scholarly journals Defensive Driving: Directing HIV-1 Vaccine-Induced Humoral Immunity to the Mucosa with Chemokine Adjuvants

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Ebony N. Gary ◽  
Michele A. Kutzler
Keyword(s):  
Humoral Immunity ◽  
Lymphoid Tissues ◽  
The Novel ◽  
Vaccine Adjuvants ◽  
Mucosal Tissues ◽  
Mucosal Surfaces ◽  
Mucosal Route ◽  
Prophylactic Vaccination ◽  
Mucosal Pathogens ◽  
Gain Access

A myriad of pathogens gain access to the host via the mucosal route; thus, vaccinations that protect against mucosal pathogens are critical. Pathogens such as HIV, HSV, and influenza enter the host at mucosal sites such as the intestinal, urogenital, and respiratory tracts. All currently licensed vaccines mediate protection by inducing the production of antibodies which can limit pathogen replication at the site of infection. Unfortunately, parenteral vaccination rarely induces the production of an antigen-specific antibody at mucosal surfaces and thus relies on transudation of systemically generated antibody to mucosal surfaces to mediate protection. Mucosa-associated lymphoid tissues (MALTs) consist of a complex network of immune organs and tissues that orchestrate the interaction between the host, commensal microbes, and pathogens at these surfaces. This complexity necessitates strict control of the entry and exit of lymphocytes in the MALT. This control is mediated by chemoattractant chemokines or cytokines which recruit immune cells expressing the cognate receptors and adhesion molecules. Exploiting mucosal chemokine trafficking pathways to mobilize specific subsets of lymphocytes to mucosal tissues in the context of vaccination has improved immunogenicity and efficacy in preclinical models. This review describes the novel use of MALT chemokines as vaccine adjuvants. Specific attention will be placed upon the use of such adjuvants to enhance HIV-specific mucosal humoral immunity in the context of prophylactic vaccination.

scholarly journals Long-lived cytotoxic T lymphocyte memory in mucosal tissues after mucosal but not systemic immunization.

1996 ◽  
Vol 184 (5) ◽  
pp. 1879-1890 ◽  
Author(s):  
W S Gallichan ◽  
K L Rosenthal
Keyword(s):  
Recombinant Adenovirus ◽  
Cytotoxic T Lymphocyte ◽  
Adenovirus Vector ◽  
Lymphoid Tissues ◽  
Mucosal Tissues ◽  
Mucosal Surfaces ◽  
One Year ◽  
Simplex Virus ◽  
Mucosal Pathogens

The induction and maintenance of long-term CTL memory at mucosal surfaces may be a critical component of protection against mucosal pathogens and is one goal towards development of effective mucosal vaccines. In these studies we have functionally evaluated short and long-term CTL memory in systemic and respiratory or genital-associated lymphoid tissues following mucosal or systemic routes of immunization. Our results indicate that shortly after immunizing mice with a recombinant adenovirus vector expressing glycoprotein B (gB) of herpes simplex virus (AdgB8), gB-specific CTL memory responses were observed in systemic and mucosal immune compartments regardless of the route of inoculation. In contrast, several months after immunization, anamnestic CTL responses compartmentalized exclusively to mucosal or systemic lymphoid tissues after mucosal or systemic immunization, respectively. Furthermore, the compartmentalized CTL memory responses in mucosal tissues were functionally observed for longer than 1.5 yr after intranasal immunization, and CTL precursor frequencies one year after immunization were comparable to those seen shortly after immunization. Therefore, to our knowledge, this is the first functional demonstration that the maintenance of anti-viral memory CTL in mucosal tissues is dependent on the route of immunization and the time of assessment. These results have important implications for our understanding of the development, maintenance, and compartmentalization of functional T cell memory and the development and evaluation of vaccines for mucosal pathogens, such as HSV and HIV.

Mechanisms of vaccine adjuvanticity at mucosal surfaces

2000 ◽  
Vol 1 (1) ◽  
pp. 3-24 ◽  
Author(s):  
Dennis L. Foss ◽  
Michael P. Murtaugh
Keyword(s):  
Molecular Mechanisms ◽  
Oral Vaccine ◽  
Vaccine Antigen ◽  
Lymphoid Tissues ◽  
Vaccine Adjuvants ◽  
Intestinal Immunity ◽  
Oral Vaccines ◽  
Rational Development ◽  
Mucosal Surfaces ◽  
Gut Mucosa

AbstractThe vast majority of pathogens invade via mucosal surfaces, including those of the intestine. Vaccination directly on these surfaces may induce local protective immunity and prevent infection and disease. Although vaccine delivery to the gut mucosa is fraught with obstacles, immunization can be enhanced using adjuvants with properties specific to intestinal immunity. In this review, we present three general mechanisms of vaccine adjuvant function as originally described by Freund, and we discuss these principles with respect to intestinal adjuvants in general and to the prototypical mucosal adjuvant, cholera toxin. The key property of intestinal adjuvants is to induce an immunogenic context for the presentation of the vaccine antigen. The success of oral vaccine adjuvants is determined by their ability to induce a controlled inflammatory response in the gut-associated lymphoid tissues, characterized by the expression of various costimulatory molecules and cytokines. An understanding of the specific molecular mechanisms of adjuvanticity in the gut will allow the rational development of safe and effective oral vaccines.

Flexible migration program regulates γδ T-cell involvement in humoral immunity

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3693-3701 ◽  
Author(s):  
Marlène Brandes ◽  
Katharina Willimann ◽  
Alois B. Lang ◽  
Ki-Hoan Nam ◽  
Chenggang Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Humoral Immunity ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Lymphoid Tissues ◽  
Migration Program ◽  
And Function

Abstractγδ T cells are inadequately defined both in terms of their migration potential and contribution to antimicrobial immunity. Here, we have examined the migration profile of human blood γδ T cells and related cell lines and correlated these findings with their distribution in secondary lymphoid tissues and their function in B-cell cocultures. We find that resting γδ T cells are characterized by an inflammatory migration program similar to cells of the innate immune system. However, T-cell receptor (TCR) triggering resulted in the rapid but transient induction of a lymph node (LN)-homing program, as evidenced by functional CCR7 expression and concomitant reduction in expression and function of CCR5 and, to a lesser degree, CCR2. Moreover, the LN-homing program was reflected by the presence of γδ T cells in gastrointestinal lymphoid tissues, notably in clusters within germinal centers of B-cell follicles. In line with these findings, VγVδ-TCR triggering resulted in prominent expression of essential B-cell costimulatory molecules, including CD40L, OX40, CD70, and ICOS. Furthermore, γδ T cells were shown to provide potent B-cell help during in vitro antibody production. Collectively, our findings agree with a role for γδ T cells in humoral immunity during the early phase of antimicrobial responses. (Blood. 2003; 102:3693-3701)

Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3805-3812 ◽  
Author(s):  
Julia I. Ellyard ◽  
Danielle T. Avery ◽  
Tri Giang Phan ◽  
Nathan J. Hare ◽  
Philip D. Hodgkin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Humoral Immunity ◽  
Lymphoid Tissue ◽  
Plasma Cells ◽  
Small Population ◽  
Lymphoid Tissues ◽  
B Cell Differentiation ◽  
Human Spleen ◽  
Human Disorders

Abstract Plasma cells (PCs) represent the final stage of B-cell differentiation and are devoted to the production of immunoglobulin (Ig). Perturbations to their development can result in human disorders characterized by PC expansion and hypergammaglobulinemia. Ig-secreting cells (ISCs) have been identified in secondary lymphoid tissues and bone marrow (BM). Most ISCs in lymphoid tissue are short-lived; in contrast, ISCs that migrate to the BM become long-lived PCs and continue to secrete immunoglobulin for extended periods. However, a small population of long-lived PCs has been identified in rodent spleen, suggesting that PCs may persist in secondary lymphoid tissue and that the spleen, as well as the BM, plays an important role in maintaining long-term humoral immunity. For these reasons, we examined ISCs in human spleen and identified a population that appears analogous to long-lived rodent splenic PCs. Human splenic ISCs shared morphologic, cellular, molecular, and functional characteristics with long-lived PCs in BM, demonstrating their commitment to the PC lineage. Furthermore, the detection of highly mutated immunoglobulin V region genes in splenic ISCs suggested they are likely to be antigen-selected and to secrete high-affinity immunoglobulin. Thus, our results suggest that splenic ISCs have an important role in humoral immunity and may represent the affected cell type in some B-cell dyscrasias.

Bacterial Attachment To Uro-Epithelial Cells: Mechanisms and Consequences

1997 ◽  
Vol 11 (1) ◽  
pp. 50-58 ◽  
Author(s):  
Hugh Connell ◽  
Maria Hedlund ◽  
William Agace ◽  
Catharina Svanborg
Keyword(s):  
Epithelial Cells ◽  
Bacterial Attachment ◽  
Mucosal Barrier ◽  
Mucosal Inflammation ◽  
Local Site ◽  
Mucosal Surfaces ◽  
Mucosal Infection ◽  
Gain Access ◽  
Host Tissues ◽  
Microbial Attachment

Microbial attachment to mucosal surfaces is a first step in mucosal infection. Specific interactions between microbial surface ligands and host receptors influence the distribution of microbes in their sites of infection. Adhesion has often been regarded as a sufficient end point, explaining tissue tropism and bacterial persistence at mucosal sites. Adherence, however, is also a virulence factor through which microbes gain access to host tissues, upset the integrity of the mucosal barrier, and cause disease. The induction of mucosal inflammation is one aspect of this process. Bacterial attachment to mucosal surfaces activates the production of pro-inflammatory cytokines that cause both local and systemic inflammation. Epithelial cells are one source of these cytokines. The binding of fimbrial lectins to epithelial cell receptors triggers transmembrane signaling events that upregulate cytokine-specific mRNA and increase cytokine secretion. P fimbriae that bind the globoseries of glycolipids cause the release of ceramides and activation of the ceramide signaling pathway which contributes to the IL-6 response. Spread of cytokines and other pro-inflammatory mediators from the local site contributes to the symptoms and signs of infection.

scholarly journals Interleukin-1 Family Cytokines as Mucosal Vaccine Adjuvants for Induction of Protective Immunity against Influenza Virus

2010 ◽  
Vol 84 (24) ◽  
pp. 12703-12712 ◽  
Author(s):  
Hiroyuki Kayamuro ◽  
Yasuo Yoshioka ◽  
Yasuhiro Abe ◽  
Shuhei Arita ◽  
Kazufumi Katayama ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Interleukin 1 ◽  
Influenza Virus Infection ◽  
Mucosal Vaccine ◽  
Vaccine Adjuvants ◽  
Mucosal Surfaces ◽  
Mucosal Vaccines ◽  
Etiological Agents ◽  
Family Cytokine

ABSTRACT A safe and potent adjuvant is needed for development of mucosal vaccines against etiological agents, such as influenza virus, that enter the host at mucosal surfaces. Cytokines are potential adjuvants for mucosal vaccines because they can enhance primary and memory immune responses enough to protect against some infectious agents. For this study, we tested 26 interleukin (IL) cytokines as mucosal vaccine adjuvants and compared their abilities to induce antigen (Ag)-specific immune responses against influenza virus. In mice intranasally immunized with recombinant influenza virus hemagglutinin (rHA) plus one of the IL cytokines, IL-1 family cytokines (i.e., IL-1α, IL-1β, IL-18, and IL-33) were found to increase Ag-specific immunoglobulin G (IgG) in plasma and IgA in mucosal secretions compared to those after immunization with rHA alone. In addition, high levels of both Th1- and Th2-type cytokines were observed in mice immunized with rHA plus an IL-1 family cytokine. Furthermore, mice intranasally immunized with rHA plus an IL-1 family cytokine had significant protection against a lethal influenza virus infection. Interestingly, the adjuvant effects of IL-18 and IL-33 were significantly decreased in mast cell-deficient W/W v mice, indicating that mast cells have an important role in induction of Ag-specific mucosal immune responses induced by IL-1 family cytokines. In summary, our results demonstrate that IL-1 family cytokines are potential mucosal vaccine adjuvants and can induce Ag-specific immune responses for protection against pathogens like influenza virus.

Which form of innovation is most appropriate?

2018 ◽  
Vol 34 (9) ◽  
pp. 4-6
Keyword(s):  
Case Studies ◽  
Design Methodology ◽  
Reading Time ◽  
Innovation Strategy ◽  
The Novel ◽  
Content Type ◽  
Pertinent Information ◽  
Exploratory Innovation ◽  
Practical Implications ◽  
Gain Access

Purpose This paper aims to review the latest management developments across the globe and pinpoint practical implications from cutting-edge research and case studies. Design/methodology/approach This briefing is prepared by an independent writer who adds their own impartial comments and places the articles in context. Findings Firms determining their innovation strategy should consider how they connect with other companies. In a close-knit network, it is most appropriate to share knowledge and resources in order to enhance current offerings. But in a network characterized by diversity among members, firms would benefit more by acting as the broker to fill structural holes and gain access to the novel ideas, knowledge and resources needed to implement exploratory innovation. Originality/value The briefing saves busy executives and researchers hours of reading time by selecting only the very best, most pertinent information and presenting it in a condensed and easy-to-digest format.

scholarly journals TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
Gillina F. G. Bezemer ◽  
Johan Garssen
Keyword(s):  
World War Ii ◽  
Wide Spectrum ◽  
The Novel ◽  
Vaccine Adjuvants ◽  
Drug Candidates ◽  
Vulnerable Patients ◽  
Medical Need ◽  
Thrombotic Complications ◽  
Novel Coronavirus ◽  
First Time

By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.

scholarly journals Clonal Evolution of CD8+T Cell Responses against Latent Viruses: Relationship among Phenotype, Localization, and Function

2014 ◽  
Vol 89 (1) ◽  
pp. 568-580 ◽  
Author(s):  
Ester B. M. Remmerswaal ◽  
Paul L. Klarenbeek ◽  
Nuno L. Alves ◽  
Marieke E. Doorenspleet ◽  
Barbera D. C. van Schaik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hcmv Infection ◽  
Clonal Evolution ◽  
Acute Infection ◽  
Cell Receptor ◽  
Lymphoid Tissues ◽  
The Novel ◽  
Memory Cells ◽  
Cell Pool

ABSTRACTHuman cytomegalovirus (hCMV) infection is characterized by a vast expansion of resting effector-type virus-specific T cells in the circulation. In mice, interleukin-7 receptor α (IL-7Rα)-expressing cells contain the precursors for long-lived antigen-experienced CD8+T cells, but it is unclear if similar mechanisms operate to maintain these pools in humans. Here, we studied whether IL-7Rα-expressing cells obtained from peripheral blood (PB) or lymph nodes (LNs) sustain the circulating effector-type hCMV-specific pool. Using flow cytometry and functional assays, we found that the IL-7Rα+hCMV-specific T cell population comprises cells that have a memory phenotype and lack effector features. We used next-generation sequencing of the T cell receptor to compare the clonal repertoires of IL-7Rα+and IL-7Rα−subsets. We observed limited overlap of clones between these subsets during acute infection and after 1 year. When we compared the hCMV-specific repertoire between PB and paired LNs, we found many identical clones but also clones that were exclusively found in either compartment. New clones that were found in PB during antigenic recall were only rarely identical to the unique LN clones. Thus, although PB IL-7Rα-expressing and LN hCMV-specific CD8+T cells show typical traits of memory-type cells, these populations do not seem to contain the precursors for the novel hCMV-specific CD8+T cell pool during latency or upon antigen recall. IL-7Rα+PB and LN hCMV-specific memory cells form separate virus-specific compartments, and precursors for these novel PB hCMV-specific CD8+effector-type T cells are possibly located in other secondary lymphoid tissues or are being recruited from the naive CD8+T cell pool.IMPORTANCEInsight into the self-renewal properties of long-lived memory CD8+T cells and their location is crucial for the development of both passive and active vaccination strategies. Human CMV infection is characterized by a vast expansion of resting effector-type cells. It is, however, not known how this population is maintained. We here investigated two possible compartments for effector-type cell precursors: circulating acute-phase IL-7Rα-expressing hCMV-specific CD8+T cells and lymph node (LN)-residing hCMV-specific (central) memory cells. We show that new clones that appear after primary hCMV infection or during hCMV reactivation seldom originate from either compartment. Thus, although identical clones may be maintained by either memory population, the precursors of the novel clones are probably located in other (secondary) lymphoid tissues or are recruited from the naive CD8+T cell pool.

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