scholarly journals IL-7-Adjuvanted Vaginal Vaccine Elicits Strong Mucosal Immune Responses in Non-Human Primates

2021 ◽  
Vol 12 ◽  
Author(s):  
Sandrine Logerot ◽  
Suzanne Figueiredo-Morgado ◽  
Bénédicte Charmeteau-de-Muylder ◽  
Abdelkader Sandouk ◽  
Anne-Sophie Drillet-Dangeard ◽  
...  
Keyword(s):  
Immune Responses ◽  
Plasma Cells ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Female Genital Tract ◽  
Vaginal Mucosa ◽  
High Endothelial Venules ◽  
Mucosal Adjuvant ◽  
Vaginal Secretions ◽  
Mucosal Immune Responses

Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to poor T-cell responsiveness upon mucosal antigenic stimulation, mucosal immunity remains difficult to obtain through vaccines and requires appropriate adjuvants. We previously demonstrated that administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses. We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant. First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the lamina propria while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes. Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization. Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA+ plasma cells in the upper vaginal mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.

scholarly journals IL-7-adjuvanted vaginal vaccine elicits strong mucosal immune responses in non-human primates

2020 ◽  
Author(s):  
Sandrine Logerot ◽  
Suzanne Figueiredo-Morgado ◽  
Bénédicte Charmeteau-de-Muylder ◽  
Abdelkader Sandouk ◽  
Anne-Sophie Drillet-Dangeard ◽  
...  
Keyword(s):  
Immune Responses ◽  
Plasma Cells ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Female Genital Tract ◽  
Vaginal Mucosa ◽  
High Endothelial Venules ◽  
Mucosal Adjuvant ◽  
Vaginal Secretions ◽  
Mucosal Immune Responses

ABSTRACTMucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to difficulties in disrupting the tolerogenic environment associated with mucosa, mucosal immunity remains difficult to stimulate through vaccines and requires appropriate adjuvants. We previously demonstrated that either administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses.We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant.First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the chorion while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes.Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization.Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA plasma cells in the mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.

Effects of intestinal survival surgery on systemic and mucosal immune responses in SIV-infected rhesus macaques

2002 ◽  
Vol 31 (6) ◽  
pp. 313-322 ◽  
Author(s):  
Yvette Y. Edghill-Smith ◽  
Kristine Aldrich ◽  
Jun Zhao ◽  
Joel Pinczewski ◽  
V.S. Kalyanaraman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaques ◽  
Mucosal Immune Responses

scholarly journals Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice

2015 ◽  
Vol 9 (1) ◽  
pp. 83-97 ◽  
Author(s):  
A Lemke ◽  
M Kraft ◽  
K Roth ◽  
R Riedel ◽  
D Lammerding ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Pool ◽  
Bone Marrow Plasma ◽  
Mucosal Immune Responses

scholarly journals Effects of Age and Social Adversity on Immune Cell Populations in a Non-Human Primate Model of Human Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 532-533
Author(s):  
Mitchell Sanchez-Rosado ◽  
Noah Snyder-Mackler ◽  
James Higham ◽  
Lauren Brent ◽  
Nicole Marzan-Rivera ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Function ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Older Individuals ◽  
Primate Model ◽  
Hla Dr ◽  
Social Adversity ◽  
Classical Monocytes

Abstract Significant hallmarks of aging are immune function decline and rising cumulative inflammation. These immunosenescent signatures are also found in individuals who experience chronic social adversity, independently of age. However, no studies to date have examined how social adversity alters immune function across the lifespan –data that are essential to identify the molecular routes through which social adversity might lead to increased aging-related disease. Over a two-year period, we investigated how age and social adversity (quantified by low social status) affected immunity. We measured immune cell proportions at baseline and their gene regulation after in vitro stimulation with pathogen molecules that stimulated both Th1 and Th2 immune responses in a population of free-ranging rhesus macaques. We first performed flow cytometry on peripheral whole blood to quantify changes on immune cell proportions across the lifespan (n=235) and in animals of different social statuses (n=141). We found significant decreases in CD20+ B cells and CD3+/CD4+ T cell proportions with age, suggesting diminished antibody production and adaptive immune responses in older individuals. Age-associated increases in CD3+/CD8+, CD3+/CD4+/CD25+ T regulatory cells and CD14-/CD16+/HLA-DR+ non-classical monocytes indicated heightened baseline inflammation in older animals. Social adversity recapitulated the effects of aging in CD14+/CD16-/HLA-DR+ classical monocytes, indicating immune deficits in phagocytosis and pathogen clearance in older and lower status individuals. Using RNA-seq, our stimulations (n=1,320) will allow us to identify molecular immune pathways that are disrupted by age and social adversity, similarities in response between age and adversity, and how the effect of adversity varies across the lifespan.

scholarly journals Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Sudhir Pai Kasturi ◽  
Pamela A. Kozlowski ◽  
Helder I. Nakaya ◽  
Matheus C. Burger ◽  
Pedro Russo ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Specific Antibody ◽  
Protective Immunity ◽  
Low Dose ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Toll Like Receptor ◽  
Immunodeficiency Virus ◽  
Vaginal Secretions

ABSTRACT Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NP-adjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Env-specific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV). IMPORTANCE The results of the RV144 HIV vaccine trial, which demonstrated a rapid waning of protective immunity with time, have underscored the need to develop strategies to enhance the durability of protective immune responses. Our recent work in mice has highlighted the capacity of nanoparticle-encapsulated TLR ligands (NP) to induce potent and durable antibody responses that last a lifetime in mice. In the present study, we evaluated the ability of these NP adjuvants to promote robust and durable protective immune responses against SIV in nonhuman primates. Our results demonstrate that immunization of rhesus macaques with NP adjuvants mixed with soluble SIV Env or a virus-like particle form of Env (VLP) induces potent and durable Env-specific antibody responses in the serum and in vaginal secretions. These responses were superior to those induced by alum adjuvant, and they resulted in enhanced protection against a low-dose intravaginal challenge with a heterologous strain of SIV in animals with TRIM5a restrictive alleles. These results highlight the potential for such NP TLR L adjuvants in promoting robust and durable antibody responses against HIV in the next generation of HIV immunogens currently being developed.

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