scholarly journals Lipopolysaccharide Derived From the Lymphoid-Resident Commensal Bacteria Alcaligenes faecalis Functions as an Effective Nasal Adjuvant to Augment IgA Antibody and Th17 Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunru Wang ◽  
Koji Hosomi ◽  
Atsushi Shimoyama ◽  
Ken Yoshii ◽  
Takahiro Nagatake ◽  
...  
Keyword(s):  
T Cells ◽  
Alcaligenes Faecalis ◽  
Nasal Administration ◽  
Vaccine Adjuvant ◽  
Adjuvant Activity ◽  
Cervical Lymph Nodes ◽  
Nasal Vaccine ◽  
Benign Nature ◽  
Nasal Immunization ◽  
Follicular T Helper Cells

Alcaligenes spp., including A. faecalis, is a gram-negative facultative bacterium uniquely residing inside the Peyer’s patches. We previously showed that A. faecalis-derived lipopolysaccharides (Alcaligenes LPS) acts as a weak agonist of toll-like receptor 4 to activate dendritic cells and shows adjuvant activity by enhancing IgG and Th17 responses to systemic vaccination. Here, we examined the efficacy of Alcaligenes LPS as a nasal vaccine adjuvant. Nasal immunization with ovalbumin (OVA) plus Alcaligenes LPS induced follicular T helper cells and germinal center formation in the nasopharynx-associated lymphoid tissue (NALT) and cervical lymph nodes (CLNs), and consequently enhanced OVA-specific IgA and IgG responses in the respiratory tract and serum. In addition, nasal immunization with OVA plus Alcaligenes LPS induced OVA-specific T cells producing IL-17 and/or IL-10, whereas nasal immunization with OVA plus cholera toxin (CT) induced OVA-specific T cells producing IFN-γ and IL-17, which are recognized as pathogenic type of Th17 cells. In addition, CT, but not Alcaligenes LPS, promoted the production of TNF-α and IL-5 by T cells. Nasal immunization with OVA plus CT, but not Alcaligenes LPS, led to increased numbers of neutrophils and eosinophils in the nasal cavity. Together, these findings indicate that the benign nature of Alcaligenes LPS is an effective nasal vaccine adjuvant that induces antigen-specific mucosal and systemic immune responses without activation of inflammatory cascade after nasal administration.

scholarly journals Cytokines: The Future of Intranasal Vaccine Adjuvants

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Afton L. Thompson ◽  
Herman F. Staats
Keyword(s):  
Animal Models ◽  
Immune Responses ◽  
Clinical Studies ◽  
Vaccine Adjuvants ◽  
Adjuvant Activity ◽  
Subunit Vaccines ◽  
E Coli ◽  
Nasal Vaccine ◽  
Intranasal Vaccine ◽  
Nasal Immunization

Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin andE. coliheat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants.

scholarly journals Chemically Synthesized Alcaligenes Lipid A Shows a Potent and Safe Nasal Vaccine Adjuvant Activity for the Induction of Streptococcus pneumoniae-Specific IgA and Th17 Mediated Protective Immunity

2020 ◽  
Vol 8 (8) ◽  
pp. 1102
Author(s):  
Ken Yoshii ◽  
Koji Hosomi ◽  
Atsushi Shimoyama ◽  
Yunru Wang ◽  
Haruki Yamaura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mucosal Immunity ◽  
Lipid A ◽  
Biologically Active ◽  
Mucosal Vaccine ◽  
Vaccine Antigen ◽  
Vaccine Adjuvant ◽  
Vaccine Adjuvants ◽  
Cervical Lymph Nodes ◽  
Nasal Vaccine

Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer’s patch resident Alcaligenes stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized Alcaligenes lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against Streptococcus pneumoniae infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for S. pneumoniae, together with Alcaligenes lipid A. Alcaligenes lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, Alcaligenes lipid A promoted PspA-specific CD4+ Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against S. pneumoniae infection. Taken together, Alcaligenes lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.

scholarly journals EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii89-ii89
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting ◽  
Spleen And Lymph Nodes ◽  
Mouse Glioma

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

565 A novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A599-A599
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Standard Of Care ◽  
Control Group ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting

BackgroundRadiation (RT) and temozolomide (TMZ), which are standard of care for patients with glioblastoma (GBM), can cause prolonged severe lymphopenia. Lymphopenia, in turn, is an independent risk factor for shorter survival. Interleukin-7 (IL-7) is a cytokine that is required for T cell homeostasis and proliferation. IL-7 levels are inappropriately low in GBM patients with lymphopenia. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 rescues treatment-induced lymphopenia and improves survival.MethodsImmunocompetent C57BL/6 mice bearing two intracranial glioma models (GL261 and CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-I7 (10 mg/kg on the final day of RT completion). We profiled the CD3, CD8, CD4, FOXP3 cells in peripheral blood over time. We also immunoprofiled cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. Survival was monitored daily.ResultsMedian survival in mice treated with NT-I7 combined with RT was significantly longer than RT alone (GL261: 40d vs 34d, p<0.0021; CT2A: 90d vs 40d, p<0.0499) or NT-I7 alone (GL261: 40d vs 24d, p<0.008; CT2A: 90d vs 32d, p<0.0154). NT-I7 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261(40d vs 47d) and CT2A (90d vs 90d). Cytotoxic CD8+ T cells were increased in both peripheral blood (0.66 x 105 to 3.34 x 105; P≤0.0001) and tumor (0.53 x 103 to 1.83 x 103; P≤0.0001) in mice treated with NT-I7 when compared to control. Similarly, NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood (0.658 x 105 to 1.839 x 105 P≤0.0001) when compared to RT alone. There were decreases in tumor infiltrating FOXP3+ T-reg cells in mice treated with NT-I7 (1.9 x 104 to 0.75 x 104 P≤0.0001) and NT-I7 + RT (1.9 x 104 to 0.59 x 104 P≤0.0001) when compared to the control group without NT-I7. In addition, NT- I7 treatment increased CD8+ T cells in thymus, spleen, and lymph nodes.ConclusionsNT-I7 enhances cytotoxic CD8+ T lymphocytes systemically and in the tumor microenvironment, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

scholarly journals T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa

2006 ◽  
Vol 80 (4) ◽  
pp. 797-801 ◽  
Author(s):  
Jana Goldmann ◽  
Erik Kwidzinski ◽  
Christine Brandt ◽  
Jacqueline Mahlo ◽  
Daniel Richter ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Nasal Mucosa ◽  
Cervical Lymph Nodes

scholarly journals Nasal Immunization with Porphyromonas gingivalis Outer Membrane Protein Decreases P. gingivalis-Induced Atherosclerosis and Inflammation in Spontaneously Hyperlipidemic Mice

2008 ◽  
Vol 76 (7) ◽  
pp. 2958-2965 ◽  
Author(s):  
Y. Koizumi ◽  
T. Kurita-Ochiai ◽  
S. Oguchi ◽  
M. Yamamoto
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Atherosclerotic Plaque ◽  
Outer Membrane Protein ◽  
Serum Levels ◽  
Aortic Sinus ◽  
Cytokines And Chemokines ◽  
Nasal Vaccine ◽  
Nasal Immunization

ABSTRACT Porphyromonas gingivalis has been shown to accelerate atherosclerotic lesion development in hyperlipidemic animals. We assessed the potential of a nasal vaccine against P. gingivalis infection for the prevention of atherosclerosis. Apolipoprotein E-deficient spontaneously hyperlipidemic (Apoeshl) mice were nasally immunized with the 40-kDa outer membrane protein (OMP) of P. gingivalis plus cholera toxin (CT) as adjuvant and then challenged intravenously with P. gingivalis strain 381. The animals were euthanized 11 or 14 weeks later. Atheromatous lesions in the proximal aorta of each animal were analyzed histomorphometrically, and the serum concentrations of 40-kDa OMP-specific antibodies and cytokines were determined. The areas of the aortic sinus that were covered with atherosclerotic plaque and the serum levels of inflammatory cytokines and chemokines were increased in Apoeshl mice challenged with P. gingivalis compared to nonchallenged mice. In comparison, nasal immunization with 40-kDa OMP plus CT significantly reduced atherosclerotic plaque accumulation in the aortic sinus and lowered the serum levels of cytokines and chemokines compared to nonimmunized animals. Nasal immunization also induced 40-kDa OMP-specific serum immunoglobulin G (IgG) and saliva IgA antibody responses. These findings suggest that systemic infection with P. gingivalis accelerates atherosclerosis in Apoeshl mice, and 40-kDa OMP plus CT may be an effective nasal vaccine for the reduction of atherosclerosis accelerated by P. gingivalis in the hyperlipidemic mouse model.

scholarly journals Optimizing manufacturing and composition of a TLR4 nanosuspension: physicochemical stability and vaccine adjuvant activity

2013 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
HW Fung ◽  
Traci JT Mikasa ◽  
Julie Vergara ◽  
Sandra J Sivananthan ◽  
Jeffrey A Guderian ◽  
...  
Keyword(s):  
Vaccine Adjuvant ◽  
Adjuvant Activity ◽  
Physicochemical Stability

Ultrasound Elastography in the Diagnosis of Malignant Cervical Lymphadenopathy in Children: Can It Replace Surgical Biopsy?

2021 ◽  
Author(s):  
Ahmed Elgendy ◽  
Eslam Elhawary ◽  
Mohamed M. Shareef ◽  
Marwa Romeih ◽  
Ahmed Ebeed
Keyword(s):  
Prospective Study ◽  
Color Doppler ◽  
Cervical Lymphadenopathy ◽  
Ultrasound Elastography ◽  
Pathological Examination ◽  
Benign Lesions ◽  
Surgical Biopsy ◽  
Cervical Lymph Nodes ◽  
Benign Nature ◽  
A Prospective Study

Abstract Introduction We aimed to assess the accuracy of ultrasound elastography in detecting pediatric malignant cervical lymph nodes, and if this modality can obviate the need for surgical biopsies. Material and Methods A prospective study from September 2017 to September 2020 included 64 children with persistent cervical lymphadenopathy. Patients were evaluated by meticulous history and physical assessment. B-mode ultrasound, color Doppler, and sonoelastography were conducted thereafter. Elastography scans were classified into five patterns, and patterns from 3 to 5 were considered as malignancies. All children underwent open biopsies followed by pathological examination. Results of tissue diagnosis were compared with patterns of elastography to determine its accuracy. Results Twenty-eight patients (43.8%) had malignant nodes and the remaining 36 (56.2%) were due to benign causes. Elastography patterns of 1 and 2 were documented in 30 patients, and all of them were diagnosed as benign lesions. Patterns of 3 to 5 were demonstrated in 34 patients. Out of them, 28 were confirmed as malignancies, while 6 children were of benign nature (false positive). Ultrasound elastography achieved sensitivity and specificity of 100 and 85.7%, respectively, and an overall accuracy of 90.6% in the differentiation between malignant and benign entities. The overall accuracy of B-mode and color Doppler were 75 and 82.2%, respectively. Conclusion Elastography is a useful tool that should be added to ultrasound modalities during the diagnosis of pediatric cervical lymphadenopathy. Surgical biopsy in eligible patients is imperative to commence proper therapy or to discharge the child. Despite favorable results of elastography, it cannot replace surgical biopsy or change its indications.

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