immunodeficiency Virus

Author

Sundling, Christopher, primary, O'Dell, Sijy, additional, Douagi, Iyadh, additional, Forsell, Mattias N., additional, Mörner, Andreas, additional, Loré, Karin, additional, Mascola, John R., additional, Wyatt, Richard T., additional, and Karlsson Hedestam, Gunilla B., additional

Published
2010
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116. Influence of Novel CD4 Binding-Defective HIV-1 Envelope Glycoprotein Immunogens on Neutralizing Antibody and T-Cell Responses in Nonhuman Primates

Author

Douagi, Iyadh, primary, Forsell, Mattias N. E., additional, Sundling, Christopher, additional, O'Dell, Sijy, additional, Feng, Yu, additional, Dosenovic, Pia, additional, Li, Yuxing, additional, Seder, Robert, additional, Loré, Karin, additional, Mascola, John R., additional, Wyatt, Richard T., additional, and Karlsson Hedestam, Gunilla B., additional

Published
2010
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124. Dendritic Cells Are Less Susceptible to Human Immunodeficiency Virus Type 2 (HIV-2) Infection than to HIV-1 Infection

Author

Duvall, Melody G., primary, Loré, Karin, additional, Blaak, Hetty, additional, Ambrozak, David A., additional, Adams, William C., additional, Santos, Kathlyn, additional, Geldmacher, Christof, additional, Mascola, John R., additional, McMichael, Andrew J., additional, Jaye, Assan, additional, Whittle, Hilton C., additional, Rowland-Jones, Sarah L., additional, and Koup, Richard A., additional

Published
2007
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126. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques.

Author

Seggewiss, Ruth, primary, Loré, Karin, additional, Guenaga, F. Javier, additional, Pittaluga, Stefania, additional, Mattapallil, Joseph, additional, Chow, Catherine K., additional, Koup, Richard A., additional, Camphausen, Kevin, additional, Nason, Martha C., additional, Meier-Schellersheim, Martin, additional, Donahue, Robert E., additional, Blazar, Bruce R., additional, Dunbar, Cynthia E., additional, and Douek, Daniel C., additional

Published
2007
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127. Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates

Author

Wille-Reece, Ulrike, primary, Flynn, Barbara J., additional, Loré, Karin, additional, Koup, Richard A., additional, Miles, Aaron P., additional, Saul, Allan, additional, Kedl, Ross M., additional, Mattapallil, Joseph J., additional, Weiss, Walter R., additional, Roederer, Mario, additional, and Seder, Robert A., additional

Published
2006
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128. In Vitro Culture During Retroviral Transduction Improves Thymic Repopulation and Output After Total Body Irradiation and Autologous Peripheral Blood Progenitor Cell Transplantation in Rhesus Macaques

Author

Loré, Karin, primary, Seggewiss, Ruth, additional, Guenaga, F. Javier, additional, Pittaluga, Stefania, additional, Donahue, Robert E., additional, Krouse, Allen, additional, Metzger, Mark E., additional, Koup, Richard A., additional, Reilly, Cavan, additional, Douek, Daniel C., additional, and Dunbar, Cynthia E., additional

Published
2006
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134. The Functional Profile of Primary Human Antiviral CD8+ T Cell Effector Activity Is Dictated by Cognate Peptide Concentration

Author

Betts, Michael R., primary, Price, David A., additional, Brenchley, Jason M., additional, Loré, Karin, additional, Guenaga, F. Javier, additional, Smed-Sorensen, Anna, additional, Ambrozak, David R., additional, Migueles, Stephen A., additional, Connors, Mark, additional, Roederer, Mario, additional, Douek, Daniel C., additional, and Koup, Richard A., additional

Published
2004
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138. Detection of Cytokine- and Chemokine-Expressing Cells at the Single Cell Level.

Author

Walker, John M., De Ley, Marc, Loré, Karin, and Andersson, Jan

Abstract

Methods for detection of cytokines and chemokines at a protein level in individual cells based on immunofluorescence or immunohistochemical (1-16) staining techniques have been developed in our laboratory. The difficulties in these procedures lie in the critical steps of fixation and permeabilization of the cells in combination with a very careful selection of suitable cytokine- or chemokine-specific antibodies. [ABSTRACT FROM AUTHOR]

Published
2004
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140. Determination of cytomegalovirus DNA load for monitoring of cytomegalovirus disease and antiviral treatment in solid organ transplant patients, comparing limiting-dilution PCR and hybrid capture assay with cytomegalovirus isolation

Author

Barkholt, Lisbeth, primary, Loré, Karin, additional, Tydén, Gunnar, additional, Lewensohn-Fuchs, Ilona, additional, Andersson, Jan, additional, Ericzon, Bo-Göran, additional, Lundgren, Göran, additional, and Ehrnst, Anneka, additional

Published
1999
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142. Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation.

Author

Adams, William C., Gujer, Cornelia, McInerney, Gerald, Galid, Jason G. D., Petrovas, Constantinos, Karisson Hedestam, Gunilla B., Koup, Richard A., and Loré, Karin

Subjects
ADENOVIRUSES, DNA viruses, LYMPHOID tissue, CELL division, BLASTOMERES
Abstract

Recombinant adenoviruses (rAds) based on types 5 (rAd5) and 35 (rAd35) have emerged as important vaccine delivery vectors in clinical testing for a variety of pathogens. A major difference between these vectors is their binding to cellular receptors used for infection. Whereas rAd5 binds coxsackie-adenovirus receptor (CAR), rAd35 binds the complement regulatory protein CD46. Although rAd35 infected and phenotypically matured human blood dendritic cells (DCs) more efficiently than rAd5, we show here that rAd35 markedly suppressed DC-induced activation of naive CD4+ T cells. rAd35 specifically blocked both DCs and anti-CD3/CD28 mAb-induced naive T-cell proliferation and IL-2 production. This effect was also observed in CD4+ memory T cells but to a lesser extent. The suppression occurred by rAd35 binding to CD46 on T cells and was independent of infection. CD46 engagement with mAb mimicked the effects of rAd35 and also led to deficient NF-?B nuclear translocation. In contrast, rAd5 and rAd35 vectors with ablated CD46 binding did not inhibit T-cell activation. Our findings provide insights into the basic biology of adenoviruses and indicate that CD46 binding may have an impact on the generation of primary CD4+ T-cell responses by Ad35. [ABSTRACT FROM AUTHOR]

Published
2011
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143. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates.

Author

Wille-Reece, Ulrike, Flynn, Barbara J., Loré, Karin, Koup, Richard A., Kedl, Ross M., Mattapallil, Joseph J., Weiss, Walter R., Roederer, Mario, and Seder, Robert A.

Subjects
IMMUNOLOGICAL adjuvants, IMMUNITY, T cells, IMMUNE response, LYMPHOID tissue, CELLULAR immunity
Abstract

Induction and maintenance of antibody and T cell responses will be critical for developing a successful vaccine against HIV. A rational approach for generating such responses is to design vaccines or adjuvants that have the capacity to activate specific antigen-presenting cells. In this regard, dendritic cells (DCs) are the most potent antigen-presenting cells for generating primary T cell responses. Here, we report that Toll-like receptor (TLR) agonists and ligands that activate DCs in vitro influence the magnitude and quality of the cellular immune response in nonhuman primates (NHPs) when administered with HIV Gag protein. NHPs immunized with HIV Gag protein and a TLR7/8 agonist or a TLR9 ligand [CpG oligodeoxynucleotides (CpG ODN)] had significantly increased Gag-specific T helper 1 and antibody responses, compared with animals immunized with HIV Gag protein alone. Importantly, conjugating the HIV Gag protein to the TLR7/8 agonist (Gag-TLR7/8 conjugate) dramatically enhanced the magnitude and altered the quality of the T helper 1 response, compared with animals immunized with HIV Gag protein and the TLR7/8 agonist or CpG ODN. Furthermore, immunization with the Gag-TLR7/8 conjugate vaccine elicited Gag-specific CD8+ T responses. Collectively, our results show that conjugating HIV Gag protein to a TLR7/8 agonist is an effective way to elicit broad-based adaptive immunity in NHPs. This type of vaccine formulation should have utility in preventive or therapeutic vaccines in which humoral and cellular immunity is required. [ABSTRACT FROM AUTHOR]

Published
2005
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144. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells.

Author

Loré, Karin, Smed-Sörensen, Anna, Vasudevan, Jayanand, Mascola, John R., and Koup, Richard A.

Subjects
DENDRITIC cells, T cells, HIV, HIV infections, VIRAL replication, CYTOMEGALOVIRUS diseases
Abstract

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of T cell immunity against pathogens such as human immunodeficiency virus (HIV)-1. At the same time, HIV-1 replication is strongly enhanced in DC-T cell clusters, potentially undermining this process. We found that immature CD123+ plasmacytoid DCs (PDCs) and CD11c+ myeloid DCs (MDCs) were susceptible to both a CCR5- and a CXCR4-using HIV-1 isolate in vitro and were able to efficiently transfer that infection to autologous CD4+ T cells. Soon after HIV-1 exposure, both PDCs and MDCs were able to transfer the virus to T cells in the absence of a productive infection. However, once a productive infection was established in the DCs, newly synthesized virus was predominantly spread to T cells. HIV-1 exposure of the MDCs and PDCs did not inhibit their ability to present cytomegalovirus (CMV) antigens and activate CMV-specific memory T cells. As a result, both PDCs and MDCs preferentially transmitted HIV-1 to the responding CMV antigen-specific CD4+ T cells rather than to nonresponding T cells. This suggests that the induction of antigen-specific T cell responses by DCs, a process crucial to immune defense, can lead to preferential HIV-1 infection and the deletion of responding CD4+ T cells. [ABSTRACT FROM AUTHOR]

Published
2005
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146. Route of Vaccine Administration Alters Antigen Trafficking but Not Innate or Adaptive Immunity.

Author

Ols, Sebastian, Yang, Lifei, Thompson, Elizabeth A., Pushparaj, Pradeepa, Tran, Karen, Liang, Frank, Lin, Ang, Eriksson, Bengt, Karlsson Hedestam, Gunilla B., Wyatt, Richard T., and Loré, Karin

Abstract

Although intramuscular (i.m.) administration is the most commonly used route for licensed vaccines, subcutaneous (s.c.) delivery is being explored for several new vaccines under development. Here, we use rhesus macaques, physiologically relevant to humans, to identify the anatomical compartments and early immune processes engaged in the response to immunization via the two routes. Administration of fluorescently labeled HIV-1 envelope glycoprotein trimers displayed on liposomes enables visualization of targeted cells and tissues. Both s.c. and i.m. routes induce efficient immune cell infiltration, activation, and antigen uptake, functions that are tightly restricted to the skin and muscle, respectively. Antigen is also transported to different lymph nodes depending on route. However, these early differences do not translate into significant differences in the magnitude or quality of antigen-specific cellular and humoral responses over time. Thus, although some distinct immunological differences are noted, the choice of route may instead be motivated by clinical practicality. • Subcutaneous and intramuscular injection target the skin and the muscle, respectively • The immunization route affects the anatomical LN cluster that is targeted • Priming of adaptive immune responses occurs in the local vaccine-draining LNs • Comparable innate and adaptive immune responses with both immunization routes Route of immunization, especially intramuscular versus subcutaneous administration, is often debated. Ols et al. use a rhesus macaque model to determine the tissues targeted by a nanoparticle vaccine administered by either route. The authors demonstrate that tissue dissemination is route dependent, but innate and adaptive immune responses develop comparably. [ABSTRACT FROM AUTHOR]

Published
2020
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147. Fcγ-Receptor-Independent Controlled Activation of CD40 Canonical Signaling by Novel Therapeutic Antibodies for Cancer Therapy.

Author

Beckmann, Karsten, Reitinger, Carmen, Yan, Xianglei, Carle, Anna, Blümle, Eva, Jurkschat, Nicole, Paulmann, Claudia, Prassl, Sandra, Kazandjian, Linda V., Loré, Karin, Nimmerjahn, Falk, and Fischer, Stephan

Subjects
*IMMUNOGLOBULINS, *DENDRITIC cells, *CANCER treatment, *CYTOKINE receptors, *IMMUNE response
Abstract

The activation of CD40-mediated signaling in antigen-presenting cells is a promising therapeutic strategy to promote immune responses against tumors. Most agonistic anti-CD40 antibodies currently in development require the Fcγ-receptor (FcγR)-mediated crosslinking of CD40 molecules for a meaningful activation of CD40 signaling but have limitations due to dose-limiting toxicities. Here we describe the identification of CD40 antibodies which strongly stimulate antigen-presenting cells in an entirely FcγR-independent manner. These Fc-silenced anti-CD40 antibodies induce an efficient upregulation of costimulatory receptors and cytokine release by dendritic cells. Finally, the most active identified anti-CD40 antibody shows activity in humanized mice. More importantly, there are no signs of obvious toxicities. These studies thus demonstrate the potent activation of antigen-presenting cells with anti-CD40 antibodies lacking FcγR-binding activity and open the possibility for an efficacious and safe combination therapy for cancer patients. [ABSTRACT FROM AUTHOR]

Published
2024
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148. SARS-CoV-2 protein subunit vaccination of mice and rhesus macaques elicits potent and durable neutralizing antibody responses

Author

Mandolesi, Marco, Sheward, Daniel J., Hanke, Leo, Ma, Junjie, Pushparaj, Pradeepa, Perez Vidakovics, Laura, Kim, Changil, Adori, Monika, Lenart, Klara, Loré, Karin, Castro Dopico, Xaquin, Coquet, Jonathan M., McInerney, Gerald M., Karlsson Hedestam, Gunilla B., and Murrell, Ben

Abstract

The outbreak and spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) is a current global health emergency, and effective prophylactic vaccines are needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is the target of neutralizing antibodies. Here, we show that adjuvanted protein immunization with soluble SARS-CoV-2 spike trimers, stabilized in prefusion conformation, results in potent antibody responses in mice and rhesus macaques, with neutralizing antibody titers exceeding those typically measured in SARS-CoV-2 seropositive humans by more than one order of magnitude. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. A follow-up to monitor the waning of the neutralizing antibody responses in rhesus macaques demonstrated durable responses that were maintained at high and stable levels at least 4 months after boosting. These data support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

Published
2021
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